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EGFR binds GRB2. 572 / 689
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"For instance, increased binding of GRB2 and SHC1 to EGFR was detected as early as 30 s, peaked at 2 min, and maintained with high intensity until 2 h (>60% of the maximal binding); in contrast, SOS1 and MAP4K3, which were also maximally detected at 2 min, were quickly dissociated as their amounts were decreased to <5% of the maxima by 30 min (Figure 4B)."
31442056
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"TDF facilitated the clearance of overexpressed A53T‐αSyn in SH‐SY5Y cells (Figure  xref and xref , Supporting Information) and promoted the interaction between GRB2 and TRKA without affecting the interaction between GRB2 and EGFR in these cells (Figure  xref )."
39159293
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"In addition, Gab1, recruited to the membrane via interactions with EGFR-bound Grb2, engages class I phosphoinositide 3 kinases (PI3Ks) to convert PtdIns(4,5)P 2 to PtdIns(3,4,5)P 3 ( xref ; xref )."
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"Growth factor receptor bound protein 2 (Grb2) binds to EGFR, followed by the binding of Grb2-associated binder protein 1 (Gab1), and it continues to recruit p85 subunit of PI3K in order to prolong or [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
33609510
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"Both phospho-Y1173 and phospho-Y1068 serve as Grb2 binding sites ( 27 ), and Grb2 bound to EGFR at the plasma membrane can further recruit SOS to activate Ras followed by MAPK cascade (Raf-MEK-ERK) ( [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
33096081
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"We incorporated mTmdZLys in place of lysine at position 109 in the SH2 domain of GRB2 ( xref ), and analysed the formation of the complex between this photo-cross-linkable GRB2 and the endogenous EGFR."
27833131
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"We also show that the truncated EGF receptor constitutively associates with the adapter proteins Shc and Grb2 which are involved in the recruitment of Ras to activated receptors."
8810340
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"Grb2 binds to the EGF receptor directly through Tyr1068 and indirectly through the Shc binding site at Tyr1173."
8193536
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"A recent report showed that GRB2 interacted directly with Ras homolog family member U (RhoU) and with activated EGFR, leading to augmented JNK1 pathway activity and cell migration XREF_BIBR."
23922722
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"Because EGFR critically regulates endometrial function and decidualization during early pregnancy xref , and GRB2 interacts with EGFR to activate Ras and its downstream kinases, ERK1/2 xref , we validated our transcriptomic results using RT-qPCR."
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"An earlier study has shown that Grb2 can interact with EGFR indirectly through Shc, enabling the SH2 domain of Grb2 to interact with other proteins."
19798056
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"GRB2 binds to EGFR for various biological processes by activating PI3K/AKT and ERK/MAPK pathways xref , xref ."
40038241
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"Notably, activated EGFR interacts with Shc and Grb2 not only at the plasma membrane but also in the endosomal compartment, where EGF induces augmented recruitment of Shc and Grb2."
19489726
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"Grb2 binding to EGFR was suppressed, but EGF induced Shc tyrosine phosphorylation and Grb2 association with Shc were not significantly decreased."
9178701
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"Since the activated sevenless is phosphorylated on tyrosine residues, we presume that the interaction between drk and sevenless is mediated by the SH2 domain of drk binding to tyrosine-phosphorylated [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
8462097
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"Subsequently, lipocortin-1 competitively inhibited Grb2 binding to EGFR, thereby blocking the recruitment of critical signaling molecules necessary for EGF actions [XREF_BIBR]."
30497693
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"A notable early example of FRET application to study endosomal signaling includes the visualization of the interaction between the EGF receptor (EGFR) and the signaling adaptor molecule Grb2 in membrane ruffles and on endosomes [ xref ]."
20538448
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"Alternatively, association of GRB2 to EGFR could be increased in the transgenic mice."
20032199
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"The association of GRB2 to the EGFR was not augmented in the transgenic mice as shown in xref ."
20032199
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"We provide proof of concept for the detection of protein proximity pairs (β-Catenin:E-Cadherin and EGFR:GRB2), and confirm assay specificity through technical controls involving reagent omission experiments, and biologically by treatment with small molecule kinase inhibitors that interrupt kinase:adaptor complexes."
32395983
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"Many of the model predictions exhibited a potential scale reduction factor of below 1.2 immediately after the " learning " period (e.g., ErbB1 expression, phosphorylated ErbB1, Grb2 bound to ErbB1, and phosphorylated Shc) while other predictions were unable to converge for the entire prediction window (e.g., phosphorylated PLC-gamma at times greater than 2 minutes)."
19900289
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"Results of co-immunoprecipitation experiments suggest that phosphotyrosines Y-1068 and Y-1173 mediate the binding of Grb2 to the EGFR."
7518560
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"Competition experiments with synthetic phosphopeptides corresponding to known autophosphorylation sites on the EGFR demonstrated that phosphopeptides containing Y-1068, and to a lesser extent Y-1086, were able to inhibit the binding of Grb2 to the EGFR, while a Y-1173 peptide did not."
7518560
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"From these studies, we concluded that Grb2 binds directly to the EGFR at Y-1068, to a lesser extent at Y-1086, and indirectly at Y-1173."
7518560
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"Moreover, blocking of the interaction between Grb2 and the phosphorylated EGF receptor with a phosphopeptide corresponding to the EGF receptor Grb2-binding site resulted in inhibition of EGF-induced p[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
7819271
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"Epidermal growth factor receptor pathway substrate 8 (EPS8)/related to the N-terminus of tre oncogene (RN-TRE) and growth-factor receptor bound protein 2 (GRB2)/Ras and Rab interactor 1 (RIN1) have been reported to coordinate the function of Rab5 GEFs and GTPase activating proteins (GAPs) for the maintenance of normal trafficking of cell membrane receptors."
31705388
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"The proposed mechanism involved in such desensitization implies GRB2 binding to the EGFR, inhibiting the interaction between STAT3 and EGFR by competitive binding to the same region of the receptor ( xref )."
20032199
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"These analyses reveal a hierarchy of interactions between Grb2 and Shc with the EGFR and indicate that Grb2 can bind the tyrosine-phosphorylated EGFR directly, as well as indirectly via Shc."
7518560
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"Grb2 binds activated EGFR at phosphotyrosines 1068/1086, and induces ERK1/2 signaling via Ras and Raf, rather than the MAP kinase pathway."
23633955
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"Both necdin and Grb2 bound preferentially to wild-type EGFR, suggesting that necdin binds to EGFR only in its active state.We then examined the interactions of necdin with EGFR deletion mutants that l[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
26655377
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"It appears that there are several redundant and possibly interdependent mechanisms, which involve : (a) EGFR binding to the clathrin endocytosis protein complex AP2, and to the phospho-tyrosine binding adaptor protein growth factor receptor bound protein 2 (Grb2); (b) ubiquitination of 15 lysines in the EGFR kinase domain by the E3 ubiquitin ligase Casitas B-lineage lymphoma (Cbl), and of 6 other lysines in the carboxy-terminus region; (c) acetylation of 3 of the latter lysines [XREF_BIBR]."
22617029
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"In necdin-null CPCs, the EGFR/ERK pathway is activated through increased interaction between EGFR and Grb2."
26655377
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"The binding of Grb2 to EGFR results in a conformation change exposing the Grb2–SH3 domains to recruit other signalling molecules including Son-of-Sevenless (SOS) [14,16] ."
22024281
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"Following activation of the EGFR kinase and autophosphorylation, the SH2 domain of Grb2 can bind to the EGFR."
12648464
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"Our adaptive signaling model is supported by recent work using phosphoproteomic approaches, which demonstrated that GRB2 was bound to EGFR in unperturbed ALK+ lung cancer cells and that EGFR phosphorylation increased in response to crizotinib treatment."
28428274
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"Recruitment of the Adaptor Protein Grb2 to EGFR Tetramers."
24697349
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"[49, 50, 51] Thus, we investigated whether SGCE loss changed the interaction between EGFR and the Cbl family or GRB2."
32714745
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"Here, we investigated how recruitment of Grb2 to EGFR is affected by the spatial organization and quaternary state of activated EGFR."
24697349
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"Sorkin and co-workers previously established that FRET can be used to detect interactions between EGFR and Grb2, but no estimates of cluster sizes were made in that study."
24697349
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"We did not observe enhanced interaction between EGFR and GRB2."
32714745
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"Recent studies also found that PLA signals corresponding to EGFR-related interactions such as those between EGFR and GRB2 or between nonphosphorylated and phosphorylated forms of EGFR were higher in NSCLC cell lines positive for EGFR mutations than in those WT for EGFR [ xref – xref ]."
29069773
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"The activated EGFR recruits and stimulates SHC, growth factor receptor-bound protein 2 (GRB2), and SOS adapter proteins, leading to the activation of Ras and MAPK cascades."
29117117
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"Following EGF stimulation, GRB2 directly binds to the cytoplasmic domain of the EGFR at phosphorylated residues Tyr1068 and Tyr1086 to initiate the activation of the Ras/MAPK pathway ( xref )."
20032199
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"Cells were prestimulated with 20 nM of either EGF or HRG and therefore AG-1478 was seen to inhibit both the EGF-induced ( xref ) and constitutive ( xref ) interaction of EGFR homomers with Grb2, in a time-dependent manner."
23700486
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"Grb2 bound EGFR clusters were dispersed at an average of 11 clusters and mum 2, whereas the Grb2-free EGFR population had a spatial organization characterized by an average cluster density of 17 clusters and mum 2."
24697349
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"We evaluated whether desensitization of EGF-induced STAT3 phosphorylation could be associated with GRB2 up-regulation and/or increased association of Grb2 to the EGFR in the transgenic mice overexpressing GH, but no significant differences in GRB2 protein content or GRB2 association to EGFR between normal and transgenic mice were found ( xref )."
20032199
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"Considering that on average 74% of EGFRs make up the Grb2 bound population and 36% the unbound population, the normalized density for 100% Grb2 bound EGFR clusters would be 16 clusters and mum 2 and 100% Grb2-free EGFR clusters would be 63 clusters and mum 2."
24697349
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"Accordingly, the estimated size of clusters containing Grb2 bound EGFR would be about 4.2 +/- 1 receptors and cluster and the estimated size of clusters free of Grb2 would be about 1.1 +/- 0.3 receptors and cluster."
24697349
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"The t 50 for 1.6 nmol/l EGF and 1 µmol/l gefitinibis sensitive to perturbations in k dp,s and k dp,i , k p,L , k A,f and k A,r , k g,f and k g,r , k i , and parameters for GRB2-EGFR binding ( k G 2 ,f and k G 2 ,r ) ( xref )."
25317724
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"This result suggests that in the context of a simple monomer and N-mer equilibrium the cluster size of the Grb2 bound EGFR is approximately 4."
24697349
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"Interestingly, the relatively rapid kinetics of EGFR-GRB2 binding, xref which may not prevail for all EGFR adaptors, produces EGFR-GRB2 complex sensitivity results that are indistinguishable from those for phosphorylated receptor ( Supplementary Figure S2a–d )."
25317724
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"The average value of 4 +/- 1 EGFR 's per EGFR and Grb2 complex from the FRET-FLIM-ICS experiments is in excellent agreement with the model prediction that the EGFR tetramer is the dominant Grb2 bound form, whereas the dominant Grb2-free form is the monomer, which also agrees well with the cluster size estimate of 1 +/- 0.3 EGFR 's from the cell averaged data."
24697349
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"42 Such a mechanism might also account for the observation that Grb2 bound EGFR is in a higher-order oligomeric complex relative to Grb2-unbound EGFR and for the positive correlation between Grb2-mRFP binding and EGFR-eGFP clustering."
24697349
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"Errfi1 inhibits Egfr signaling, while Grb2 binds to Egfr and induces Erk/Jun signaling."
38486710
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"GRB2 can bind the epidermal growth factor receptor (EGFR), and Daly et al. [XREF_BIBR] reported it to be associated with breast cancer."
26402252
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"Unlike the EGF receptor and other receptors that bind to Grb2 directly, FGF receptors do not bind directly to Grb2 upon FGF stimulation."
9182757
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"These results suggest that necdin suppresses the interaction between EGFR and Grb2 to downregulate the RAS/ERK signaling in CPCs.Because the EGFR/ERK pathway is involved in the control of cellular pro[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
26655377
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"Third, the distribution and proportion of Grb2 bound EGFR oligomers revealed by theoretical modeling indicated a predominance of the EGFR tetramer as the major Grb2 bound form."
24697349
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"56 To conclude, EGFR higher-order oligomers bind Grb2 and therefore should be considered, along with the classical EGFR dimer, in models of EGFR signaling."
24697349
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"Among these, the SHC adaptor protein was phosphorylated in absence of EGF, the other adaptor, GRB-2 was constitutively associated with the Glu627-EGF receptor in vivo and in vitro, and mitogen-activated protein kinase was constitutively phosphorylated."
7642641
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"Recently, Yang et al. work demonstrated that α-LA targets epidermal growth factor receptor and growth factor receptor-bound protein 2 (EGFR-Grb2) interaction and induce inhibition of EGFR-MAPK/ERK sig[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
31176736
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"Therefore, our data with AG-1478 clearly demonstrate that (i) EGFR homomers are constitutively interacting with Grb2 in HEK293FT cells, which may be due to some constitutive activity of the receptor, at least with regard to the Grb2 pathway in this cell line, (ii) EGF- as well as HRG-induced Grb2 recruitment strictly depends on receptor activation (constitutive or ligand-induced), and (iii) the recruitment of Grb2 to HER3 is observed only when HER3 is engaged in a heteromer complex with another receptor subtype such as EGFR."
23700486
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"However, the author suggests to explore the precise mechanism of α-LA-mediated disruption of EGFR-Grb2 interaction by including a large number and different types of EGFR-mutant cancers cell lines [ 1[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
31176736
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"After ligand binding, EGFR associates with growth factor receptor bound protein 2 (GRB2), followed by Rat sarcoma (RAS) activation."
38745775
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"After EGF binding, the GRB2 adaptor protein binds activated EGFR at phosphosite Tyr1068, and triggers mitogen-activated protein kinase (MAPK) pathway activation ( Rojas et al., 1996 )."
25625231
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"Complexes that contain SHC have been reported to be better at activating RAS than those without SHC (i.e., direct binding of GRB2 to EGFR) [XREF_BIBR]."
28513565
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"Interaction between activated EGFR and Grb2 at the endosomes upon EGF stimulation was proven by FRET microscopy [5]."
19887107
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"Strong evidence exists for the presence of EGFR–Grb2 complexes in endosomes (Di Guglielmo et al., 1994; Fortian and Sorkin, 2014; Oksvold et al., 2000)."
34515735
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"Together, the data in Fig. 7 demonstrate that endocytosis separates the bulk of EGFR–Grb2 complexes from KRAS and NRAS, which remain primarily at the plasma membrane."
34515735
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"This observation suggests there is a pool of EGFR–Grb2 complexes that are capable of maintaining RAS activity at the plasma membrane and thus of sustaining ERK1/2 activity beyond the 15-min EGF stimulation.To directly test whether a small pool of EGFR–Grb2 complexes at the plasma membrane is responsible for sustained ERK1/2 activation, surface EGFRs were blocked by cetuximab, a humanized mouse EGFR mAb that competes with EGF for binding to EGFR and inhibits its downstream signaling (Kawamoto et al., 1983; Mandic et al., 2006; Yoshida et al., 2008)."
34515735
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"Hence, in response to EGF- 274 receptor autophosphorylation, a pre- existing Grb2 and Sosl complex binds to the EGF receptor, recruiting Sos to the plasma membrane where the Ras pro- tein is located."
8236435
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"EGFR–Grb2 complexes are then rapidly internalized, resulting in their robust accumulation in endosomes observed after 3–5 min and sustained for at least 1 h."
34515735
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"Thus, EGFR–Grb2 complexes, some presumably associated with SOS, are transiently positioned in close proximity to RAS while passing through the plasma membrane during the initial 1–5 min after EGF stimulation, which correlates with the maximal activation of RAS in HeLa cells (Pinilla-Macua et al., 2016)."
34515735
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"Subsequent internalization of ∼85–90% of EGFR–Grb2 complexes into early and sorting endosomes results in rapid (within 10 min) segregation of these complexes from all RAS species, which remain mainly localized at the plasma membrane, and from NRAS and HRAS, which are also present in PRC, Golgi, and TERC."
34515735
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"The SH2 domain of Grb2 may bind to the auto phosphorylation site Y1068 of the EGF receptor, and the SH3 domains of Grb2 may bind to the carboxy-terminal domain of Sos."
8490966
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"In contrast to the activated EGF receptor, which binds the Grb2 and Sosl complex directly, activation of insulin receptors leads to recruitment of Grb2-Sosl to two tyrosine phosphoryl- ated proteins, [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
8236435
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"To conclude, it is important to consider that a “negative” function of endocytosis (i.e., separation of EGFR–Grb2 complexes from the major pool of RAS) may not be universally applicable to all cell types."
34515735
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"With this approach, we confirm the previously characterized interaction between Grb2 and the EGF receptor, and we identify novel partners of the IGF-1 receptor and of the JAK proteins."
9175787
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"With this approach, we confirm the previously characterized interaction between Grb2 and the EGF receptor, and we identify novel partners of the IGF-1 receptor and of the JAK proteins."
9175787
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"We therefore tested whether a phosphopeptide based on this sequence would be capable of influencing the interaction of EGF receptor and Grb2."
8490966
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"The importance of the kinase domain of HER3 (not removed by the truncation) for EGFR-dependent Grb2 interaction is in agreement with the recent structural study showing that although the HER3 kinase domain is not functional in terms of kinase activity, it can activate the EGFR kinase domain by formation of the asymmetric dimer xref ."
23700486
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"The inducibility of the Grb2Sos interaction by EGF implies that binding of EGF receptor to the SH2 domain of Grb2 transmits a conformational change to its SH3 domains, increasing their affinity for SO[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
8490966
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"Conversely, ShcC failed to bind EGFR or Grb2 and undergo phosphorylation ( xref ), confirming that it is not a physiological substrate of the EGFR, as previously shown ( xref )."
24430869
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"Protein:protein interactions (PPIs) underlie fundamental biological processes, such as transcriptional regulation (e.g., p53:MDM2 [ xref ]), signal transduction (e.g., GRB2-EGFR [ xref ]), and membrane fusion (e.g., SARS-CoV-2 RBD:ACE2 [ xref ])."
37450482
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"The biology behind the positive feedback loop in our example model is as follows [ xref ]: in response to growth factor stimulation, Gab1 is recruited to the plasma membrane through binding to the ErbB1-Grb2 complex."
23803171
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"As shown in Figure XREF_FIG, GSTP1 and GRB2 could be detected in the immunoprecipitation complex of phospho-EGFR antibody in 30 ng/mL EGF stimulated CNE2 cells, and could not be detected by the pretreatment of the cells with 1 mum EGFR inhibitor PD153035, which indicates that GSTP1 and GRB2 can interact with phospho-EGFR, are downstream targets of EGFR signaling pathway."
21711528
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"ShcD, however, was found to have a binding profile similar to that of ShcA and ShcB, in which EGF stimulates ShcD tyrosine phosphorylation and induces its interaction with EGFR and Grb2 ( xref )."
24430869
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"It is therefore likely that tyrosine 1068 is the major site of interaction of EGF receptor with Grb2, although it is clearly possible that other sites could also play a role."
8490966
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"8 The assay relies in the expression, in A549 EGFR biosensor cells (A549-EGFRB cells), of a SRC Homology 2 domain (SH2) of GRB2 that specifically binds to activated EGFR, fused to Green Fluorescent Protein (GFP)."
22573732
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"For example, activated EGFR binds to Shc and Grb2, which recruits Sos to the plasma membrane to activate Ras."
26771606
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"Errfi1 inhibits Egfr signaling, while Grb2 binds to Egfr and induces Erk/Jun signaling."
38486710
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"The biology behind the positive feedback loop in our example model is as follows [XREF_BIBR] : in response to growth factor stimulation, Gab1 is recruited to the plasma membrane through binding to the ErbB1 and Grb2 complex."
23803171
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"In this case, a multi-level logical description would be most appropriate : active Grb2 (i.e., Grb2 bound to ErbB1 homo- or heterodimers) activates Gab1 to level 1, whereas Grb2 AND PIP3 activate Gab1 to level 2."
23803171
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"Our adaptive signaling model is supported by recent work using phosphoproteomic approaches, which demonstrated that GRB2 was bound to EGFR in unperturbed ALK+ lung cancer cells and that EGFR phosphorylation increased in response to crizotinib treatment ( xref )."
28428274
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"The issue closes with a paper by Del Piccolo and Hristova, who employ a Förster resonance energy transfer-based method to analyze the interaction of epidermal growth factor receptor and the cytoplasmi[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
28930647
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"Here we use a simple modelling approach together with experiments to show that the establishment of the threshold requires both the multiplicity of binding sites and cooperative binding of Cbl and Grb2 to the EGFR."
26264748
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"It has been shown that EGF activated EGFR interacts with Grb2 at the plasma membrane and in endosomes XREF_BIBR, XREF_BIBR."
22900938
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"The adaptor protein Grb2 (growth factor receptor binding protein 2) binds to EGFR, which leads to activation of Ras-MAPK (mitogen activated protein kinase) cascade."
14498832
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"Besides, we performed the association between gene GRB2 and EGFR after adjusting tumor purity in the correction section in TIMER2.0 database."
33649481
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"Following activation of EGFR, the SH2 domain of Grb2 can bind to the EGFR either directly (via Y1068 and Y1086) or indirectly via tyrosine phosphorylated Shc (Sasaoka et al., xref )."
24381541
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"After EGF stimulation, the Grb2 SH2 domain binds to the EGF receptor directly or indirectly through proteins such as Shc, FAK, Syp, and IRS-1, by recognizing phosphotyrosine (pTyr)-containing sequences."
18830565
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"Indeed, a recent study found drug-induced association of GRB2 with EGFR in multiple cancers harboring fusions of ALK, RET, NTRK1 and ROS1, including in patient samples of primary tumors, resistant tumors, and metastases xref ."
39488530
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"The model represents ErbB1 synthesis and degradation; EGF ligand binding to ErbB1; receptor dimerization and activation; activation of the signaling pathways associated with the binary interactions between ErbB1 + Shc, Shc + Grb2, ErbB1 + Shc-Grb2, ErbB1 + Grb2, and Grb2 + Sos; deactivation of ErbB1 following PTP + ErbB1 interactions; and dissociation of active Shc from ErbB1."
20179207
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"A plausible explanation for cooperativity is that when Cbl and Grb2 are simultaneously bound to EGFR (via pY1045 and pY1068 and pY1086, respectively), they are in a state of enforced proximity, which increases the likelihood of the three species (EGFR, Cbl and Grb2) of binding to each other XREF_BIBR."
26264748
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"After auto-phosphorylation, EGFR binds GRB2 to activate SOS, a GTP-exchange factor that converts RAS-GDP into active RAS-GTP and subsequently actives MAPK1/3."
28428083
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"The relative lack of importance of the +2 position in determining EGFR efficiency allows specification of Grb2 binding independent of EGFR phosphorylation."
30012625
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"The primary protein-receptor interactions included Grb2 binding to ErbB1 (ErbB1-Grb2) and Shc binding directly to ErbB1 (ErbB1-Shc)."
20179207
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"For example, phosphorylation at Tyr 920 controls PI3K and Akt signaling through regulation of interactions of EGFR with p85, while phosphorylation at Tyr 1068 stimulates binding of EGFR with Grb2, which can trigger Ras and mitogen activated protein (MAPK) signaling XREF_BIBR."
24340049
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"In agreement with the autophosphorylation data, c-Cbl and Grb2 interact strongly with EGFR homodimers, and poorly with EGFR : HER2 heterodimers (XREF_FIG)."
23027125
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"Here, we showed that a synthetic phosphopeptide encompassing the autophosphorylation site 1068 of EGFR formed a complex with endogenous Grb2 after this peptide was delivered into intact cells by a cell-permeable peptide import technique."
8910327
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"The tyrosine phosphorylated tail of the EGF receptor binds Ras-GAP, PLCy, Grb2 and Shc ([8,111; AG Batzer, D Rotin, JM Ure, EY Skolnik, J Schlessinger, unpublished data)."
8193536
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"These results indicate that the binding of Grb2 to the phosphorylated Tyr-1068 of EGFR is crucial to the EGF-induced Ras/mitogen-activated protein kinase signaling pathway."
8910327
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"Hence, Grb2 binds directly, and indirectly via Shc, to the activated EGF receptor."
8193536
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"For example, the GRB2 adaptor protein binds activated EGFR at phosphorylated Tyr1068 XREF_BIBR, and phosphorylated Tyr1173 provides a docking site for the Shc scaffold protein, which is involved in mitogen activated protein kinase (MAPK) signaling activation XREF_BIBR."
25343452
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"Therefore, we hypothesize that a single EGFR molecule can be simultaneously associated with functionally distinct Grb2 interaction partners during and after endocytosis."
24259669
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"The binding of Cbl and Grb2 to EGFR depended on protein concentrations and binding affinities : protein concentrations were carefully measured, while binding affinities were indirectly determined by fitting ubiquitination dose response curves under various experimental conditions, within well defined experimental constrains taken from published studies (XREF_SUPPLEMENTARY)."
26264748
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"Once transphosphorylated, EGFR binds to growth factor receptor bound protein 2 (GRB2) and recruits SHC, which next activates son of sevenless 1 (SOS1), a guanine nucleotide exchange factor, to induce RAS to exchange guanosine triphosphate (GTP) to guanosine diphosphate (GDP)."
36403983
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"For method development, we focus on the interaction between the RTK epidermal growth factor receptor (EGFR) and the adaptor protein growth factor receptor-bound protein 2 (Grb2)."
28734476
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"For the EGFR-Grb2 interactions examined here, we assume that adaptor protein monomers bind to active RTK dimers ( 23,51,52,63 )."
28734476
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"The latter possibility is supported by the observation that Grb2, which binds directly to phosphorylated Y1068 and Y1086 in activated EGFR, interacts with c-Cbl proline-rich domains via its SH3 domain and recruits Cbl to EGFR."
19489726
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"Using NSCLC patient specimens and xenograft models, we have previously identified an association of EGFR:GRB2 complexes and response to EGFR inhibition [ xref ] and more recently identified a correlation between MET:GRB2 complexes and response to MET kinase inhibitors [ xref ]."
29522507
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"Next, we found two components of the Egfr pathway, whose function consists of the adaptor molecule Grb2 binding to Egfr with the subsequent activation of the pathway."
30096798
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"The stoichiometry of the EGFR-Grb2 complex is unknown, so we consider the formation of complexes with different numbers of adaptor protein monomers."
28734476
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"GST-SH2 TrM also blocked the binding of GRB2/EGFR, GRB2/PDGFR, GRB2/GAB1 and GRB2/SHC (Figure 5H)."
35832075
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"In response to EGF receptor activation and autophosphorylation, the Grb2 and Sos complex binds to the EGF receptor, recruiting Sos to the plasma membrane where Ras protein is located."
8193536
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"A marked reduction in the GRB2 and EGFR complex and absence of SOS-EGFR were observed in PC-9/ZD cells, even though the protein levels of GRB2 and SOS in PC-9 and PC-9/ZD cells were comparable."
15761868
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"Although EGFR palmitoylation by palmitoyltransferases 20 (DHHC20), an enzyme that mediates the transfer of palmitate to cysteine residues in the target substrate, consecutively downregulates the EGFR-[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
34242725
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"Earlier studies have verified that the interaction between EGFR and Grb2 is observable in this experimental design ( 32,53 )."
28734476
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"EGFR-GRB2 complex binds to SOS via its SH3 domain and leads to membrane localization of SOS [ xref – xref ]."
36284306
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"In Fig. 2 , we show the results for the binding of Grb2 to EGFR in the presence of ligand."
28734476
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"Applying a similar PLA approach to measure the interactions between EGFR and its adaptor protein GRB2 as a surrogate for EGFR activity, we found no relationship between EGFR activity and response to KRASG12Ci in the same samples."
39836411
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"In Fig. 3 , we present data collected for EGFR-Grb2 interactions in the absence of ligand."
28734476
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"The EGF receptor binds Grb2 directly, and its Grb2 binding sites are also required for recruitment of Gab1 (Okutani et al. 1994; Rodrigues et al. 2000); thus, the EGF receptor may recruit Gab1 via Grb2-Gab1 complexes."
10871282
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"The redundancy of GRB2/GRAP complex recruitment to multiple EGFR sites represents a means by which the cell can ensure a robust ERK response and indicates that this signaling axis is the most importan[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
31585087
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"Efficient energy transfer between CFP and YFP should only occur if CFP and YFP are less than 50A apart, which requires direct interaction of the EGFR and Grb2 fused to these fluorescent moieties [3]."
11084343
sparser
"Shc bound to pEGFR associates with growth factor receptor-bound protein 2 (Grb2), while Grb2 can directly associate with pEGFR [ xref , xref ]."
27902699
reach
"We first examined the adaptor protein, Growth factor receptor bound protein 2 (Grb-2), which contains an SH2 domain and two SH3 domains and can directly bind the EGFR XREF_BIBR."
24662916
sparser
"Phosphorylated EGFR can bind to the SH2 region of Grb2, thereby recruiting Grb2 to EGFR."
30524285
reach
"Recruitment of Grb-2 to the EGFR is important for plasma membrane recruitment and consequent tyrosine phosphorylation of the scaffolding protein, Grb2-associated-binding protein 1 (Gab-1) XREF_BIBR."
24662916
reach
"XREF_FIG b, the dose- and time dependent increases in Grb2 SH2 binding to EGFR were obvious both by far-Western (~ 180 KDa band on upper panel) and SH2-PLA (Ct value in lower panel)."
26112401
sparser
"The adaptor protein Grb2 (growth factor receptor-binding protein 2) binds to EGFR, which leads to activation of Stat3 pathways [ xref ] ."
23691485
sparser
"These mechanisms are represented by the binding of CBL via a singly phosphorylated EGFR, of by binding through GRB2 to a doubly phosphorylated EGFR."
35748700
reach
"To determine the necessity of the RhoU SH3 binding sites in coupling to the GRB2 and EGFR complex in vivo, we coimmunoprecipitated endogenous EGFR and GRB2 with Flag-RhoU."
21508312
reach
"Of interest, although dominant negative (DN) RhoU (T63N) interacted with EGFR and GRB2 complexes, deletion of the RhoU C-terminal extension abolished this interaction (XREF_FIG)."
21508312
sparser
"Since we use this model to study the interaction between EGFR and Grb2, we incorporate prior knowledge about both proteins into our theoretical model."
28734476
sparser
"Grb2 exists as both monomers and dimers in the cytoplasm, but only Grb2 monomers interact with EGFR."
28734476
reach
"For instance, increased binding of GRB2 and SHC1 to EGFR was detected as early as 30 s, peaked at 2 min, and maintained with high intensity until 2 h (> 60% of the maximal binding); in contrast, SOS1 and MAP4K3, which were also maximally detected at 2 min, were quickly dissociated as their amounts were decreased to < 5% of the maxima by 30 min (XREF_FIG)."
31442056
reach
"The phosphorylated tyrosine residues of EGF receptor act as an initiation signal to recruit the Shc- Growth factor receptor-bound protein 2 (Grb2)-Ras complex and phospholipase Cγ in the cytoplasm, resulting in Son of sevenless-mediated Ras activation and intracellular Ca -mediated protein kinase C activation [2]."
34703820
reach
"Of greater importance, we further show that RhoU is also capable of synergizing with activated EGFR in JNK and AP1 mediated transcriptional activity in a manner dependent on SH3 binding, as the DM RhoU, which is physically uncoupled from GRB2 and EGFR complex, is unable to synergize with activated EGFR in either JNK and AP1 activation or increased cell motility."
21508312
reach
"Specific signaling and endocytic proteins also are cocaptured after EGF stimulation included the ubiquitin ligase Cbl, endocytic proteins including Eps15/R and dynamin2, and the EGFR-binding scaffold protein Grb2."
39292879
sparser
"Since reduced p66 ShcA isoform is associated with increased survival [ xref ], we next assessed whether p66 ShcA could be involved in regulating As 2 O 3 -mediated increased interaction between EGFR with Grb2."
23178716
sparser
"Unlike the tyrosine phosphorylation and Grb2 interaction with the EGFR, repeated peroxide exposure (at R4 response point) did not significantly affect Pyk2 Tyr-881 phosphorylation (Figures xref and xref ) or the Grb2 content of the Pyk2 immunoprecipitates (Figures xref and xref )."
21258655
sparser
"In xref C, a schematic illustration as well as representative total internal reflection fluorescence (TIRF) microscopy images of the selected bait-prey interaction between the epidermal growth factor receptor (EGFR) and the downstream molecule Grb2 are shown."
32252486
reach
"GRB2 directly binds EGFR and activates ERK1/2 and AKT in a Ras-dependent manner ."
40038241
sparser
"Additionally, our thermodynamic model makes several assumptions about the EGFR-Grb2 interaction."
28734476
sparser
"It is therefore likely that the interaction of Grb2 with the EGF receptor serves to relocalize a con- stitutively active Sosl from the cytosol to the plasma membrane, increasing the local concent[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
8236435
sparser
"In contrast to the activated EGF receptor, which binds the Grb2-Sosl complex directly, activation of insulin receptors leads to recruitment of Grb2-Sosl to two tyrosine-phosphoryl- ated proteins,[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
8236435
sparser
"Hence, in response to EGF- 274 receptor autophosphorylation, a pre- existing Grb2-Sosl complex binds to the EGF receptor, recruiting Sos to the plasma membrane where the Ras pro- tein is locat[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
8236435
reach
"Epidermal growth factor receptor (EGFR) tyrosine phosphorylation and recruitment of its adaptor proteins, Shc and Grb2, to EGFR were detected by immunoprecipitation and Western blot analysis."
14674888
sparser
"The highest photo-cross-linking yield for Grb2-D104mPyTK was observed when cells were stimulated with EGF for 15 min (Figure S11B in), indicating that the Grb2–EGFR interaction is transient and dynamic, resembling some other known EGF-dependent protein–protein interactions. xref "
28422494
sparser
"This means that just over two-thirds of the unliganded EGFR dimers that are not bound to Grb2 exist in the active configuration."
28734476
sparser
"First, we assume that only one model of EGFR:Grb2 stoichiometry applies over the broad EGFR and Grb2 concentration ranges covered in these experiments."
28734476
reach
"Activated EGFR or HER family members bind to Grb2 and Sos, resulting in the activation of the Ras and Raf pathway and phosphorylation of mitogen activated protein kinases (MAPK) [XREF_BIBR - XREF_BIBR]."
18996136
sparser
"Thus upon autophosphorylation of the EGFR cytoplasmic domain the SH2 domain adapter protein Grb2 binds to phosphotyrosine residues, particularly Y-1068 in the tail region ( xref )."
23163768
sparser
"Tyrosine 1068 (Y1068) phosphorylation of EGFR is crucial for the activation of downstream signaling pathways through the interactions of EGFR with growth factor receptor-bound protein 2 (Grb2) or Grb2-associated binder 1 xref and serves as a predictive biomarker for assessing clinical responses to EGFR-TKIs xref ."
38689087
sparser
"This reduced EGFR kinase dependence of the peroxide-induced R4 response was correlated to a significant reduction in the degree of peroxide-induced EGFR tyrosine phosphorylation ( xref ), attenuated peroxide-induced association of EGFR with Grb2 (Figures xref and xref ), and a strong redistribution of EGFR away from the plasma membrane to the cytosol (Figures xref and xref )."
21258655
sparser
"The functional consequence of Grb2 binding to the activated EGF receptor appears to be linked to the EGF- dependent accumulation of active (GTP-bound) Ras."
8193540
sparser
"The Grb2 Y160 residue plays a structurally critical role in the Grb2-Grb2 interaction, and phosphorylation or mutation of Y160 prevents EGFR:Grb2 condensation."
35507881
sparser
"These results identify an EGFR:Grb2 protein condensation phase transition as a regulator of signal propagation from EGFR to the MAPK pathway."
35507881
sparser
"12 and 13 , and assuming free fluorophore rotation, the separation of the fluorescent proteins in the EGFR-Grb2 complex can be estimated as 44.6 ± 1.7 Å. Furthermore, we examine the EGFR-Grb2 binding [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
28734476
sparser
"Under slightly different conditions, however, we report observations of an EGFR:Grb2 condensation-phase transition without any SOS or other crosslinking molecule."
35507881
sparser
"Reconstitution of a Membrane-Surface EGFR:Grb2 Protein Condensate."
35507881
sparser
"We reconstituted an EGFR:Grb2 protein condensation-phase transition on supported membranes using the C-terminal region of EGFR (residues 991 to 1186, where the signal peptide of EGFR is not included in numbering), which is expressed along with a His6 tag and a SUMO tag at the N-terminal end of the construct."
35507881
sparser
"The largest module consists of 32 ODEs and describes Grb2 binding to the EGF receptor as well as to phosphorylated Shc."
18755034
sparser
"Formation of the EGFR TAIL :Grb2 protein condensates requires a multivalent crosslinking interaction."
35507881
sparser
"These results indicate that comprehensive controls are necessary for the accurate quantitative analysis of the specific EGFR-Grb2 interaction."
32252486
sparser
"We developed a PLA to measure the interaction between EGFR and GRB2."
25587191
sparser
"Moreover, cell lines with increased EGFR:GRB2 PLA signal had increased abundance of Tyr 1068 phosphorylated EGFR ( xref ) and a robust interaction between EGFR and GRB2 as determined by coimmunoprecipitation ( xref )."
25587191
sparser
"These studies indicate that the functional consequence of association of the activated EGF receptor with Grb2 is accumulation of active Ras."
8193540
sparser
"Mutation of palmitoylated cysteine residues increases EGFR interaction with Grb2."
27153536
sparser
"c-Cbl is recruited to activated EGFR either by directly binding to their TKB domain at the phosphotyrosine residue 1045 in EGFR [15] or by an indirect mechanism mediated by Grb2 – the SH3 domains of G[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
18400375
sparser
"Phosphorylation of EGFR Y1068 leads to GRB2 binding to EGFR which can increase downstream signalling of MEK/MAPK pathway."
29156708
sparser
"Applying a similar PLA approach to measure the interactions between EGFR and its adaptor protein GRB2 as a surrogate for EGFR activity, we found no relationship between EGFR activity and response to KRASG12Ci in the same samples."
39836411
reach
"Furthermore, Western blotting of Grb2 immunoprecipitates with anti-EGFR showed that Grb2 was bound to the EGFR in response to EGF."
11370743
reach
"Furthermore, C. psittaci-specific Pmp17G activated Chlamydial invasion in a dependent way by recognizing EGFR, activating Tyr1068 phosphorylation of EGFR, and forming the EGFR–Grb2 complex, contributing to intracellular attachment and internalization during C. psittaci infection (18)."
35529835
reach
"To demonstrate the utility of rsTagRFP as a switchable pcFRET acceptor, we next studied the interaction between EGFR and Grb2 that is induced upon stimulation with epidermal growth factor (EGF) in mammalian cells."
20659687
reach
"It has been shown that EGF activated EGFR interacts with Grb2 at plasma membrane and in endosomes."
20659687
reach
"Whereas Grb2 bound to Shc and EGFR in response to EGF, both Shc and Cbl were constitutively associated with the receptor."
11370743
reach
"Grb2 binds to the activated EGFR and acts as an adaptor to recruit the E3 ubiquitin ligase Casitas B lineage lymphoma protein to start internalization."
20659687
sparser
"To study the mechanism of receptor activation in greater detail we examined activation mediated Grb2 binding to the EGFR mutants."
27153536
reach
"Recruitment of the EGFR together with Grb2 to clathrin coated pits (CCPs) was found to be a key feature in our assay."
24658383
reach
"Next, we studied the interaction between endogenous EGFR and fluorescent Grb2."
24658383
reach
"This basic interaction between Grb2 and EGFR appeared without any additional EGFR activation and may be caused by the stimulating nature of the antibody coated surface and/or the presence of growth factor containing serum."
24658383
reach
"However, the interaction of EGFR and Grb2 can be clearly stimulated; the addition of EGF resulted in a prominent increase of the Grb2-YFP fluorescence within EGFR enriched mu-patterns."
24658383
reach
"We were able to confirm the enrichment of the EGFR and Grb2 complex in CCPs."
24658383
sparser
"The calculated rate constants showed that EGF facilitated the associations of GRB2 with EGFR."
29505756
sparser
"EGF‐induced ERK phosphorylation is enhanced in Ndn‐null APs, in which the interaction between EGFR and the adaptor protein Grb2 is strengthened (Figure  xref ), suggesting that necdin suppresses the EGFR/ERK signaling pathway in APs."
34338396
sparser
"GRB2 primarily associated with immobile EGFR dimers and trimers ( Fig. 4 F)."
29505756
reach
"For example, after binding to EGFR, Grb2 recruits SoS1 (a Ras guanine nucleotide exchange factor) cell membrane localization, thereby activating the Ras/Raf/ERK signaling cascade XREF_BIBR, XREF_BIBR."
29463844
reach
"These results suggest that the cytoplasmic domain of EGFR binds GRB2 in multiple conformations and that the conformation bias depends on the size of the EGFR cluster."
29243093
reach
"This landmark study provided support that signaling can occur from regions other than the plasma membrane, and is supported by later fluorescence resonance energy transfer (FRET) studies that detected[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
22397948
sparser
"These interactions between EGFR and Grb2 were detected based on the colocalization of fluorescent spots."
29505756
sparser
"Due to the optical diffraction limit of microscopy, the observed overlapping of fluorescent spots did not necessarily indicate direct interaction between EGFR and GRB2."
29505756
reach
"Fig. 8 A shows that Grb2-MEKK1 complex associated with EGFR after UVC irradiation."
17029735
reach
"Both phospho-Y1173 and phospho-Y1068 serve as Grb2 binding sites ( 27 ), and Grb2 bound to EGFR at the plasma membrane can further recruit SOS to activate Ras followed by MAPK cascade (Raf-MEK-ERK) ( [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
33096081
sparser
"Phosphorylated Y1068 on EGFR binds to the adapter molecule Grb2."
19143022
sparser
"After autophosphorylation, EGFR bound directly or indirectly to Grb-2 to activate Ras, then activated the downstream silk/threonine protein kinase Raf, thereby phosphorylating ERK1/2."
33537004
sparser
"SH3BGRL3 has proline-rich motifs, which could interact with phosphorylated-EGFR through growth factor receptor-bound protein 2 in Akt-related signaling pathways to promote EMT in tumor cells ( xref )."
39492939
reach
"Subsequently, Grb2 bound to the phosphotyrosine sites on the EGFR , recruiting both SOS and SOS , and a lateral protein condensation phase transition proceeded to various degrees depending on the specific protein concentrations in each experiment."
35507881
sparser
"We did not observe enhanced interaction between EGFR and GRB2 (Figure S6H, Supporting Information)."
32714745
sparser
"Observations of a two-component EGFR:Grb2 condensate that we report here, with a Grb2-Grb2 interaction serving as the primary crosslinker, relieve SOS of its requisite crosslinking role."
35507881
sparser
"GRB2 is required for survival of cells with mutant EGFR [ xref ] and the interaction between EGFR and GRB2 is abrogated by erlotinib, resulting in loss of downstream ERK signaling [ xref , xref ]."
25587191
reach
"Treatment with Rg3 promoted the interaction between GRB2 and TRKA (Figure  3a,b) with no discernible impact on the interaction between GRB2 and EGFR (Figure 3a,c) in SH‐SY5Y cells."
39159293
sparser
"However, mutation of C1025 has the strongest increas in the binding of EGFR with the adapter protein Grb2."
27153536
sparser
"Both CME and several NCE pathways are involved in EGFR internalization. [ xref ] The ubiquitination of EGFR is necessary for all internalization pathways, and the ubiquitin ligase responsible for EGFR ubiquitination is Cbl, a ring‐finger domain E3 ubiquitin ligase. [ xref ] Cbl can directly bind to EGFR, or indirectly bind to EGFR via the adaptor protein Grb2. [ xref , xref ] The EGFR‐Grb2‐Cbl complex is necessary for NCE, with previous studies showing that EGFR mutants lacking Grb2 binding sites are completely defective for NCE. [ xref , xref ] Our results indicated that SGCE knockdown caused induction of EGFR internalization, and increased the interaction between EGFR and c‐Cbl but not that between EGFR and Grb2."
32714745
reach
"TDF facilitated the clearance of overexpressed A53T‐αSyn in SH‐SY5Y cells (Figure S13e and f, Supporting Information) and promoted the interaction between GRB2 and TRKA without affecting the interaction between GRB2 and EGFR in these cells (Figure 8b–d)."
39159293
sparser
"Work done by Gay et al. using CGP78850 (compound 41 , Fig.  xref ), a selective Grb2 SH2 domain-binding inhibitor having a mixed phosphoramidite/phenyl ester – protected phosphonic acid group, showed that this compound could block the association of Grb2 with activated epidermal growth factor receptor (EGFR) in living cells and inhibit the growth of cells driven by PTK signaling through Ras (Gay et al., xref )."
19444322
sparser
"We also measured the interaction between EGFR and an adaptor protein, GRB2, which bridges the phosphorylated C-terminal region of the receptor and other cytoplasmic proteins."
29505756
reach
"Our results support the concept that EGFR interacts with Grb2 in both constitutive and EGF dependent manners and this interaction is independent of HER3 co-expression."
23700486
reach
"Phosphorylated EGFR is bound by growth factor receptor-bound protein 2 (GRB2), which in turn recruits the son of sevenless (SOS1) to the plasma membrane."
38271825
sparser
"This landmark study provided support that signaling can occur from regions other than the plasma membrane, and is supported by later fluorescence resonance energy transfer (FRET) studies that detected[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
22397948
sparser
"The duration of the interaction between EGFR and GRB2 was defined as the time from their association to their subsequent dissociation."
29505756
sparser
"c-CBL is also recruited to EGFR through an adaptor protein, GRB2 which binds to phosphorylated tyrosine sites on EGFR (mainly Y1068 and Y1086) promoting ubiquitination and degradation of this receptor[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
28923280
sparser
"An intermediary molecule, growth factor receptor-bound protein 2 (GRB2), binds phosphorylated EGFR by employing its own SH2 domains."
40075634
reach
"The reaction of association between active EGFR and Grb2 is represented using an open headed ' transport ' arrow and a circle headed ' catalysis ' arrow as a local rule adopted in this map ver."
16729045
sparser
"We also demonstrated the ability of the peptides to block the binding of the GRB2 SH2 domain to EGFR in a mammalian cell-based binding assay."
10400318
reach
"The functional consequence of Grb2 binding to the activated EGF receptor appears to be linked to the EGF- dependent accumulation of active (GTP bound) Ras."
8193540
sparser
"After treatment with EGF, cell-free extracts were produced and the ability of phage-derived peptides to inhibit the interaction between the EGFR and the GRB2 protein was examined by means of an immuno[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
10400318
reach
"GRB2 is required for survival of cells with mutant EGFR [XREF_BIBR] and the interaction between EGFR and GRB2 is abrogated by erlotinib, resulting in loss of downstream ERK signaling [XREF_BIBR, XREF_BIBR]."
25587191
sparser
"After autophosphorylation, EGFR binds directly or indirectly to the GRB2 complex to activate the Ras protein."
34539858
reach
"For example, it has been reported that Grb2 and Shc bind to activated EGFR via their phosphotyrosine residues and function as adaptors of downstream signaling."
16729045
reach
"We developed a PLA to measure the interaction between EGFR and GRB2."
25587191
reach
"Moreover, cell lines with increased EGFR : GRB2 PLA signal had increased abundance of Tyr 1068 phosphorylated EGFR (XREF_FIG) and a robust interaction between EGFR and GRB2 as determined by coimmunoprecipitation (XREF_FIG)."
25587191
reach
"Although GRB2 binds to the EGF receptor and the PDGF #-receptor, it does not become tyrosine phosphorylated in response to 48 L. Claesson-Welsh ligand stimulation."
8199353
reach
"The Grb2 and Sos complex binds to the EGF receptor, thus recruiting SOSto the plasma membrane where Ras is located."
15335710
sparser
"Although association of Grb2 with EGFR increased at a concentration of 100-μmol/L UTP compared with that with 25-μmol/L UTP ( Figure 1 ), it remained lower than when cells were stimulated with either [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
21356361
reach
"We studied the effect of increasing doses of AG-1478 on the recruitment of Grb2 to EGFR and HER3 homo- and heteromers."
23700486
sparser
"In all of the cell types tested, Grb2 was associated with EGFR when cells were treated with EGF but was only present at lower levels in response to injury or 25-μmol/L UTP."
21356361
reach
"The adaptor protein Grb2 (growth factor receptor binding protein 2) binds to EGFR, which leads to activation of Stat3 pathways [XREF_BIBR]."
23691485
reach
"Another predicted regulator of Acad8 was miR-433-3p, which regulates genes involved in development, like the transcription factor CREB [35] and the Egfr binding adaptor protein GRB2 [36]."
37167320
reach
"In contrast, GRB2 binding to pEGFR and pH2AX peptides was comparable to that of GRB2 (Fig. 3G)."
34348893
reach
"Our immunoprecipitation results indicate that there are enhanced interactions between EGFR and Ras and EGFR and Grb2 after both 3- (XREF_FIG) and 14-days (XREF_FIG)."
26928584
sparser
"Epidermal growth factor receptor (EGFR) BRET structure-function studies identify the tyrosine residues 1068, 1114, and 1148 as the main residues mediating the interaction of EGFR with the adapter protein Grb2."
17715395
sparser
"The technique has also been used to investigate the binding of EGFR to the adaptor protein Grb2 [ xref ]."
31164594
sparser
"On and off rates for the EGFR–Grb2 interaction were measured, with three states being observed."
31164594
sparser
"The hypothesis proposed was that Grb2 repeatedly interacts with EGFR for short times, accelerating substrate transitions in a way that increases the time constant of association."
31164594
sparser
"The N-terminus of LRRK1 interacts with Grb2, an adaptor protein for EGFR, and LRRK1 forms a complex with EGFR via Grb2 in response to EGF stimulation."
22337768
sparser
"The generation and sorting of extracellular vesicles of different sizes by endosomal-sorting-complex-required-for-transport proteins and the AAA + ATPase VPS4 in HEK293 cells is the topic of an exciti[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
28930647
sparser
"It was recently shown that selective measurement of Grb2-EGFR interaction could prognostically predict therapeutic response, moreso than abundance or phosphorylation of EGFR ( xref )."
27450453
reach
"The interaction between GRB2 and EGFR were experimentally verified ; both were characterized in the KEGG “Non-small cell lung cancer pathway” (pathway #5223)."
32170141
sparser
"It has been shown that EGF-activated EGFR interacts with Grb2 at the plasma membrane and in endosomes xref , xref ."
22900938
sparser
"The EGF receptor binds Grb2 directly, and its Grb2-binding sites are also required for recruitment of Gab1 ( xref ; xref ); thus, the EGF receptor may recruit Gab1 via Grb2-Gab1 complexes."
10871282
reach
"However, mutation of C1025 has the strongest increas in the binding of EGFR with the adapter protein Grb2."
27153536
sparser
"Grb2 interacts directly with epidermal growth factor receptor (EGFR) and regulates the signal transductions of Ras/MEK/MAPK (especially the extracellular signal-regulated kinase, ERK) ( xref , xref )."
36344721
reach
"Third, the EGFR exon 25-26 deletion mutation identified in lung cancer increased colony formation in soft agar and the interaction between EGFR and Grb2 similar to what was observed with the C1025A mutant."
27153536
reach
"EGF‐induced ERK phosphorylation is enhanced in Ndn‐null APs, in which the interaction between EGFR and the adaptor protein Grb2 is strengthened (Figure 21b), suggesting that necdin suppresses the EGFR/ERK signaling pathway in APs."
34338396
reach
"Pre-clinical studies showed cetuximab decreased cell proliferation and phosphorylation of EGFR, and blocked the binding of the adaptor protein Grb2 to EGFR upon activation by EGF [XREF_BIBR]."
21777178
sparser
"Notably, unlike EGFR and RIP1, rasfonin began to increase the level of Grb2 at a dose of 1 μM (Fig. xref ), whereas its treatment provided a more than 3 fold increase in Grb2 than either EGFR (3.86 fold: Grb2/actin minus EGFR/actin) or RIP1 (3.18 fold: Grb2/actin minus RIP1/actin) at the same concentration (12 μM), suggesting that, in addition to RIP1, both EGFR and Grb2 may be associated with the inhibition of rasfonin on autophagy and may play a regulatory role in rasfonin-dependent necroptosis."
35831301
sparser
"Given the RIP1 interacts with Grb2 and EGFR, we next examined whether Grb2 was able to regulate the expression of RIP1 in the cells with or without rasfonin treatment."
35831301
sparser
"On the other hand, binding of Grb2 SH2 domain to EGFR results in RAS activation triggering Raf/MEK/Erk signaling which are mainly involved in cell proliferation ( Fig. 1 ) [39,40] ."
20519133
sparser
"Alternatively, blocking palmitoylation increased the association of EGFR with the MAPK adaptor Grb2 and decreased that with p85."
32127496
sparser
"To analyze the spatiotemporal regulation of EGFR-Grb2 interactions in living cells, we have combined imaging microscopy with a modified method of measuring fluorescence resonance energy transfer (FRET) on a pixel-by-pixel basis using EGFR fused to cyan fluorescent protein (CFP) and Grb2 fused to yellow fluorescent protein (YFP)."
11084343
reach
"SHP2 is also relevant to the crosstalk between TGFbeta and EGF signaling during EMT, as EGF activates SHP2 activity by recruitment of the adaptor protein GAB1 to the EGF receptor and Grb2 complex [XREF_BIBR]."
27367735
sparser
"Efficient energy transfer between CFP and YFP should only occur if CFP and YFP are less than 50A apart, which requires direct interaction of the EGFR and Grb2 fused to these fluorescent moieties [3]."
11084343
reach
"An EGFR derived phosphopeptide bound Grb2 with a KD of 0.7 microM, whereas the Shc derived phosphopeptide bound Grb2 with a KD of 0.2 microM."
8940013
sparser
"Therefore, we assumed that the interaction between EGFR and Grb2 could convey necrotic signaling to RIP1 to induce necroptosis upon rasfonin stimulation."
35831301
sparser
"For example, phosphorylation at Tyr-920 controls PI3K/Akt signaling through regulation of interactions of EGFR with p85, while phosphorylation at Tyr-1068 stimulates binding of EGFR with Grb2, which can trigger Ras/mitogen-activated protein (MAPK) signaling xref ."
24340049
reach
"With the opposite BRET orientation, HER3 truncation means that Grb2 and Venus can only bind to EGFR in the HER3trunc, Rluc8, and EGFR complex, which results in less donor-acceptor proximity than binding to HER3 and Rluc8."
23700486
reach
"Again, a higher order complex could enable recruitment of Grb2 and Venus to a second untagged EGFR protomer rather than HER3 and Rluc8, which would be expected to result in a lower BRET signal as is indeed observed in XREF_FIG compared to 6b."
23700486
reach
"The importance of the kinase domain of HER3 (not removed by the truncation) for EGFR dependent Grb2 interaction is in agreement with the recent structural study showing that although the HER3 kinase domain is not functional in terms of kinase activity, it can activate the EGFR kinase domain by formation of the asymmetric dimer XREF_BIBR."
23700486
sparser
"Following EGFR activation, the MAPK signaling pathway is triggered by the growth factor receptor-bound protein 2 (Grb2) binding directly to EGFR via Y1068 and Y1086 or indirectly by SHC binding Y1173 and Y1143 ( xref )."
28693199
reach
"Preclinical studies revealed cetuximab could decrease cell proliferation and phosphorylation of EGFR, and blocked the binding of the adaptor protein Grb2 to EGFR upon activation by EGF [XREF_BIBR]."
20046965
sparser
"Thus, GRB2 associates only with the activated tyrosine-phosphorylated EGFR."
1322798
sparser
"Grb2, which is constitutively associated via its SH3 domain with Grb2-associated binder 1 (Gab1), binds to the EGFR."
15194442
sparser
"As expected we found that EGF stimulated an association of EGF-R with Grb2, PRL, however, blocked this association."
8702944
sparser
"In cells expressing the EGF receptor, growth hormone was able to promote GRB-2 association with the EGF receptor, MAP kinase activation, and c- fos induction."
10459005
sparser
"This case study identifies one such mutation: a novel EGFR-GRB2 RNA fusion detected using whole transcriptome sequencing (WTS) that demonstrated a remarkable response to osimertinib, a third-generation EGFR TKI, in a patient with diffusely metastatic pulmonary adenocarcinoma with multiple cerebral metastases."
37234142
sparser
"This patient had a novel EGFR-GRB2 RNA fusion that may have played a role in the responsiveness of her late-stage cancer to osimertinib therapy."
37234142
sparser
"Interestingly, a novel EGFR-GRB2 fusion was detected in this tumor by whole transcriptome sequencing (Figure  xref )."
37234142
sparser
"The EGFR-GRB2 fusion is significant due to its ability to activate downstream pathways without the binding of a ligand to the EGFR."
37234142
reach
"EGFR is able to activate PI3K through a series of reactions : active EGFR binds adaptor protein Grb2, which recruits the docking protein Gab1, which contains pYXXM motifs to which SH2 domains on the regulatory subunit of PI3K (p85) bind, thereby bringing the catalytic subunit of PI3K (p110) in proximity to its membrane bound lipid substrates [XREF_BIBR]."
18641990
sparser
"This was the rationale for treatment with osimertinib for this patient with an atypical EGFR-GRB2 fusion."
37234142
reach
"Interestingly, direct Cbl binding to pTyr1045 appears to play a minor, if any, role in the CME of EGFR, whereas Grb2 mediated interaction with EGFR is critical [XREF_BIBR]."
18793634
sparser
"To our knowledge, this is the first-ever case report of a patient with an EGFR-GRB2 RNA fusion abnormality treated with osimertinib."
37234142
reach
"The EGFR interacts with adaptor proteins Grb2 and SOS, activating Ras and Raf, followed by phosphorylation of Mitogen activated protein kinase and ERK and extracellular signal regulated kinase (ERK)."
28560291
sparser
"Grb2 binding to EGFR was suppressed, but EGF-induced Shc tyrosine phosphorylation and Grb2 association with Shc were not significantly decreased."
9178701
sparser
"We report on a unique EGFR-GRB2 fusion in a 48-year-old female never-smoker."
37234142
sparser
"In response to epidermal growth factor (EGF) stimulation, the N terminal proline-rich domains of PI3K-C2β mediates the interaction of the enzyme with both epidermal growth factor receptor (EGFR) and G[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
30691999
sparser
"On whole transcriptome sequencing, this patient was found to have a novel EGFR-GRB2 RNA fusion transcript similar to other EGFR fusions described in the literature."
37234142
sparser
"Furthermore, it has been shown that when quiescent cells are stimulated with epi- dermal growth factor (EGF), Grb2 rapidly binds to the phosphorylated EGF receptor."
8389569
sparser
"In another study, they combined micro-patterned surfaces with TIRFM to measure the interaction of growth factor receptor-bound protein 2 (Grb2) with EGFR [ xref ]."
25922915
reach
"Notably, components of the EGF signaling network, Adam10, a metallopeptidase that processes EGF, and Grb2, an adaptor protein that binds directly to the EGF receptor, exhibited a greater importance for transgenic than for tumor TFs (XREF_FIG, blue dots)."
21464922
reach
"As NS5A did not appear to disrupt the interaction between c-Cbl, Grb2 and EGFR, we next assessed whether the effect on EGFR ubiquitination could be explained by the effects of NS5A on the interactions between the adaptor CMS and either EGFR or c-Cbl."
25872741
reach
"We developed a PLA to detect EGFR and GRB2 complexes that could be quantified using the AQUA (R) method of automated quantitative immunofluorescence (QIF) 18, eliminating any subjective interpretation of the results and allowing the objective and reproducible measurement of the obtained signal."
27449805
reach
"Several studies have suggested that the recruitment of CIN85 and Grb2 to EGF-R via Cbl regulates receptor internalization and degradation [17-20]."
16246327
reach
"The use of the PLA assay to detect EGFR binding to GRB2 as a surrogate for activation has been previously described [17] but never quantitatively measured."
27449805
sparser
"Most importantly, α-LA disrupts the interaction of EGFR and Grb2, which prevents the activation of EGFR signaling and the MAPK/ERK pathway."
28993193
sparser
"EGFR and GRB2 interaction, correlates with active EGFR signaling and leads to activation of MAPK/ERK pathway."
27449805
sparser
"A PLA developed to detect EGFR:GRB2 interaction was measured by quantitative immunofluorescence (QIF) using AQUA ® technology."
27449805
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"For example, it would not be possible to extract the correct event, ' Grb2 binds EGFR ', from the sentence A in XREF_FIG without coreference."
30010737
reach
"Thus, under the experimental conditions described here, indirect recruitment of Grb2 or CIN85 to the EGF-R (via binding of their SH3 domains to proline rich motifs in the C-terminal half of Cbl) is di[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
16246327
reach
"Meanwhile, it would not be possible to interconnect two events, ' Grb2 binds EGFR ' and ' Grb2 binds Shc ', from the sentence C without CR."
30010737
reach
"Direct Grb2 recruitment to EGF-R is not essential for EGF-R internalization in NIH3T3 and B82 cells [55-57]."
16246327
reach
"It was proven that the interaction between IGF1R, PTPN1, EGFR, GRB2, JAK2, STAT3, FGFR2 and VEGFA could regulate the apoptosis and proliferation of islet cells and could induce the formation of islet matrix [XREF_BIBR]."
33221752
sparser
"The use of the PLA assay to detect EGFR binding to GRB2 as a surrogate for activation has been previously described [17] but never quantitatively measured."
27449805
reach
"This resulted in increased binding of another adaptor protein Grb2 to the Src and EGFR complex and the subsequent activation of Ras and MAPKs."
11907028
sparser
"Therefore, we used the well-described interaction between the EGFR and Grb2."
34652152
sparser
"When growth factor receptor-bound protein 2 (GRB2) binding to EGFR, it becomes one the best activators for KRAS pathway."
39654099
sparser
"In another example from the same figure, SOS is shown catalyzing guanine nucleotide exchange in Ras; Ras is shown binding to plasma membrane, and SOS can be recruited to the plasma membrane via its binding through Grb2 to the ErbBs (or more indirectly via Shc)."
17016517
reach
"Activating this site mainly mediates the EGFR binding to Grb2, activating the Ras pathway, which in turn phosphorylates 1/2ERK [45]."
39741309
reach
"The GOT1 network also contains GRB2, which binds to EGFR and stimulates KRAS signaling ."
38496547
sparser
"We further propose, as shown in xref , c, that Grb2 binding to activated EGFR prevents p38-induced internalization of ligand-bound EGFR, and that such internalization can be observed in Grb2-depleted cells, as demonstrated in xref ."
34032851
sparser
"We used the techniques of image correlation spectroscopy (ICS) and lifetime-detected Förster resonance energy transfer (also known as FLIM-based FRET or FLIM–FRET) to measure ligand-induced receptor clustering and Grb2 binding to activated EGFR in BaF/3 cells."
24697349
sparser
"Multiple molecules of Grb2 can bind to a single EGFR ( xref ), which may sterically hinder the interaction of the EGFR dileucine motif with AP2, thus preventing p38-dependent endocytosis of EGF-activated receptors."
34032851
sparser
"BaF/3 cells were stably transfected with fluorescently labeled forms of Grb2 (Grb2–mRFP) and EGFR (EGFR–eGFP)."
24697349
reach
"Recruitment of SHC and Grb2 to EGFR elicits extracellular signal regulated kinase (ERK) activation XREF_BIBR - XREF_BIBR."
21258366
sparser
"Sorkin and co-workers previously established that FRET can be used to detect interactions between EGFR and Grb2, but no estimates of cluster sizes were made in that study. xref "
24697349
sparser
"Whilst there are conflicting studies [ xref ], Cbl is thought to interact primarily with EGFRvIII through Grb2, which attenuates Cbl-dependent internalisation and degradation of the EGFRvIII receptor leading to sustained proliferative signalling [ xref ]."
33432111
sparser
"The model is an extension of our earlier model xref and now includes EGFR–Grb2 binding in addition to the processes considered in the original model (i.e., ligand–receptor binding, self-interactions capable of mediating receptor oligomerization, and receptor autophosphorylation)."
24697349
sparser
"Significantly, in agreement with our new experimental observations, the model predicts that Grb2 associates predominantly with EGFR tetramers."
24697349
sparser
"These results suggest that necdin suppresses the interaction between EGFR and Grb2 to downregulate the RAS/ERK signaling in CPCs."
26655377
sparser
"A rule-based model reported earlier xref was extended to include one new rule for Grb2 interaction with phosphorylated EGFR (pEGFR) (Figures xref and xref )."
24697349
reach
"In contrast to Shc, Grb2 and Ash bound to EGF receptor but did not form a stable complex with the NGF receptor."
8108130
sparser
"Besides the Ras-Raf-MEK signaling, the PI3K-Akt pathway is the second major EGFR-mediated signal transduction pathway, involving binding of Grb2 to the EGFR and subsequent association with Gab1 (Grb2-associated-binding protein 1; predominantly via the C-terminal SH3 domain) and the p85 subunit of PI3K (phosphoinositide 3-kinases; via pTyr residues of Gab1), resulting in the production of phosphatidylinositol (3,4,5)-triphosphate (PIP3) and activation of Akt. xref Like SOS1, Gab1 forms a constitutive complex with Grb2, xref whereas the association between Grb2:Gab1 and PI3K-p85 can be enhanced by EGF addition xref ( xref E–H)."
34652152
reach
"Furthermore, Grb2–EGFR complexes were found in coated pits, and Grb2 was shown to be necessary for the EGFR recruitment into coated pits ( Fig. 2 ) [29,30,48] ."
19278030
reach
"Interestingly, direct Cbl binding to pTyr1045 appears to play a minor, if any, role in the CME of EGFR, whereas Grb2-mediated interaction with EGFR is critical [36] ."
19278030
sparser
"These results suggest that the cytoplasmic domain of EGFR binds GRB2 in multiple conformations and that the conformation bias depends on the size of the EGFR cluster."
29243093
trips
"Live-cell fluorescence imaging reveals high stoichiometry of Grb2 binding to the EGF receptor sustained during endocytosis."
24259669
sparser
"We have observed the interaction between GFP-tagged EGFR and a cytoplasmic protein GRB2 that had been tagged with TMR-labeled Halo protein in living cells."
29243093
sparser
"Strong evidence exists for the presence of EGFR–Grb2 complexes in endosomes ( xref ; xref ; xref )."
34515735
sparser
"Grb2-bound EGFR clusters were dispersed at an average of 11 clusters/μm 2 , whereas the Grb2-free EGFR population had a spatial organization characterized by an average cluster density of 17 clusters/μm 2 ."
24697349
sparser
"The Src homology 2 domain-containing protein Grb2 binds to the tyrosine-phosphorylated ErbB1 molecule and activates at least three signalling pathways, Ras-Raf-MEK-ERK, phosphoinositide 3-kinase (PI3K)-AKT, and JAK-STAT signalling pathways, for cell proliferation, survival, and migration, and their continuous abnormal activation eventually leads to cancer cell tumourigenesis, invasiveness, and metastasis xref – xref , xref – xref ."
31831814
reach
"To assay the interaction between EGFR and Grb2 in yeast, we used the intracellular domain of EGFR with L834R mutation as the membrane protein by fusing several types of lipidation motifs at both the N-terminus (Gpa1p motif; Gpa1N) and the C-terminus (Ras1p motif; Ras1C and Ste18p motif; Ste18C)."
26581329
reach
"The results of the intracellular domain of EGFR and Grb2 interaction showed that our Ggamma recruitment systems could be exploited as a convenient heterologous system to discern the strong binders to the phosphotyrosines in the intracellular domain of EGFR, and therefore would provide the basis for studying other receptor tyrosine kinases as well."
26581329
sparser
"2A and 3 A), we validated whether the EGFR-Grb2 interaction is involved in the α-LA-induced reduction of cell proliferation."
28993193
sparser
"FRET–FLIM–ICS Measurements Reveal That Grb2 Is Associated with Higher-Order EGFR Clusters."
24697349
sparser
"Considering that on average 74% of EGFRs make up the Grb2-bound population and 36% the unbound population, the normalized density for 100% Grb2-bound EGFR clusters would be 16 clusters/μm 2 and 100% Grb2-free EGFR clusters would be 63 clusters/μm 2 ."
24697349
sparser
"Accordingly, the estimated size of clusters containing Grb2-bound EGFR would be about 4.2 ± 1 receptors/cluster and the estimated size of clusters free of Grb2 would be about 1.1 ± 0.3 receptors/cluster."
24697349
sparser
"This result suggests that in the context of a simple monomer/ N -mer equilibrium the cluster size of the Grb2-bound EGFR is approximately 4."
24697349
reach
"Failure of Grb2 to bind EGFR is likely due to the hypo-phosphorylation of Tyr-1068."
39001381
sparser
"14 This Tyr-X-Asn-X sequence is found in EGFR but not in the insulin receptor; therefore, GRB2 can bind directly to EGFR but not to the insulin receptor."
11706405
reach
"This binding surface is responsible for the specificity of each SH2 and for the preferential binding of GRB2 to peptides containing the phosphorylated Tyr-X-Asn-X motif.14 This Tyr-X-Asn-X sequence is[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
11706405
reach
"We found that Grb2 recruitment to EGFR depended on EGF presence, which was significantly blocked by EGFR inhibitors.In another study, the effect of clathrin-mediated endocytosis on protein interactions was investigated [45]."
40177382
reach
"By contrast, the binding of Grb2 to the EGFR was similar in both cell types."
11853876
reach
"The interaction between Grb2 and activated EGF receptor is likely to be mediated by the SH2 domain of Grb2 binding to one, or more, of the tyrosine autophosphorylation sites in the carboxy-terminal ta[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
8490966
reach
"Together, these results suggest that the EGFR and Grb2 complex is required for the LPS induced activation of NRas and LPS induced cholangiocyte expression of the proinflammatory mediator, IL6."
25915403
reach
"We therefore tested whether a phosphopeptide based on this sequence would be capable of influencing the interaction of EGF receptor and Grb2."
8490966
sparser
"The EGFR-binding adaptor, Grb2, binds to the phosphotyrosine residues of the activated receptor ( xref ) and to the guanine nucleotide exchange factor, SOS, through two SH3 domains of GRB2."
25414766
sparser
"In necdin-null CPCs, the EGFR/ERK pathway is activated through increased interaction between EGFR and Grb2."
26655377
sparser
"On activation of certain RTKs such as EGFR and MET, Gab1 is recruited to the plasma membrane via interaction with EGFR-bound Grb2 or directly with MET, followed by the phosphorylation of a number of tyrosine residues on Gab1 ( xref )."
26246598
sparser
"As Grb2 binding to the EGFR decreases, ligand-induced EGFR intracellular signaling also decreases [93] ."
30098332
sparser
"Moreover, the positive correlation between clustering of EGFR and EGFR–Grb2 interaction is consonant with the concept that the nonrandom spatial organization of receptor dimers, in our case, tetramers, can concentrate signaling complexes in space and time."
24697349
reach
"When activated epidermal growth factor receptor (EGFR) and pBpA containing Grb2 are co-expressed and treated with UV light, a larger molecular weight band is detected suggesting the binding of EGFR to Grb2."
19318213
reach
"Upon EGFstimulation of the cell, binding of Sos to the EGF receptor and Grb2 complex brings a significant portion of Sos to the membrane."
8490966
sparser
"Instead, Gab1 likely becomes enriched within clathrin structures as a result of interactions with EGFR or Grb2 ( xref )."
26246598
sparser
"As shown in Fig.  xref b, the dose- and time-dependent increases in Grb2 SH2 binding to EGFR were obvious both by far-Western (~180 KDa band on upper panel) and SH2-PLA (Ct value in lower panel)."
26112401
sparser
"To explore the translational application of SH2-PLA, we analyzed binding of Grb2 SH2 to EGFR in lung cancer patient tissues."
26112401
sparser
"Together, the data in xref demonstrate that endocytosis separates the bulk of EGFR–Grb2 complexes from KRAS and NRAS, which remain primarily at the plasma membrane."
34515735
sparser
"In this study, we employed a Bioluminescence-RET (BRET)-based assay to monitor the most proximal event in EGFR activation, namely Grb2 interaction with the activated EGFR."
30347205
reach
"It reduces the level of EGFR (ERBB)-receptor expression [XREF_BIBR] and inhibits binding of GRB2 to EGFR."
28086243
sparser
"This observation suggests there is a pool of EGFR–Grb2 complexes that are capable of maintaining RAS activity at the plasma membrane and thus of sustaining ERK1/2 activity beyond the 15-min EGF stimulation."
34515735
sparser
"Of the subset of GPCRs tested, we only observed an increase in the EGFR-Grb2 BRET ratio for the AT 1 R and vasopressin 1b receptor (V 1b R)."
30347205
sparser
"For the other GPCRs, their activation led to no change or a slight decrease in the EGFR-Grb2 BRET ratio."
30347205
sparser
"To directly test whether a small pool of EGFR–Grb2 complexes at the plasma membrane is responsible for sustained ERK1/2 activation, surface EGFRs were blocked by cetuximab, a humanized mouse EGFR mAb that competes with EGF for binding to EGFR and inhibits its downstream signaling ( xref ; xref ; xref )."
34515735
sparser
"In the first pathway, adaptor protein Grb2 containing SH2 domain binds to activated EGFR and interacts with and activates Ras [ xref ]."
34069119
sparser
"To extend our observations that AT 1 R-EGFR transactivation may be independent of G q/11 and β-arrestin, we also performed EGFR-Grb2 BRET assays in CRISPR-mediated G q/11 and β-arrestin knockout HEK293 cell lines ( xref )."
30347205
sparser
"Comparable AngII-induced EGFR-Grb2 BRET ratios were observed in all three cell lines ( xref )."
30347205
reach
"EGF-R dimerization and JAK1 activation led to the recruitment of growth factor receptor-bound protein-2 (Grb2)."
38065462
sparser
"For the Grb2-EGFR assay, we showed that EGFR transactivation is independent of G q/11 coupling and does not apparently involve the AT 1 R carboxy-terminal tail or interaction with arrestin."
30347205
sparser
"EGFR-Grb2 recruitment was also recapitulated in other standard cell lines (CHO-K1 and NIH-3T3) and in primary isolated VSMCs, indicating the versatility of this approach to measure EGFR transactivation."
30347205
sparser
"Secondly, these GPCRs may not be recruiting Grb2 as part of their activation process or, alternatively, there is an association but it is different in nature to that generated by the AT 1 R and V 1b R. Indeed, for a number of the GPCRs that did not show enhanced EGFR-Grb2 association, we actually observed decreased BRET ratios following ligand stimulation."
30347205
sparser
"It could be reasonably argued that this reflects dynamic changes in an equilibrium between association, dissociation and reconfiguration of putative EGFR-Grb2 complexes – where the balance may favor dissociation or reconfiguration that leads to an increased distance between the donor and acceptor moieties."
30347205
sparser
"EGFR–Grb2 complexes are then rapidly internalized, resulting in their robust accumulation in endosomes observed after 3–5 min and sustained for at least 1 h."
34515735
sparser
"Thus, EGFR–Grb2 complexes, some presumably associated with SOS, are transiently positioned in close proximity to RAS while passing through the plasma membrane during the initial 1–5 min after EGF stimulation, which correlates with the maximal activation of RAS in HeLa cells ( xref )."
34515735
sparser
"Furthermore, Grb2–EGFR complexes were found in coated pits, and Grb2 was shown to be necessary for the EGFR recruitment into coated pits ( Fig. 2 ) [29,30,48] ."
19278030
sparser
"In vitro interaction of cell-free synthesized EGFR with Grb2."
27456041
sparser
"Importantly, residues near pY and Asn influence the binding affinity, which explains why BCR-ABL can inhibit EGFR binding to SH2 GRB2 ."
35651316
reach
"After ligand binding, EGFR associates with growth factor receptor bound protein 2 (GRB2), followed by Rat sarcoma (RAS) activation."
38745775
sparser
"We found EGFR bound to GRB2, suggesting how EGFR signaling can control this network and drive resistance to ALK TKI by facilitating EGFR:GRB2 signaling complexes."
27811184
reach
"The Grb2 SH2-domain also binds the phospho-tyrosine-containing motifs of EGFR family proteins to mediate the activation of the EGFR signaling pathway [22,23]."
36233320
sparser
"Subsequent internalization of ∼85–90% of EGFR–Grb2 complexes into early and sorting endosomes results in rapid (within 10 min) segregation of these complexes from all RAS species, which remain mainly localized at the plasma membrane, and from NRAS and HRAS, which are also present in PRC, Golgi, and TERC."
34515735
sparser
"In summary, the results of this study demonstrate that α-LA, a novel antioxidant, targets the EGFR-Grb2 interaction and inhibits EGFR-MAPK/ERK signaling in NSCLC cell lines, enhancing the effect of EG[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
28993193
sparser
"In addition, the precise mechanism regulating the α-LA-mediated disruption of the EGFR-Grb2 interaction must be explored in vivo ."
28993193
sparser
"Although G q/11 was absolutely required for ERK1/2 phosphorylation following AngII-stimulation, in contrast, we observed a sustained EGFR-Grb2 interaction when cells were pretreated with YM-254890."
30347205
reach
"Once activated, EGFR binds to growth factor receptor-bound protein 2 (GRB2) and recruits SH2 domain-containing transforming protein (SHC)."
39632791
sparser
"Grb2 interacts with the phosphotyrosine residues of the activated EGFR and also interacts with the guanine-nucleotide exchange factors (GEFs) such as Ras-GRF or SOS xref ."
32317666
reach
"Earlier work has shown that the signaling activity of EGFR is potentiated in endosomes, as judged by a high stoichiometry of Grb2 binding to EGFR [XREF_BIBR]."
26575183
sparser
"Once transphosphorylated, EGFR binds to growth factor receptor bound protein 2 (GRB2) and recruits SHC, which next activates son of sevenless 1 (SOS1), a guanine nucleotide exchange factor, to induce RAS to exchange guanosine triphosphate (GTP) to guanosine diphosphate (GDP)."
36403983
sparser
"The Grb2 protein bound only to EGF-activated ErbB1 in this cellular system, and not to NRG-activated ErbB1 in a heterodimer with ErbB4."
11737890
sparser
"To conclude, it is important to consider that a “negative” function of endocytosis (i.e., separation of EGFR–Grb2 complexes from the major pool of RAS) may not be universally applicable to all cell types."
34515735
sparser
"Analyzing how the spatiotemporal interaction of EGFR with GRB2 in living cells regulates the MAPK signaling pathway has always been a research focus."
38540680
sparser
"GRB2 can also bind to EGFR through binding to Shc [ xref ]."
38540680
sparser
"One study reported the application of the lifetime FRET approach to imaging protein–protein interactions in live cells between the epidermal growth factor receptor (EGFR) and the adapter protein Grb2 [ xref ]."
34940262
sparser
"Demonstrating BRETs utility in this field, BRET studies helped identify tyrosine residues 1068, 1114, 1148 as the main residues mediating interaction of EGFR with Grb2 (Tan et al., xref )."
23577003
sparser
"In the meantime, during the utilization of FRET imaging microscopy by researchers to study receptor complexes implicated in Ras activation and Ras binding proteins in EGFR endocytosis, it was discovered that GRB2 can interact with EGFR either directly or by binding with Shc on the cell surface and endosomes, thereby recruit Ras [ xref ], because when the mutant YFP-Shc-3F, where all three GRB2 binding sites (Tyr239, Tyr240, and Tyr 317) were replaced by phenylalanines, was co-expressed with GRB2-CFP and EGF-Rh, both GRB2 and Shc were effectively drawn into the endosomes."
38540680
reach
"Grb2 can bind EGFR directly or through another SH2 containing protein, Shc."
11498013
sparser
"Additionally, there is also evidence to suggest that the EGFR tetramer may be the predominant form bound to GRB2 within the cell, as indicated by the distribution and proportion of GRB2-bound EGFR oligomers using techniques of image correlation spectroscopy (ICS) and lifetime-detected Förster resonance energy transfer (also known as FLIM-based FRET or FLIM-FRET) [ xref ]."
38540680
sparser
"Studies analyzing the interaction between GRB2 and EGFR mutants in vivo have shown that phosphorylation of Tyr1068 and Tyr1173 is crucial for the binding of the GRB2 SH2 domain to EGFR."
38540680
sparser
"The multifunctional Grb2 adapter protein binds the EGFR at phospho-Tyr1068 once the EGFR is activated [ xref ]."
22754566
sparser
"In the internalization pathway of EGFR, in addition to activating the signal cascade of the GRB2-SH2 interaction, the interaction between EGFR and GRB2 also apparently mediates opposing effects on signaling: downregulation through internalization degradation."
38540680
sparser
"It has been shown that EGF-activated EGFR interacts with Grb2 at plasma membrane and in endosomes ( xref ; xref )."
20659687
sparser
"The SH3 region of GRB2 binds to the proline-rich region of Cbl, while the SH2 region of GRB2 binds to the phosphorylated residue of EGFR [ xref ]."
38540680
sparser
"In contrast, after EGF addition, Grb2-rsTagRFP photoswitching resulted in a striking and reversible ~20% modulation of the EGFR-EYFP fluorescence both at the plasma membrane and on endosomes, strongly suggesting the occurrence of pcFRET due to the EGFR-Grb2 interactions at these locations."
20659687
sparser
"To provide additional evidence for the switchable pcFRET, we next measured the EGFR-EYFP and Grb2-rsTagRFP interaction in live cells, using the FLIM technique."
20659687
sparser
"Grb2 binds to the activated EGFR and acts as an adaptor to recruit the E3 ubiquitin ligase Casitas B lineage lymphoma protein to start internalization."
20659687
sparser
"pcFRET made it possible to monitor EGFR-Grb2 interaction in the same cells at different time points before and after EGF stimulation."
20659687
sparser
"The EGFR-Grb2 interaction has been previously observed in the same compartments with a three-channel FRET imaging using the EGFR-EYFP and Grb2-ECFP fusion proteins ( xref )."
20659687
sparser
"By contrast, the binding of Grb2 to the EGFR was similar in both cell types."
11853876
sparser
"GRB2 binds the EGFR and contains one SH2 domain and two SH3 domains, which are crucial for IL3 signaling in hematopoietic stem and progenitor cell."
32419823
reach
"When EGFR activation is highly expressed, growth factor receptor-bound protein 2 (Grb2) binds to EGFR either directly through Y1068 and Y1086 or indirectly through SHC binding Y1173 and Y1143."
38201528
sparser
"Sorkin, A., McClure, M., Huang, F., Carter, R. (2000): Interaction of EGF receptor and grb2 in living cells visualized by fluorescence resonanceenergytransfer(FRET)microscopy."
12924628
sparser
"Interestingly, the interaction of Grb2 with epidermal growth factor receptor has a role in its internalisation by clathrin-coated pits [25,26] ."
15251454
reach
"Although a selective EGFR kinase inhibitor completely abolished Ang II induced recruitment of Grb2 to EGFR and markedly attenuated Ang II induced ERK activation, it had no effect on Ang II induced PYK2 tyrosine phosphorylation or its association with c-Src and Grb2."
9931105
reach
"We could not detect an increase in binding between EGFR and GRB2, ruling out a possible contribution of increased P-EGFR to P-ERK in this model."
21278786
reach
"The cross linked Grb2 and EGFR complex was detected for 8 out 9 Grb2 mPyTK mutants; the D104mPyTK mutant gave the highest photo-cross-linking yield followed by the V105mPyTK, Q106mPyTK and N143mPyTK mutants (XREF_FIG b and Figure S10 in SI)."
28422494
sparser
"Indeed, Grb2 associates with the EGFR either directly or indirectly (via Shc) through multiple major EGFR autophosphorylation sites [16,21] ."
19263517
sparser
"However, weakly phosphorylated EGFRvIII can still associate with Grb2, and hence indirectly associate with CBL."
25210647
sparser
"The Grb2 SH2 domain binds to Tyr1068 of EGFR and Tyr317 of Shc while its SH3 domains bind to mSos1."
8940013
sparser
"C-Cbl directly binds to Py1045 or indirectly binds to the pY1068/pY1086 residues of EGFR via the GRB2 adaptor protein [ xref ]."
38745188
reach
"EGFR-GRB2 complex binds to SOS via its SH3 domain and leads to membrane localization of SOS [26–29]."
36284306
sparser
"EGFR is able to activate PI3K through a series of reactions: active EGFR binds adaptor protein Grb2, which recruits the docking protein Gab1, which contains pYXXM motifs to which SH2 domains on the regulatory subunit of PI3K (p85) bind, thereby bringing the catalytic subunit of PI3K (p110) in proximity to its membrane-bound lipid substrates [ xref ]."
18641990
reach
"The multifunctional Grb2 adapter protein binds the EGFR at phospho-Tyr1068 once the EGFR is activated [XREF_BIBR]."
22754566
sparser
"As mentioned above, the ubiquitination regulation of EGFR by Cbl is either directly, through binding to its pY1045 site, or indirectly, through Grb2 binding to the pY1068 or pY1086 site. xref Our experiment ruled out the possibility of Cbl indirectly binding to EGFR through Grb2 (Figure  xref )."
34609770
sparser
"As Grb2-EGFR interaction depends on phosphorylation of the EGFR, this demonstrates that the EGFR kinase remains active until translocation to inner vesicles of MVBs."
16859684
sparser
"These discoveries were extended to mammalian systems, where it was shown that the Grb2 SH2 domain could inducibly bind the tyrosine phosphorylated epidermal growth factor receptor (EGFR) while bound constitutively to son of sevenless (SOS), a guanine nucleotide exchange factor for Ras."
20965179
reach
"After phosphorylation of EGFR, EGFR forms a complex with proteins Grb2 and Sos, or interacts with them through the adaptor molecule Shc."
31742207
sparser
"In streptolysin O permeabilised cells, a tyrosine phosphopeptide, EGFR-Y1068P, which binds to the SH2 domain of Grb2, totally blocks growth factor induced formation of complexes between Grb2 and Shc or EGF receptor, and also blocks activation of nucleotide exchange on Ras."
7970708
sparser
"Since the goal of the CORT technique is to identify target proteins for particular growth factor receptors, we assessed whether GRB2 associates with the EGFR."
1322798
reach
"Like c-Cbl, Grb2 bound EGFR more efficiently following EGF or BTC stimulation for 15 min compared with the other EGFR ligands (XREF_FIG)."
19531065
reach
"Therefore, we assumed that the interaction between EGFR and Grb2 could convey necrotic signaling to RIP1 to induce necroptosis upon rasfonin stimulation."
35831301
sparser
"Foremost among these is the Ras/Raf/mitogen-activated protein kinase (MAPK) pathway, in which the adaptor protein Grb2 binds to phosphorylated tyrosine residues of EGFR, thus activating the Son of sevenless protein. xref This protein in turn activates the G-protein Ras, which initiates a cascade of phosphorylation of MAPKs, which are specific serine/threonine kinases."
26398757
sparser
"Using a proximity ligation assay, Smith and colleagues recently showed that in 25% of surgical specimens collected from NSCLCs harboring a KRAS mutations, EGFR associates with the growth factor receptor–bound protein 2 (GRB2) [ xref ]."
26468985
reach
"First, we investigated whether the three peptide candidates induced a physical interaction between EGFR and Grb2 or Gab1 and SHP2."
25179402
sparser
"To test whether nicotine-activated EGFR was able to bind to Grb2, MCF10A cells were treated with nicotine or EGFR and immunoprecipitation was then performed (Figure xref )."
22085699
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"For example, the SH2 domain-containing Grb2 protein binds to the autophosphorylated EGF receptor bringing the guanine nucleotide exchange factor, SOS, to the membrane where it induces the exchange of [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
15951036
reach
"After EGF stimulation, the Grb2 SH2 domain binds to the EGF receptor directly or indirectly through proteins such as Shc, FAK, Syp, and IRS-1, by recognizing phosphotyrosine (pTyr)-containing sequences."
18830565
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"It was discovered that the asterriquinone natural products and synthetic analog tetrahydro asterriquinone E directly inhibited the binding of Grb2 adapter protein to tyrosine-phosphorylated EGF recept[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
22658083
sparser
"Inducibility and quantification of EGFR-Grb2 interaction."
24658383
sparser
"After the receptor transphosphorylation, activated EGFR residues can not only directly bind to GRB2, but also preferentially recruit SHC through its PTB domain or SH2 domain [ 33 ]."
32846211
sparser
"Next, we studied the interaction between endogenous EGFR and fluorescent Grb2."
24658383
reach
"Grb2 may bind to EGFR with or without Shc."
11583913
sparser
"This basic interaction between Grb2 and EGFR appeared without any additional EGFR activation and may be caused by the stimulating nature of the antibody coated surface and/or the presence of growth factor containing serum."
24658383
sparser
"However, the interaction of EGFR and Grb2 can be clearly stimulated; the addition of EGF resulted in a prominent increase of the Grb2-YFP fluorescence within EGFR-enriched μ-patterns."
24658383
sparser
"However, this notion was challenged by the demonstration that the majority of active EGF receptors and associated signaling molecules localize to early endosomes shortly after ligand stimulation [ xref – xref ], and that active EGF receptor interacts with Grb2 [ xref ] and engages the major signaling pathways required for cell survival and mitogenesis after endocytosis [ xref , xref ]."
23434660
sparser
"Sensitivity of EGFR-Grb2 interaction."
24658383
sparser
"CCPs represent the main structures for the endocytosis of activated EGFRs xref , and the interaction of Grb2 with the EGFR plays a decisive role in the initial steps of clathrin-mediated internalization xref , xref ."
24658383
sparser
"We continued our work by analyzing the relevance of CCPs for the binding of Grb2 to the EGFR."
24658383
sparser
"Those results fit the model of an increased retention time of Grb2 bound to the activated EGFR."
24658383
reach
"Indeed as found by several groups, Drk binds both to the activated Sevenless receptor and SOS, and Grb2 binds both to the activated EGF receptor and mammalian SOS (MmSOS) [28,65,125,133,170, 195,213]."
7819271
reach
"Previous single-molecule measurements of the association between EGFR and GRB2 in vitro suggested that EGFR exists in multiple molecular states [32]."
29505756
reach
"Cluster distribution at 10nM EGF shows nearly 95% of the EGFR tetramers containing at least one bound Grb2, while monomers, dimers, and trimers are predominantly (~ 98%) free of Grb2."
26016476
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"Finally, the assay provides additional biological insight: for the present study we used the μ-patterning approach for a quantitative analysis of the EGFR-Grb2 interaction."
24658383
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"16 Given that receptor-adaptor association is required for downstream signaling, however, computing the IC 50 for EGFR and GRB2 complex formation may provide additional insight."
25317724
reach
"Interestingly, the relatively rapid kinetics of EGFR-GRB2 binding, 17 which may not prevail for all EGFR adaptors, produces EGFR and GRB2 complex sensitivity results that are indistinguishable from those for phosphorylated receptor."
25317724
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"On top, the Sf21 microsomes functionalized with receptor molecules represent an ideal platform for structural and functional in vitro studies as exemplified by investigation of the EGFR and Grb2 interaction."
27456041
sparser
"In addition, RhoU is involved in EGFR-mediated signaling, leading to AP1 transcriptional activity and cell migration in pancreatic cancer cells, events that require its interaction with the Grb2–EGFR complex."
21508312
reach
"The duration of the interaction between EGFR and GRB2 was defined as the time from their association to their subsequent dissociation."
29505756
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"31 In the epidermal growth factor (EGF) signaling pathway, GRB2 can associate with autophosphorylated epidermal growth factor receptor (EGFR) indirectly via its SH2 domain binding to tyrosine-phosphor[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
18804415
reach
"The EGFR and GRB2 complex adopts multiple conformations, as demonstrated in a previous in vitro study [32]."
29505756
reach
"These interactions between EGFR and Grb2 were detected based on the colocalization of fluorescent spots."
29505756
reach
"As Grb2 binding to the EGFR decreases, ligand induced EGFR intracellular signaling also decreases [93]."
30098332
reach
"Due to the optical diffraction limit of microscopy, the observed overlapping of fluorescent spots did not necessarily indicate direct interaction between EGFR and GRB2."
29505756
sparser
"EGF treatment induced the interactions of EGFR with Grb2, c-Src, Shc1, FAK, Gab1, and itself."
33050232
sparser
"Because Grb2 is constitutively associated with Sos, the binding of Grb2 to phosphorylated EGF-R results in the recruitment of Sos to the plasma membrane."
17993263
sparser
"It reduces the level of EGFR (ERBB)-receptor expression [ xref ] and inhibits binding of GRB2 to EGFR (Figure xref )."
28086243
reach
"The binding of phosphor-EGFR with the GRB2/SOS1 complex sustains the activity of KRAS, leading to EGFR-TKI resistance in lung cancer [ 27 ]."
32561477
sparser
"Yamauchi et al ( xref ) demonstrated in cell culture systems that GH caused JAK2-dependent tyrosine phosphorylation of EGFR’s cytoplasmic domain independent of EGFR kinase activity and that this allowed Grb2 to bind EGFR and activate the ERK cascade."
32835785
sparser
"Ang II also increased the association of the adaptor protein Grb2 with the EGF-R. These findings indicate that Src and Pyk2 act upstream of the EGF-R and that the majority of Ang II-induced ERK phosphorylation is dependent on trans-activation of the EGF-R. Ang II-induced ERK activation in C9 cells is initiated by a PKCdelta-dependent but Ca(2+)-independent mechanism and is mediated by the Src/Pyk2 complex through trans-activation of the EGF-R."
11809859
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"For example, adding the chemotherapy drug combination—pemetrexed and carboplatin to an oral Gefitinib may improve outcomes [ 45 ] since GRB2 binds EGFR and promotes the EGFR phosphorylation and then a[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
32561477
reach
"The binding of Grb2 to EGFR results in a conformation change exposing the Grb2–SH3 domains to recruit other signalling molecules including Son-of-Sevenless (SOS) [14,16] ."
22024281
reach
"Most importantly, alpha-LA disrupts the interaction of EGFR and Grb2, which prevents the activation of EGFR signaling and the MAPK and ERK pathway."
28993193
sparser
"Therefore, it is tempting to speculate that hPIV3-C interaction with GRB2 and EGFR pathway participates in such deregulation of airway epithelium homeostasis to promote hPIV3 replication and spreading."
19806178
sparser
"For example, EGFR phospho-Y974 (pY974) has been shown to recruit SHC, signal transducer and activator of transcription 5 (STAT5), and Src, while EGFR pY1173 binds to Grb2, SHC, phospholipase C gamma 1, and Src homology region 2 domain-containing phosphatase-1 ( xref )."
38536914
sparser
"Cbl was basally associated with the adaptor protein growth factor receptor-binding protein 2 (Grb2), and this interaction was further enhanced by EGF stimulation; however, the interaction was entirely mediated via the Grb2 Src homology 3 (SH3) domains, suggesting that binding of Grb2 SH2 domain to EGF receptor provides one mechanism of Cbl's association with the EGF receptor."
8662998
sparser
"For example, the GRB2 adaptor protein binds activated EGFR at phosphorylated Tyr1068 xref , and phosphorylated Tyr1173 provides a docking site for the Shc scaffold protein, which is involved in mitogen-activated protein kinase (MAPK) signaling activation xref ."
25343452
sparser
"Proline-rich motifs in the N-terminus of RhoU mediate its interaction with GRB2 and the EGFR."
21508312
sparser
"Growth factor receptor bound protein 2 (Grb2) binds to EGFR, followed by the binding of Grb2-associated binder protein 1 (Gab1), and it continues to recruit p85 subunit of PI3K in order to prolong or [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
33609510
reach
"The underlying mechanism seems to involve recruitment of a Grb2 c and Cbl complex to Grb2 specific docking sites of EGFR, and concurrent acceleration of receptor ubiquitylation and desensitization."
11823423
reach
"In addition, Gab1, recruited to the membrane via interactions with EGFR-bound Grb2, engages class I phosphoinositide 3 kinases (PI3Ks) to convert PtdIns(4,5)P to PtdIns(3,4,5)P (Rodrigues et al., 2000; Kiyatkin et al., 2006)."
39024272
reach
"We have previously examined the localization of fluorescently labeled Grb2 expressed at the physiological level and found that EGFR–Grb2 complexes are maintained and accumulate in endosomes in HeLa cells during at least the first hour of cell stimulation by EGFR ligands (Fortian and Sorkin, 2014)."
30586319
reach
"Unexpectedly, endogenous HRAS was not present in endosomes containing EGFR–Grb2 complexes in the same cells (Pinilla-Macua et al., 2016)."
30586319
sparser
"Why were the 1 mins and 2 mins time points chosen to examine EGFR-PIP2 and EGFR-GRB2 interactions, respectively?"
39513999
reach
"Specific signaling and endocytic proteins also are co-captured after EGF stimulation included the ubiquitin ligase Cbl, endocytic proteins including Eps15/R and dynamin2, and the EGFR-binding scaffold protein Grb2."
38903101
sparser
"Alternatively, please provide evidence of their interactions at earlier time points (e.g. 15-30 seconds for EGFR-PIP2 and 1 mins for EGFR-GRB2)."
39513999
sparser
"In addition, EGF receptor (Tyr992) induces PKC-dependent ERK 1/2 phosphorylation via PLCγ ( xref ); EGF receptor (Tyr1068) associates with the adaptor Grb2, which is the main step in EGF receptor-dependent induction of RAS/MAPK ( xref )."
23277024
reach
"The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is activated by various receptor tyrosine kinases (RTKs), such as EGFR, which binds the adaptor protein growth factor receptor bound protein 2 (GRB2) and GRB2 associated binding protein 1 (GAB1) to recruit and activate PI3K at the cell membrane."
33123479
sparser
"These values were assessed by an ELISA-type assay that measures their ability to inhibit the binding of the phosphorylated carboxy-terminal intracellular domain of the epidermal growth factor recepto[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
10021933
reach
"GRB2 can also bind to EGFR through binding to Shc [42]."
38540680
reach
"The EGF receptor can interact with Grb2 and the associated SOS protein stimulates ras."
8735986
reach
"In the internalization pathway of EGFR, in addition to activating the signal cascade of the GRB2-SH2 interaction, the interaction between EGFR and GRB2 also apparently mediates opposing effects on signaling: downregulation through internalization degradation."
38540680
reach
"Receptor clusters of 100 increase the efficiency of Grb2 rebinding to a second EGFR by 6 fold, compared to randomly distributed receptors at this normal expression level."
20459599
reach
"Based upon parameter fitting, we estimated that the association (k on) and dissociation (k off) rate constants between Grb2 and EGFR are 0.0072 (nM x s) -1 and 9.34/s, respectively."
20459599
reach
"The activated EGF receptor forms a complex with the adapter proteins, Shc and Grb2, thereby recruiting Sos, the GDP-GTP exchanger for Ras."
10967198
sparser
"An epidermal growth factor receptor mutant lacking all known autophosphorylation sites is unable to bind to the GRB2 molecule, yet can still induce SHC phosphorylation and RAS activation in fibrobl[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
7553858
sparser
"For the first mutation, both the network and pathway-like models predict the same steady-state levels because in the absence of Shc binding, Grb2 recruits Sos at the same rate in both models via direc[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
16233948
reach
"Additionally, there is also evidence to suggest that the EGFR tetramer may be the predominant form bound to GRB2 within the cell, as indicated by the distribution and proportion of GRB2-bound EGFR oligomers using techniques of image correlation spectroscopy (ICS) and lifetime-detected Förster resonance energy transfer (also known as FLIM-based FRET or FLIM-FRET) [61]."
38540680
sparser
"For the second mutation, the predictions of the two models differ because unphosphorylated Shc can bind EGFR, and this binding competes with Grb2–EGFR binding in the pathway-like model but not in the [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
16233948
reach
"From these studies, we concluded that Grb2 binds directly to the EGFR at Y-1068, to a lesser extent at Y-1086, and indirectly at Y-1173."
7518560
reach
"The Binding of Shc1 and Grb2 to EGFR Phosphosites Can Be Enchanced by Sequence Changes That Would also Increase Phosphorylation by c-Src."
30012625
reach
"Functional interaction of the EGFR with Grb2 and Shc1."
24577528
reach
"Owing to these attractive features, rsTagRFP has been used to monitor the interaction between epidermal growth factor receptor (EGFR) and growth factor receptor binding protein 2 (Grb2) in live cells by means of pcFRET with EYFP as a donor (XREF_FIG,)."
22054544
reach
"After ligand stimulation, activated EGFR binds GRB2 and GRB2-associated binding protein 1 (GAB1) to recruit PI3K."
28428083
sparser
"Activating this site mainly mediates the EGFR binding to Grb2, activating the Ras pathway, which in turn phosphorylates 1/2ERK [ xref ]."
39741309
reach
"After auto-phosphorylation, EGFR binds GRB2 to activate SOS, a GTP-exchange factor that converts RAS-GDP into active RAS-GTP and subsequently actives MAPK1/3."
28428083
reach
"The SH2 sites of Grb2 can bind phosphotyrosine-1068 of ErbB1 (monomer or dimer) (interaction-9), and the SH3 site of Grb2 can bind cytosolic SOS (interaction-12)."
17016517
reach
"In this pathway, activated EGFR binds GRB2 associated binding protein 1 together with growth factor receptor bound protein 2 to recruit PI3K."
29805554
sparser
"Further, MaMTH was applied as the screening tool to identify dynamic PPIs, and it allows mapping phosphorylation sites that mediate adapter binding [i.e. GRB2 binding to epidermal growth factor recept[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
26610415
sparser
"Furthermore, Western blotting of Grb2 immunoprecipitates with anti-EGFR showed that Grb2 was bound to the EGFR in response to EGF (Fig. 8D)."
11370743
sparser
"To assay the interaction between EGFR and Grb2 in yeast, we used the intracellular domain of EGFR with L834R mutation (EGFR L834R,cyto ; that is constitutively dimerized and activated even in the absence of EGF xref xref ) as the membrane protein by fusing several types of lipidation motifs at both the N-terminus (Gpa1p motif; Gpa1N) and the C-terminus (Ras1p motif; Ras1C and Ste18p motif; Ste18C)."
26581329
sparser
"The results of the intracellular domain of EGFR and Grb2 interaction showed that our Gγ recruitment systems could be exploited as a convenient heterologous system to discern the strong binders to the phosphotyrosines in the intracellular domain of EGFR, and therefore would provide the basis for studying other receptor tyrosine kinases as well."
26581329
sparser
"Ectopically expressed Mig6 or mutant Mig6 deficient for Grb2 binding (PP319/20AA) coimmunoprecipitated with EGFR and inhibited EGFR autophosphorylation, as shown by western analysis ( xref D)."
22975324
sparser
"We supposed that under the stimulation of EGF, p‐EGFR interacted with GRB2, and further indirectly interacted with RhoV to activate RhoV and its downstream proteins."
36898847
sparser
"When incorporated at appropriate positions, N -methylpyrroletetrazole-lysine enabled robust site-selective photo-crosslinking of a GST homodimer in E. coli and EGFR-Grb2 (Growth factor receptor bound [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
34968810
reach
"Additionally, Grb2 and Shc also bind to the activated EGFR via their phosphorylated tyrosine residues, which then serve as an adaptor for the downstream Ras signaling and STAT signaling, respectively (XREF_FIG)."
28121014
trips
"Results of co-immunoprecipitation experiments suggest that phosphotyrosines Y-1068 and Y-1173 mediate the binding of Grb2 to the EGFR."
7518560
trips
"Competition experiments with synthetic phosphopeptides corresponding to known autophosphorylation sites on the EGFR demonstrated that phosphopeptides containing Y-1068, and to a lesser extent Y-1086, were able to inhibit the binding of Grb2 to the EGFR, while a Y-1173 peptide did not."
7518560
trips
"From these studies, we concluded that Grb2 binds directly to the EGFR at Y-1068, to a lesser extent at Y-1086, and indirectly at Y-1173."
7518560
trips
"These analyses reveal a hierarchy of interactions between Grb2 and Shc with the EGFR and indicate that Grb2 can bind the tyrosine-phosphorylated EGFR directly, as well as indirectly via Shc."
7518560
sparser
"After EGF binding, the GRB2 adaptor protein binds activated EGFR at phosphosite Tyr1068, and triggers mitogen-activated protein kinase (MAPK) pathway activation ( Rojas et al., 1996 )."
25625231
reach
"Another EGFR binding adaptor protein is growth factor receptor bound protein 2 (Grb2), which binds activated EGFR through its Src homology 2 (SH2) domain XREF_BIBR."
24295852
sparser
"This activation cascade involves the binding of growth factor receptor-bound protein 2 (Grb2) to EGFR, which then recruits Grb2-associated binding protein 1 (Gab1), ultimately enhancing or prolonging the activity of the Akt signalling pathway through the recruitment of the p85 subunit of PI3K [ xref , xref ]."
39963060
sparser
"For the TIR-FRET screening of larger cell collectives, we performed three separate steps: (1) setting up of a membrane associated test system for probing the interaction between the epidermal growth factor receptor (EGFR) and the growth factor receptor-bound protein 2; (2) use of the Epac-SH188 sensor for quantitative evaluation under the microscope; and (3) application of a TIR fluorescence reader to probe the interaction of GFP with Nile Red."
30717378
reach
"Evidences have shown that GRB2 forms a complex with activated EGFR and the RAS specific guanine nucleotide exchange factor SOS1, thereby mediating the growth factor induced activation of RAS XREF_BIBR, XREF_BIBR."
23776563
sparser
"As depicted in Fig. 1 (pathway a), it is now known that activated EGF receptor binds the adaptor protein Grb2 through an interaction between autophosphorylated tyrosine on the receptor and the SH2 d[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
8024811
sparser
"According to our above results, ADAM12 might correlated with Shc-EGFR complex, Grb2-EGFR complex ( Fig. 3 C), EGFR tyrosine kinase inhibitor resistance, PI3K-Akt signaling pathway, Ras signaling pathw[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
37418984
sparser
"Furthermore, C. psittaci -specific Pmp17G activated Chlamydial invasion in a dependent way by recognizing EGFR, activating Tyr1068 phosphorylation of EGFR, and forming the EGFR–Grb2 complex, contributing to intracellular attachment and internalization during C. psittaci infection ( xref )."
35529835
sparser
"Binding activity of Cy3–Grb2 to the phosphorylated EGF receptor was examined."
16499962
sparser
"Depending on the EGF stimulation of the cells, EGF receptor was co-precipitated with Grb2, demonstrating the specific binding activity of the Cy3–Grb2 to the phosphorylated EGF receptor ( Fig. 3a )."
16499962
sparser
"This is potentially due to "multi-state" interactions between intact receptors and adaptors, as suggested for EGFR-Grb2 interactions measured by single-molecule analysis [ xref ]."
20459599
sparser
"Cy3–Grb2 diffusing in observation buffer can associate with the phosphorylated EGF receptor of permeabilized cells."
16499962
sparser
"Binding of GRB2 to the p-EGFR Tyr1068 is crucial to the EGFR-induced MAPK signaling pathway [ xref ]."
29152086
sparser
"ACK1 is shown to bind EGFR in a Grb2-dependent manner and aids EGFR downregulation with its functional ubiquitin association domain (UBA) ( Grovdal et al., 2008; Kato-Stankiewicz et al., 2001; Shen et[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
20359967
reach
"sem-5 encodes an adaptor protein similar to vertebrate GRB2 ( Clark et al., 1992 ) that binds to the activated LET-23 EGF receptor and recruits the guanine nucleotide exchange factor SOS-1 to the plas[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
18805410
sparser
"Thus, the binding of Grb2 to phosphorylated EGF receptor results in the recruitment of Sos to the plasma membrane and has been proposed as a model for activation of membrane-bound Ras [39] ."
12069817
reach
"For the first mutation, both the network and pathway-like models predict the same steady-state levels because in the absence of Shc binding, Grb2 recruits Sos at the same rate in both models via direc[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
16233948
sparser
"The adaptor protein Grb2 (growth factor receptor-binding protein 2) binds to EGFR, which leads to activation of Ras-MAPK (mitogen-activated protein kinase) cascade."
14498832
sparser
"In this pathway, activated EGFR associates with growth factor receptor-bound protein 2 (Grb2) directly or through Shc ( Batzer et al., 1994 )."
24681003
reach
"In contrast to the activated epidermal growth factor receptor that binds the GRB2 and Sos complex directly, activation of the insulin receptor results in the interaction of GRB2-Sos with IRS-1 and Shc, thus linking the insulin receptor to Ras signaling pathways."
8316835
reach
"Further, MaMTH was applied as the screening tool to identify dynamic PPIs, and it allows mapping phosphorylation sites that mediate adapter binding [i.e. GRB2 binding to epidermal growth factor recept[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
26610415
reach
"Grb2, which is constitutively associated via its SH3 domain with Grb2 associated binder 1 (Gab1), binds to the EGFR."
15194442
sparser
"Our aim was to elucidate the effect of the ligand (EGF) and clinically tested inhibitors on the interaction of EGFR with growth factor receptor-bound protein 2 (Grb2)."
40177382
sparser
"The GOT1 network also contains GRB2, which binds to EGFR and stimulates KRAS signaling xref , xref ."
38496547
reach
"We found EGFR bound to GRB2, suggesting how EGFR signaling can control this network and drive resistance to ALK TKI by facilitating EGFR : GRB2 signaling complexes."
27811184
sparser
"Thus, we have previously incorporated a photoreactive amino acid, -benzoyl--phenylalanine (Bpa; a), into the Src homology 2 (SH2) domain of the full-length GRB2 protein in mammalian cells and analyzed[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
21185312
sparser
"It has been shown by a number of laboratories that the SH2 domain of Grb2 binds to the tyrosine phosphorylated EGF receptor [33,51,72,73] ."
10393272
sparser
"Following EGFR activation, Cbl is recruited through its constitutive binding partner Grb2 which directly binds to the EGFR tyrosine kinase binding domain via its SH2 domain ( xref )."
25619714
reach
"As depicted in Fig. 1 (pathway a), it is now known that activated EGF receptor binds the adaptor protein Grb2 through an interaction between autophosphorylated tyrosine on the receptor and the SH2 dom[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
8024811
sparser
"The interaction between GRB2 and EGFR were experimentally verified xref ; both were characterized in the KEGG “Non-small cell lung cancer pathway” (pathway #5223)."
32170141
sparser
"We have previously examined the localization of fluorescently labeled Grb2 expressed at the physiological level and found that EGFR–Grb2 complexes are maintained and accumulate in endosomes in HeLa cells during at least the first hour of cell stimulation by EGFR ligands ( xref )."
30586319
sparser
"Earlier work has shown that the signaling activity of EGFR is potentiated in endosomes, as judged by a high stoichiometry of Grb2 binding to EGFR [ xref ]."
26575183
sparser
"Unexpectedly, endogenous HRAS was not present in endosomes containing EGFR–Grb2 complexes in the same cells ( xref )."
30586319
sparser
"Previous studies have reported p66Shc's ability to bind epidermal growth factor receptor (EGFR) and Grb2 in the absence of receptor stimulation in various cell types [ xref , xref , xref , xref ]."
27048591
sparser
"The SH2 domain of GRB2 binds to the tyrosine auto- phosphorylation sites of activated EGF receptor [14], suggesting that the interaction of Sem-5 with Let-23 is direct."
8307166
sparser
"Subsequently Grb2 binds to the EGFR."
17049626
sparser
"The Grb2/Sos complex binds to the activated EGFR through the SH2 domain of Grb2, recruiting Sos to the plasma membrane where the Ras protein is located."
15110798
sparser
"Furthermore, the binding of the adapter protein Grb2 to the phosphorylated tyrosine residues of EGFR prevents the p38-mediated CME of ligand-bound EGFR dimers, even when phosphorylated at p38-target r[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
35093568
sparser
"Interaction between activated EGFR and Grb2 at the endosomes upon EGF stimulation was proven by FRET microscopy [5] ."
19887107
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"32 For example, Grb2 could interact with and activate EGFR, which stimulates EGFR internalization and degradation."
37132043
sparser
"Protein:protein interactions (PPIs) underlie fundamental biological processes, such as transcriptional regulation (e.g., p53:MDM2 [ xref ]), signal transduction (e.g., GRB2-EGFR [ xref ]), and membrane fusion (e.g., SARS-CoV-2 RBD:ACE2 [ xref ])."
36945557
sparser
"Phosphorylated EGFR is bound by growth factor receptor-bound protein 2 (GRB2), which in turn recruits the son of sevenless (SOS1) to the plasma membrane."
38271825
sparser
"Unlike other RTKs like EGFR which bind to Grb2 directly, FGFRs do not directly bind to Grb2 upon FGF stimulation [ xref ]."
39031286
reach
"Phosphorylation of EGFR Y1068 leads to GRB2 binding to EGFR which can increase downstream signalling of MEK and MAPK pathway."
29156708
sparser
"These values were determined in our EGFR (Epidermal Growth Factor Receptor) assay, which measures the potency of a compound to inhibit the binding of the phosphorylated intracellular domain of EGFR t[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
10571147
sparser
"Using pcFRET, EGFR-Grb2 interactions could be detected in the same cells at different time points, both before and after EGF stimulation."
22054544
sparser
"While the proliferation assay and simulations report results in different units, it is notable that the maximum in the formation of the ErbB1-Grb2 plus ErbB1-Shc complexes and cell proliferation corresponded to the same dose of EGF."
20179207
reach
"EGFR binds to Grb2, Shc, Src, PLC-γ1, Crk, Stat5, Ptp-2c, and SHP1."
30241301
sparser
"Subsequently, lipocortin-1 competitively inhibited Grb2 binding to EGFR, thereby blocking the recruitment of critical signaling molecules necessary for EGF actions [ xref ]."
30497693
sparser
"2,19,22 Binding affinity was assessed by an ELISA-type assay that measures the ability of a compound to inhibit the binding of the phosphorylated C-terminal [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
11055351
sparser
"Of particular importance are the proline-rich regions for binding to the SH3 domain of Grb2 and tyrosine residues phosphorylated by the EGF receptor [ 1 , 2 ]."
36084556
reach
"Primary epithelial cells, HCLEs, and endothelial cells (PAEs) infected with the wild-type EGFR (E1-PAE) were stimulated with media change (control), injury (w), UTP, or EGF to determine recruitment of[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
21356361
sparser
"When activated epidermal growth factor receptor (EGFR) and pBpA containing Grb2 are co-expressed and treated with UV light, a larger molecular weight band is detected suggesting the binding of EGFR to Grb2 ( xref )."
19318213
reach
"The comparison of betacellulin (BTC) with EGF revealed an increased ERK activation with BTC due to a greater extend of Y1068EGFR tyrosine phosphorylation and subsequent increased recruitment of Grb2 t[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
16337776