IndraLab

Statements

CBL binds EGFR. 559 / 597
2 95 10 | 11 192 249
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"Therefore, we conclude that direct interaction between Cbl and EGFR may not be necessary for ligand-receptor endocytosis in vertebrate and invertebrate cells."
21340027
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"To test binding of Cbl proteins to EGFR, we prepared whole lysates from EGF-stimulated A-431 cells and incubated them for 1 hr at 4°C with immobilized GST–Cbl proteins."
10635327
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"Interestingly, we also observed that binding of c-Cbl to EGFR was decreased in the presence of delta-catenin (XREF_FIG)."
29629558
biogrid
No evidence text available
20562913
sparser
"To address this question, we co-transfected EGFR or EBC3 with c-Cbl into HEK293 cells and analysed the tyrosine phosphorylation, ubiquitination, and c-Cbl binding of EGFR and EBC3 in response to EGF s[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
18255265
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"[75, 76] 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
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"This mechanism does not apply to stress induced degradation of EGFR because no activation of EGFR or Cbl binding to EGFR is required for stress induced degradation of EGFR."
27034618
sparser
"After 15 min, more c-Cbl-EGFR interaction was detected in the control cells."
23774213
biogrid
No evidence text available
27059931
sparser
"There is accordingly reason to believe that the observed ubiquitination following interaction of the EGFR with Cbl is qualitatively different depending on how Cbl is positioned when encountering the E[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
15475003
sparser
"Although our data do not allow us to conclusively state that EGFR-Cbl binding in KS cells is constitutive, our data support the notion that the presence of kindlin-1 is required to ensure correct regulation of the EGFR-Cbl complex."
30248333
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"The EGFR is endocytosed and sorted to lysosomes upon incubation of cells with EGF, and in both these processes, recruitment of Cbl to the EGFR has been demonstrated to play a role [3,4,7,12,16,18,19,2[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
15475003
biogrid
No evidence text available
22591401
sparser
"Ubiquitination of the EGFR and Cbl associated with immunoprecipitated EGFR was quantified, normalized to total EGFR (IP: EGFR), and averaged from three experimental repeats ( xref )."
31260484
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"This fits well with the reports that c-Cbl primarily binds EGFR via Grb2."
19531065
sparser
"Nino et al. found that USP25 restrained the degradation of the EGFR by assisting in the association of the E3 ubiquitin ligase c-Cbl with EGFR, thereby modulating the amplitude of ubiquitylation on the receptor. ( xref )."
35096833
biogrid
No evidence text available
19155296
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"C-Cbl can bind to the human EGFR in two ways, either directly to phosphorylated tyrosine 1045, or indirectly via binding to Grb2, which in turn binds to phosphorylated tyrosines -1068 and -1086 of the receptor."
21332354
sparser
"Thus, the association of Cbl with the EGFR exhibits a unique dose–response behaviour that correlates with a similar behaviour of the Cbl-mediated ubiquitination of the EGFR."
23799367
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"2.7 SGCE Knockdown Promotes Interaction between EGFR and c-Cbl."
32714745
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"Both direct binding of Cbl to the EGFR and indirect binding of Cbl to the EGFR through Grb2 has been reported to result in ubiquitination of the EGFR ."
15475003
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"We found that delta-catenin binds closely to sites EGFR Y1045 and competes with c-Cbl for EGFR binding leading to reduction in binding between EGFR and c-Cbl."
29629558
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"All these results suggested that PLEK2 suppressed EGFR degradation through the competitive inhibition of the interaction between EGFR and c-CBL."
31182136
biogrid
No evidence text available
24797263
sparser
"Since (a) EGF-induced EGFR ubiquitination level is compromised in the presence of CTEN, (b) CTEN modulates the c-Cbl-EGFR interaction without altering pY1045 and pY1068 levels, and (c) c-Cbl protein levels are not altered by CTEN expression ( xref ), we investigated whether CTEN could interact with c-Cbl and therefore affect EGFR ubiquitination."
23774213
hprd
No evidence text available
11994282
sparser
"Moreover, both EGFR ubiquitination and interaction of EGFR with c-Cbl were markedly reduced in LINC01485-overexpressed gastric cancer cells."
32904620
sparser
"The former seems to be supported by our results showing that c-Cbl-EGFR interaction was markedly reduced in the presence of CTEN after 15 min EGF treatment."
23774213
sparser
"Furthermore, the interaction of c-Cbl with EGFR was reduced in cells expressing mutant EGFR ( Hartman et al., 2013 )."
26093903
biogrid
No evidence text available
7782294
sparser
"To influence the localization of EGFR without chemically perturbing the clathrin-coated pits, we used a mutant of EGFR (Y1045F) that does not bind directly to the E3 ubiquitin-ligase c-Cbl [ xref ]."
26575183
sparser
"We demonstrated that 14-3-3σ downregulated ligand-induced EGFR degradation by inhibiting EGFR-c-Cbl association and subsequent c-Cbl-mediated EGFR ubiquitination."
33391517
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"HPV E5 can also disrupt the interaction between the EGFR and the E3 ligase c-Cbl, reducing EGFR ubiquitination and degradation, thereby enhancing mitogenic signalling [ xref ]."
33427604
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"Although Grb2 does not contribute directly to EGFR ubiquitination, Cbl binding to EGFR and receptor ubiquitination decrease dramatically when Grb2 can not bind the receptor."
26264748
hprd
No evidence text available
7657591
sparser
"The phosphorylation of EGFR (Tyr1068) is associated with the recruitment of Cbl, a protein that ubiquitylates the EGFR and targets it for degradation ( xref )."
19155296
sparser
"Cbl directly interacts with a phosphotyrosine residue (tyrosine 1045) on EGFR via its SH2 domain and catalyses the mono-ubiquitination of EGFR [18,19] ."
18255265
biogrid
No evidence text available
28198003
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"For instance, the E3 ligase Cbl associates with EGFR and, upon activation with EGF and the interaction with Cbl, EGFR undergoes lysosomal degradation [XREF_BIBR]."
25400118
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"The interaction between EGFR and the ubiquitin ligase Cbl and adaptor protein CIN85, as well as ESCRT complex recruitment play important roles in the process of downregulating EGFR."
15782507
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
"Co-immunoprecipitation and ubiquitylation assays were employed to examine whether ERβ1 alters epidermal growth factor receptor (EGFR) protein degradation and the interaction between EGFR and the ubiquitin ligase c-Cbl."
23158001
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"Thus, binding of Cbl to the activated EGFR and recruitment of CIN85 couples EGFR to clathrin-mediated endocytosis [ xref ]."
12559039
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"Then, the c-Cbl binds to EGFR and facilitates EGFR ubiquitination and lysosomal degradation."
29629558
sparser
"Therefore, we analyzed the interaction between c-Cbl and EGFR in cells stimulated for 5 min with EGF using an experimental procedure in which immunoprecipitation of cell lysates with anti-EGFR was fol[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
22974559
sparser
"SPR analyses showed that WT-CBL and CBL-Y371S fragments (47–435) bind tyrosine-phosphorylated EGFR peptide (LQRpYSSDPTGA) with K d ’s of 1.2 and 0.6 μM, respectively (Table xref , Supplementary Fig. xref )."
33627783
biogrid
No evidence text available
10635327
biogrid
No evidence text available
17182860
sparser
"To determine whether kindlin-1–dependent changes to EGFR altered c-Cbl association with the receptor, we analyzed c-Cbl-EGFR binding by co-immunoprecipitation (IP) in WT and KS cells treated with DMSO or concanamycin A under growth conditions."
30248333
reach
"Cdc42 is proposed to function in a positive feedback loop with the EGFR whereby epidermal growth factor (EGF) stimulates activation of Cdc42 and its interaction with specific target proteins : Cdc42, in turn, inhibits EGFR degradation by preventing binding of c-Cbl to EGFR."
18435854
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"Mechanistically, we demonstrated that rLZ-8 bound to EGFR to induce EGFR autophosphorylation at tyrosine1045 and trigger ubiquitination by inducing the formation of EGFR and Cbl complexes, resulting in the degradation of EGFR; however, Cbl-shRNA abolished rLZ-8-induced EGFR degradation."
28198003
sparser
"As demonstrated in , the Grb2 mutant, as well as N-Cbl, inhibited ubiquitination of wt EGFR upon incubation of the cells with EGF on ice, as well as upon incubation with EGF at 37°C. This demonstrates[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
15475003
reach
"EGFR is ubiquitinated by the E3 ubiquitin ligase Cbl, which binds to activated EGFR directly and indirectly through the Grb2 adaptor protein."
20513767
reach
"We observed that the binding between c-Cbl and EGFR was decreased in the presence of delta-catenin."
29629558
biogrid
No evidence text available
20124286
biogrid
No evidence text available
18508924
reach
"To describe the dynamics of EGFR ubiquitination, we therefore restricted our analysis to the dynamics of the Cbl : EGFR interaction and assumed that ubiquitination is simply proportional to the amount of Cbl bound EGFR (Equation 15 in XREF_SUPPLEMENTARY)."
26264748
biogrid
No evidence text available
8662998
sparser
"Overexpression of ErbB-2, can inhibit Cbl-mediated downregulation of EGFR by forming heterodimers with the activated EGFR and preventing Cbl binding to the activated EGFR ( xref )."
20501843
sparser
"Cbl binds to activated EGFR and recruits CIN85."
21275903
reach
"This decreases the binding between c-Cbl and EGFR and inhibits EGFR ubiquitination, endocytosis, and lysosomal sorting."
29629558
reach
"The EGFR Y1045F mutation profoundly reduces but does not completely eliminate Cbl recruitment and ligand induced receptor ubiquitination, as Cbl may still bind EGFR indirectly through Grb2 [16,22-24]."
19263517
reach
"Several reports proposed that the recruitment of Cbl to the activated EGFR leads to ubiquitination of the cytoplasmic tail of the receptor, thereby promoting endocytosis and lysosomal degradation [35,[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
18096367
reach
"Numerous studies suggest that under conditions of normal signaling, Cbl can efficiently interact with the EGF receptor but not with ErbB2, ErbB3 or ErbB4."
11248544
biogrid
No evidence text available
23418353
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"Combining this with the data from Grovdal et al. [XREF_BIBR], who described that a direct association of c-Cbl with EGFR pY1045 was important for MVB sorting of EGFR, we surmised that aberrant EGFR sorting into lysosomes in RBE cells was caused by an impaired association between c-Cbl and EGFR through pY1045."
22591401
reach
"Since CIN85 is recruited by c-Cbl in EGFR and Cbl complex, the interaction between CIN85 and c-Cbl should not affect EGFR and Cbl complex."
25005938
reach
"It has been reported that activated Cdc42, through an interaction with its targets and effectors, inhibits the binding of c-Cbl to EGFR and thus prevents c-Cbl from catalyzing EGFR ubiquitination and [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
23142484
hprd
No evidence text available
11239464
reach
"Cbl can bind EGFR either directly by binding to phosphorylated Y1045, or indirectly via the adaptor protein Grb2, which binds to phosphorylated Y1068 and Y1086."
18288481
sparser
"CIN85 is thought to regulate endocytosis of receptor by binding to EGFR indirectly through Cbl and recruiting components of the endocytic machinery, such as endophilins, but CIN85 does not affect Cbl-mediated ubiquitination of the EGFR ( xref )."
21275903
hprd
No evidence text available
10092522
reach
"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
sparser
"Furthermore, we found that 14-3-3σ inhibited EGF-induced EGFR degradation after EGFR activation by interfering with EGFR-c-Cbl association and subsequent c-Cbl mediated EGFR ubiquitination."
33391517
sparser
"Taken together, these results indicate that δ-catenin reduces the binding of c-Cbl to EGFR, resulting in decreased EGFR ubiquitination and enhanced EGFR stability in the cell membrane."
29629558
sparser
"Since hypo-phosphorylation of Tyr1045 and a diminished association of c-Cbl and EGFR were considered as the responsible mechanisms, upregulation of Tyr1045 phosphorylation might be a useful alteration in EGFR-targeted therapy."
22591401
reach
"Using co-immunoprecipitation, we found that LGR4 knockout enhanced the levels of EGFR-bound CBL in MDA231-EGFR cells (Fig. 7d), suggesting that LGR4 functions to impair the EGFR-CBL interaction."
34099494
sparser
"Concentrating on two members of EGFR ligand family, i.e. EGF and AR, we show that AR and EGF induced similar patterns of short term EGFR and c-Cbl phosphorylation, physical association of c-Cbl with EGFR, and EGFR ubiquitination; however, as previously reported for TGF-α ( xref ), the effects of AR were much more transient than those of EGF."
19173594
sparser
"These are either dependent on the phosphotyrosine binding domain of c-Cbl that directly binds to the EGFR or on the region C-terminal of the Ring finger, which allows for indirect binding to an alternative site on the receptor."
15465819
sparser
"By using the CO-IP experiment, we found that si CDC34 drastically enhanced c-Cbl-EGFR interaction in H460, A549, and H1975 cells ( xref k)."
32114396
reach
"The E3 RING ligase Cbl, which contains c-Cbl, Cbl-b, and Cbl-c, can directly bind to EGFR."
32714745
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"As phosphorylation can cause large structural changes to binding, we sought to investigate the effect of multiple phosphorylation on the binding between c-Cbl and EGFR or Sprouty2, in continuation with our earlier work XREF_BIBR."
20877636
sparser
"Although interaction with endosomal proteins and sorting of the EGFR to inner membranes of MVBs depend on the direct Cbl-EGFR interaction [9–11] , indirect binding of Cbl through Grb2 is apparently c[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
16859684
sparser
"Figure xref G shows an inverse relationship, whereby the levels of EGFR-14-3-3σ association increased with the stepwise increase of 14-3-3σ expression, while the levels of EGFR-Cbl association correspondingly decreased."
33391517
sparser
"As previously reported for SHIP2, RNA interference-mediated knockdown of PR130 in COS-7 cells resulted in increased EGF-induced proteasome-dependent EGFR degradation, and an increased interaction of EGFR with the E3 ligase c-Cbl."
19825976
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"[16] Our study revealed that SGCE interacted with c-Cbl, and SGCE knockdown promoted EGFR degradation by increasing the interaction between EGFR and c-Cbl."
32714745
reach
"After endocytosis, CIN85 in association with EGFR and Cbl complex on endosomal membrane recruits several ESCRT components to endosome for ESCRT assembly."
25005938
biogrid
No evidence text available
22203672
sparser
"However, the deletion mutation of LINC01485 (nucleotides 340–391) partially restored EGFR ubiquitination and the interaction between EGFR and c-Cbl."
32904620
reach
"This is consistent with the notion that binding of CBL to the EGFR requires receptor autophosphorylation, which is abolished by RALT mediated kinase inhibition."
20421427
biogrid
No evidence text available
23158001
reach
"Whilst our data does not allow us to conclusively state that EGFR-Cbl binding in KS cells is constitutive, our data does support the notion that the presence of kindlin-1 is required to ensure correct[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
30248333
sparser
"Since ubiquitination of EGFR is also mediated by c-Cbl [21] , both directly via EGFR-SH2 domain interactions, and indirectly via a second adaptor protein, Grb2 [22] , we investigated if the interact[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
22974559
reach
"Further, only indirect binding of Cbl to the EGFR through Grb2 is considered important for recruitment of the EGFR to clathrin coated pits [18,19] and thus essential for ligand induced endocytosis of [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
15475003
sparser
"Conceivably, the interactions between EGFR and c-Cbl may be summarized in a sequential model ( Figure 7 )."
10635327
sparser
"A further immuno-coprecipitation assay was conducted to examine the binding of EGFR and c-Cbl and EGF, but not anisomycin, induced the EGFR binding to c-Cbl (D)."
19138820
sparser
"PTEN inactivation decreased EGFR ubiquitination and promoted EGFR expression by destabilizing the EGFR-Cbl complex, which in turn inhibited extracellular matrix degradation in cartilage tissues and activated chondrocyte autophagy."
35428355
sparser
"Then, the c-Cbl binds to EGFR and facilitates EGFR ubiquitination and lysosomal degradation ( xref ; xref ; xref )."
29629558
biogrid
No evidence text available
18271526
sparser
"Evidently, the peptide only slightly affected binding of c-Cbl to EGFR, but it almost completely abolished the interaction with the shorter viral form of Cbl."
10635327
sparser
"Finally, quercetin increased the interaction between EGFR and Cbl, and also induced the tyrosine phosphorylation of Cbl."
20082303
sparser
"Moreover, the internalized EGFR induced by anisomycin was not associated with c-Cbl, whereas those induced by EGF were phosphorylated at Tyr1045 and clearly associated with c-Cbl (B–D)."
19138820
sparser
"To describe the dynamics of EGFR ubiquitination, we therefore restricted our analysis to the dynamics of the Cbl:EGFR interaction and assumed that ubiquitination is simply proportional to the amount of Cbl-bound EGFR ( xref )."
26264748
reach
"On the other hand, several other studies suggested that c-Cbl binds with EGFR in the presence of EGF and facilitates EGFR downregulation."
29629558
reach
"We found that USP13 inhibits mutant EGFR degradation by a process that leads to the accumulation of ubiquitinated (K48 and K63) EGFR, which is bound to c-Cbl and USP13."
33210294
sparser
"Cbl can bind EGFR either directly by binding to phosphorylated Y1045, or indirectly via the adaptor protein Grb2, which binds to phosphorylated Y1068 and Y1086 (Fig.  xref ) (Levkowitz et al. xref ; Waterman et al. xref )."
18288481
sparser
"The levels of EGFR ubiquitination, the interaction between EGFR and 14-3-3σ, and the association of EGFR with c-Cbl after EGF stimulation, in 14-3-3σ overexpressing or knockdown cells were examined to elucidate the mechanism by which 14-3-3σ inhibits EGFR degradation."
33391517
reach
"This would probably affect the amount of EGFR bound Cbl."
21085658
sparser
"C-cbl activity and the association of c-cbl-EGFR were increased by ER stress."
24457597
reach
"Finally, quercetin increased the interaction between EGFR and Cbl, and also induced the tyrosine phosphorylation of Cbl."
20082303
reach
"On the other hand, it has been reported that c-Cbl interacts with EGFR either directly through phosphorylated Tyr1045, or indirectly through Grb2."
29629558
sparser
"So, lnc-EGFR maintains activation of EGFR by inhibiting the interaction between EGFR and c-CBL, leading to the stimulation of Treg differentiation."
30838159
reach
"Thus our findings provide further evidence that v-cbl possesses a novel and evolutionarily conserved phosphotyrosine binding domain and that the dual capability of EGF receptor binding by cbl involves two distinct mechanisms."
9174060
sparser
"In particular, AR stimulates a transient c-Cbl binding to EGFR ( xref )."
19531065
reach
"However, there is only low and transitent c-Cbl recruitment to EGFR following HB-EGF stimulation in spite of the heavy Tyr1045 phosphorylation."
19531065
reach
"In a study about the EGFR-ERK signaling pathway, the reaction rate of c-Cbl and EGFR binding was reduced by a factor of 100 or 1000 by regulating an ODE model to mimic the effects of the endocytosis impairment."
26697484
biogrid
No evidence text available
10428778
sparser
"It has further been demonstrated that the EGFR can be ubiquitinated both by direct interaction of Cbl with the EGFR through pTyr1045 as well as by indirect interaction of Cbl with the EGFR through bin[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
15475003
reach
"This inhibitory effect is due to a decrease in the interaction between the adapter protein c-Cbl and EGFR, but not the phosphorylation state of EGFR."
17545148
biogrid
No evidence text available
15465819
reach
"We analysed the association between Cbl and EGFR in vivo."
23799367
reach
"To test if alphaPIX also interferes with complex formation between c-Cbl and EGFR, we performed co-immunoprecipitation experiments."
26177020
sparser
"ERβ1 induces degradation of EGFR by enhancing the EGFR-c-Cbl interaction."
23158001
biogrid
No evidence text available
17242169
sparser
"EGFR binds to the E3 ubiquitin ligase c-Cbl in response to EGF, either at the plasma membrane or on early endosomes, which in turn promotes polyubiquitination of EGFR, resulting in degradation ( xref )."
30248333
trips
"The EGFR mutants were constitutively associated with the E3 ubiquitin ligase Cbl but did not associate with the adaptor protein CIN85 on the addition of ligand."
16849543
sparser
"Our experiments with the Y1045F mutant of EGFR, which does not bind c-Cbl directly, show that clustering of phosphorylated EGFR is caused by the aggregation of the ubiquitinated receptor in clathrin-coated pits."
26575183
biogrid
No evidence text available
15210722
sparser
"So far through a series of three studies [ xref – xref ] we found that (1) EGCG alters lipid organization on the plasma membrane, (2) EGCG promote the internalization of nonactivated monomer EGFR into cytosol, thus, inhibiting the activation of EGFR by EGF, (3) as a result, treatment with EGCG causes marked reduction of phosphorylated (activated) EGFRs, that are otherwise preferentially present in lipid rafts, (4) EGCG-induced EGFR internalization requires neither the binding of c-Cbl to EGFR nor a phosphorylation of EGFR at tyrosine residue, suggesting that this internalization is mediated by a different mechanism that is observed in EGF-treated cells, and (5) phosphorylation of EGFR at serine1046/1047 mediated by p38MAPK is essential for EGCG-induced EGFR internalization ( xref )."
21274257
sparser
"In this regard, it is noteworthy that conditions that prevent EGFR interaction with Cbl or its Cbl-dependent ubiquitinylation lead to a more prolonged stay of EGFR in early/recycling endosomal compartments [ xref , xref , xref ]."
19948031
biogrid
No evidence text available
10086340
hprd
No evidence text available
16729043
reach
"Ligand mediated recruitment of Cbl to the EGFR leads to multiple mono-ubiquitination of the receptor and targeting for lysosomal degradation."
18706412
sparser
"It has been reported that cetuximab‐resistant cells have increased EGFR levels due to reduced degradation from loss of binding to Cbl. [ xref ] Our study revealed that SGCE interacted with c‐Cbl, and SGCE knockdown promoted EGFR degradation by increasing the interaction between EGFR and c‐Cbl (Figure  xref )."
32714745
sparser
"C-Cbl binds to EGFR either directly through phosphorylated Tyr1045, or indirectly through Grb2 ( xref )."
29629558
reach
"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
reach
"In support of an endosomal role for c-Cbl, Burke et al. [20] have shown that association between EGFR and c-Cbl occurs in the early endosome."
12507554
reach
"On the other hand, we observed that TMEM52B suppression failed to substantially affect the interaction between c-Cbl and EGFR or ubiquitination of EGFR."
33641663
reach
"We also show that the Cbl and EGF receptor complex is predominantly associated with CrkII and is distinct to the Grb2, Shc, and Sos1 complex that associates with the EGF receptor."
9416834
biogrid
No evidence text available
14627991
reach
"delta-Catenin competes with c-Cbl for EGFR binding, which results in a reduction of binding between c-Cbl and EGFR and thus decreases the ubiquitination of EGFR."
29629558
sparser
"Both direct and indirect binding of Cbl to activated EGFR are reported to result in ubiquitination of the EGFR [1] ."
17382318
sparser
"All negative feedback loops arise from five mechanisms: (i) the kinases ERK1/2 and p90RSK downregulate their own activation by phosphorylation of SOS1, a guanine nucleotide exchange factor (GEF) for Ras, (ii) the phosphatase SHP1 binds to the autophosphorylated ErbB1-homodimers and dephosphorylates them, (iii) Ras positively influences its GTPase activating protein RasGAP via PI3K, (iv) the ubiquitin ligase c-Cbl binds to ErbB1, leading to degradation of the receptor in the lysosome and (v) Ras potentiates the Rab5a-GEF activity of Rin1 and thus increases the formation of endocytic vesicles."
19662154
reach
"Recently, Grovdal et al. showed that direct binding of Cbl to the EGF receptor is critical for lysosomal sorting of receptors, in contrast to the indirect binding via Grb2 [15]."
17904548
sparser
"To elucidate the mechanism of how lnc-EGFR blocks EGFR ubiquitination, we determined if lnc-EGFR interferes with the interaction of EGFR with c-CBL by performing an immunoprecipitation assay."
28541302
biogrid
No evidence text available
15210722
reach
"However, the binding deficient Y1045F EGFR mutant is internalized almost as efficiently as the wild-type EGFR, indicating that direct binding of Cbl to EGFR is not necessary for EGFR endocytosis XREF_BIBR."
21340027
reach
"It is well known that direct association between EGFR (pTyr1045) and c-Cbl is required to sort the EGFR to lysosomes for degradation, XREF_BIBR, XREF_BIBR leading us to examine the ubiquitination of EGFR to investigate whether LINC01485 and EGFR association modulates c-Cbl-mediated EGFR ubiquitination."
32904620
reach
"This is consistent with the notion that direct binding of Cbl to the EGFR is not essential for initial internalization of activated EGFR."
15475003
biogrid
No evidence text available
22266821
reach
"We have previously reported that Cbl interacts with EGFR in MECs."
20940296
sparser
"DMC also increased the interaction between EGFR and Cbl and induced the tyrosine phosphorylation of Cbl."
22849866
sparser
"Cdc42 is proposed to function in a positive feedback loop with the EGFR whereby epidermal growth factor (EGF) stimulates activation of Cdc42 and its interaction with specific target proteins: Cdc42, in turn, inhibits EGFR degradation by preventing binding of c-Cbl to EGFR."
18435854
sparser
"C-Cbl can bind to the human EGFR in two ways, either directly to phosphorylated tyrosine-1045, or indirectly via binding to Grb2, which in turn binds to phosphorylated tyrosines -1068 and -1086 of the receptor ( xref )."
21332354
sparser
"On the other hand, we observed that TMEM52B suppression failed to substantially affect the interaction between c-Cbl and EGFR or ubiquitination of EGFR ( xref )."
33641663
reach
"The RING-finger E3 ubiquitin ligase CBL binds to EGFR and favors its ubiquitination for lysosomal degradation [XREF_BIBR], whereas the E3 ubiquitin ligase CHIP promotes HER2 ubiquitination and degradation [XREF_BIBR]."
27203743
trips
"These data suggest that the binding of Cbl to epidermal growth factor receptor through Grb2 is necessary and sufficient for Cbl function during clathrin-mediated endocytosis."
12839496
reach
"The interaction between EGFR and c-Cbl has been shown to depend upon receptor phosphorylation at tyrosine residue 1045, the major docking site for c-Cbl."
16969069
sparser
"Phosphorylated EGFR binds the E3 ubiquitin ligase Cbl, which adds ubiquitin at several lysine residues ."
25721765
sparser
"In the present study, peritumoral Cbl and EGFR expression were associated with tumor recurrence and survival, however, the role of intratumoral Cbl and EGFR on HCC recurrence and survivability was weakened after hepatectomy."
26474280
reach
"Our model predicted the decrease in EGFR bound Cbl per EGFR in Y992F cells compared to that in the WT cells; this result was then validated by measuring the level of Cbl-b co-immunoprecipitated with EGFR (XREF_FIG)."
21085658
biogrid
No evidence text available
23774213
sparser
"CBL Interaction with EGFR during Mitosis."
30544639
sparser
"Further downstream processing to late endosomes/lysosomes depends on the ubiquitination of the EGFR, which is initiated by binding of the E3 ubiquitin ligase Cbl to phospho-tyrosine residues of the EGFR."
29176966
sparser
"We have shown previously that a Cdc42 mutant (Cdc42(F28L)), capable of spontaneously exchanging GDP for GTP (referred to as "fast-cycling"), transformed NIH 3T3 cells because of its ability to interfere with epidermal growth factor receptor (EGFR)-Cbl interactions and EGFR down-regulation."
15824104
reach
"As an adaptor protein, CIN85 is recruited by c-Cbl to EGFR and Cbl complex [XREF_BIBR]."
25005938
biogrid
No evidence text available
17545148
sparser
"Furthermore, we demonstrated that 14-3-3σ inhibited EGF-induced EGFR degradation after EGFR activation by interfering with the EGFR-c-Cbl interaction and subsequent c-Cbl-mediated EGFR ubiquitination."
33391517
reach
"Previously it was shown that the activated EGFR binds to cbl, which, in turn, recruits CIN85 to the endocytic pit."
22833562
sparser
"On the other hand, the protooncogene Cbl forms a complex only with ErbB1 ( xref )."
10648571
biogrid
No evidence text available
15962011
sparser
"Nonetheless, significant more c-Cbl proteins were bound to EGFR in the present of CTEN before 15 min."
23774213
reach
"PTEN inactivation decreased EGFR ubiquitination and promoted EGFR expression by destabilizing the EGFR-Cbl complex, which in turn inhibited extracellular matrix degradation in cartilage tissues and activated chondrocyte autophagy."
35428355
sparser
"Cbl proteins interact with the activated EGFR via their N-terminal TKB domain [ xref ] which is intact in the Cbl-c Δex7 protein."
31260484
reach
"The activation of EGFR by EGF leads to the binding and ubiquitylation of the receptor by c-Cbl, which then recruits CIN85 to EGFR and Cbl complex to initiate the receptor endocytosis [XREF_BIBR, XREF_BIBR - XREF_BIBR]."
25005938
reach
"We propose that while indirect binding of Cbl to the EGFR via Grb2 is required for a ubiquitination pattern allowing endocytosis through clathrin coated pits, direct binding of Cbl to the EGFR is requ[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
15475003
biogrid
No evidence text available
23799367
biogrid
No evidence text available
18316398
sparser
"The Cbl-bound activated EGFR is ubiquitinylated and recognition of ubiquitin signal by the endosomal protein complex required for transport (ESCRT) protein complexes facilitates sorting of the receptor into inner vesicles of the multivesicular body for eventual lysosomal degradation ( xref xref xref )."
20940296
sparser
"C-Cbl binds EGFR in the absence or presence of EGF xref ."
32114396
biogrid
No evidence text available
22394513
reach
"The modified parameters were the rate constant for the forward reaction of the EGFR phosphorylation (k 3), the binding of EGFR to Cbl (k 5), GAP (k 7), and Shc (k 8) (steps 3, 5, 7, and 8)."
21333004
sparser
"Using rapamycin-inducible heterodimerization we show that c-Cbl is unable to associate with ErbB1 in a ErbB1-ErbB2 heterodimer most likely because ErbB2 is unable to phosphorylate the c-Cbl binding site on ErbB1."
10490623
sparser
"Indeed, it has been reported that the estrogen receptor beta-1 (ERβ1) induces the degradation of EGFR by enhancing the EGFR-Cbl interaction in basal-like breast cancer cells."
33114139
reach
"The interaction of CIN85 with EGFR and Cbl complex and phosphatidic acid targeted the internalized proteins to membrane areas enriched with fusogenic lipid."
25005938
sparser
"This novel result suggests that HPV16 E5 may, at least in part, upregulate EGFR-mediated signal transduction by inhibiting the interaction of c-Cbl with the EGFR, thereby decreasing c-Cbl-mediated degradation of the EGFR."
15735736
sparser
"As shown, lnc-EGFR, but not its R1 mutant or control diminished the interaction of EGFR with c-CBL ( xref ), suggesting that lnc-EGFR binds to EGFR, blocking its ubiquitination by c-CBL and the subsequent degradation."
28541302
reach
"Following ligand activation, the EGFR is bound by c-Cbl which promotes receptor internalization and degradation [47]."
11223028
reach
"EGFR interacted with Cbl-b and c-Cbl in PC9/GR cells; however, the interaction was greater in the si-MYO1D-treated cells."
| PMC
biogrid
No evidence text available
25521828
sparser
"Despite rapidity of the EGF effect, we observed no association of c-Cbl with activated ErbB-1, implying that the interaction is indirect."
8649804
sparser
"These results are in good agreement with previous findings showing that blocking c-Cbl binding to the EGFR is enough to inhibit EGFR internalization by the NCE pathway [ xref ], and that both c-Cbl and EGFR concentrations are determinants for the cellular activation and extension of the pathway [ xref ]."
33202887
reach
"In cell culture studies, the indirect binding of EGFR to Cbl through Grb2 is necessary for receptor internalization, whereas endosomal sorting requires direct binding to Cbl XREF_BIBR, XREF_BIBR."
21340027
biogrid
No evidence text available
10428778
biogrid
No evidence text available
22833562
reach
"Based on the high ubiquitination level seen after HB-EGF, it is surprising that we found a low c-Cbl binding to EGFR after this ligand (see discussion)."
19531065
biogrid
No evidence text available
23457600
sparser
"In in vitro experiments using His-CDC34 purified from E. coli and Flag-EGFR from 293T cells, we found that increased levels of c-Cbl supressed CDC34-EGFR interaction ( xref m), while increased dosages of CDC34 diminished c-Cbl-EGFR binding ( xref n)."
32114396
biogrid
No evidence text available
23153581
sparser
"Furthermore, we analyzed the binding of EGFR to Cbl, a known regulator of this receptor's ubiquitination [ xref , xref ]."
27811356
sparser
"In the presence of EGFcyt, coimmunoprecipitation of c-Cbl with EGFR revealed reduced c-Cbl–EGFR interaction compared with mock, which increased markedly on EGF treatment."
22745586
biogrid
No evidence text available
23897813
reach
"Through the constitutive CIN85-endophilin interaction, CIN85 links EGFR and Cbl complex with endocytic machinery of clathrin coated pits [XREF_BIBR, XREF_BIBR]."
25005938
sparser
"Moreover, the binding of CBL to EGFR followed the same pattern as ubiquitination, with CBL again binding to EGFR at low doses during mitosis, but not during interphase."
30544639
sparser
"However, temporal differences in their regulatory activities are apparent since c-Cbl interaction with EGFR is strongest at an early stage of EGFR trafficking when the receptor is rapidly ubiquitinate[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
26093903
reach
"However, the association between c-Cbl and EGFR was transient in cells treated with AR in that there was virtually no co-immunoprecipitation after 5 and 15 min."
19173594
sparser
"Cbl's variant SH2 domain binds to phosphotyrosine 1045 of the activated EGF receptor [14] ."
16246327
biogrid
No evidence text available
21772844
hprd
No evidence text available
18273061
biogrid
No evidence text available
19836242
trips
"We found that ephrinA5 enhanced c-Cbl binding to EGFR, thus promoted ubiquitylation and degradation of the receptor."
19270726
sparser
"For example, both EGFR and ErbB4 have multiple binding sites for the adaptor proteins Shc and Grb2, but only EGFR binds the ubiquitin ligase Cbl, whereas ErbB4 is unique in binding Nck."
16738552
biogrid
No evidence text available
26177020
biogrid
No evidence text available
17971399
biogrid
No evidence text available
16105874
reach
"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
sparser
"Following ligand activation, the EGFR is bound by c-Cbl which promotes receptor internalization and degradation [47] ."
11223028
reach
"However, we have previously established that binding of Cbl to the EGFR, as well as EGFR ubiquitination, are strongly reduced in the EGFR-Y1045+ mutant, and absent or negligible in EGFR-Y1068/86+ mutant XREF_BIBR."
26264748
reach
"Thus, we concluded that delta-catenin may interfere with direct binding between c-Cbl and EGFR phosphorylated at Tyr1045."
29629558
sparser
"EGFR activation results in the binding of Cbl to EGFR Tyr1045 for LIRD, and this EGFR downregulation was impaired in EGFR mutant-expressing cells."
25742791
sparser
"Inhibiting p38 kinase by the kinase inhibitor or knockdown by RNAi causes significant reduction of tyrosine phosphorylation at Y1045 of EGFR, which is required for EGFR binding to the E3 ubiquitin ligase Cbl, thus results in defect in ubiquitination and degradation of EGFR [ xref ]."
27034618
sparser
"It was reported that PTEN promotes ubiquitylation and downregulation of receptor tyrosine kinases such as epidermal growth factor receptor (EGFR) by enhancing the formation of the EGFR–CBL complex (Vivanco et al, xref )."
22730341
sparser
"We demonstrated that a physiological concentration of AR induced recycling of endogenous EGFR to the plasma membrane, which correlated closely with transient association of EGFR with c-Cbl and transient EGFR ubiquitination."
19173594
sparser
"C-Cbl binds to tyrosine-phosphorylated EGFR through its tyrosine-kinase-binding (TKB) domain, allowing recruitment of ubiquitin conjugating enzymes and transfer of ubiquitin to phosphorylated EGFR."
23774213
sparser
"Altogether, our results suggest that USP25, by affecting c-Cbl binding to the EGFR, could protect the receptor from c-Cbl-mediated ubiquitylation."
33202887
sparser
"Moreover, we scored a slight but reproducible increase in the physical interaction between c-Cbl and the activated EGFR in the absence of USP25, suggesting that the depletion of USP25 could favor EGFR/c-Cbl interaction."
33202887
biogrid
No evidence text available
18273061
reach
"C-Cbl, an E3 ubiquitin ligase, inactivates ligand bound EGFR through EGFR and Cbl complex formation leading to its degradation [XREF_BIBR]."
24387052
sparser
"Interestingly, c-Cbl does not interact with other EGFR family members, including HER2 ( Levkowitz et al., 1996 )."
14507736
biogrid
No evidence text available
19531499
biogrid
No evidence text available
11370743
sparser
"Moreover, the lack of FLNa interfered with EGFR interaction with the ubiquitin ligase c-Cbl."
19213840
sparser
"In contrast, direct binding of Cbl to phosphotyrosine 1045 of the epidermal growth factor receptor was required for epidermal growth factor receptor polyubiquitination, but was not essential for Cbl-yellow fluorescent protein localization in epidermal growth factor receptor-containing compartments."
12839496
reach
"However, temporal differences in their regulatory activities are apparent since c-Cbl interaction with EGFR is strongest at an early stage of EGFR trafficking when the receptor is rapidly ubiquitinate[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
26093903
reach
"Similarly, GAPex5, a Rab5 exchange factor, inhibits binding of Cbl to EGFR by an unknown mechanism not mediated by Rab5 [XREF_BIBR]."
18793634
biogrid
No evidence text available
8662998
sparser
"Several studies have shown that c-Cbl can bind to EGFR either directly to the phosphorylated Tyr1045 residue or indirectly via Grb2 ( xref )."
29629558
reach
"For example, both EGFR and ErbB4 have multiple binding sites for the adaptor proteins Shc and Grb2, but only EGFR binds the ubiquitin ligase Cbl, whereas ErbB4 is unique in binding Nck."
16738552
reach
"As described above, binding of the ubiquitin ligase Cbl to EGFR is central in the downregulation."
18288481
reach
"A model compatible with most current data is that c-Cbl binds to kinase-active EGFR, mediates receptor ubiquitination, and then dissociates."
12648467
sparser
"C-Cbl binds only to tyrosine-phosphorylated EGFR."
18765569
reach
"However, delta-catenin did not affect the binding between c-Cbl and the EGFR Y1045F mutant, suggesting that indirect binding of c-Cbl to EGFR via Grb2 is not affected by delta-catenin."
29629558
biogrid
No evidence text available
17880946
sparser
"Since E5 has been shown to form a complex with the EGFR, we tested the hypothesis that E5 affects the interaction of c-Cbl with the EGFR."
15735736
sparser
"Numerous studies suggest that under conditions of normal signaling, Cbl can efficiently interact with the EGF receptor but not with ErbB2, ErbB3 or ErbB4."
11248544
biogrid
No evidence text available
15383614
sparser
"C-Cbl binds tyrosine-phosphorylated EGFR both directly, through its SH2 domain ( xref ; xref ), and indirectly, via Grb2 ( xref ; xref ; xref ), and ubiquitinates EGFR."
18765569
sparser
"A dramatic increase in c-Cbl binding to EGFR in KS cell lysates was observed, with or without treatment with concanamycin A ( xref e), suggesting that increased constitutive c-Cbl binding in the absence of kindlin-1 may result in increased targeting of EGFR for lysosomal degradation."
30248333
reach
"In HCC827 cells without EGF co-incubation, silencing of CDC34 led to increased recruitment of c-Cbl by EGFR; upon erlotinib treatment, knockdown of CDC34 reduced EGFR and c-Cbl interaction."
32114396
reach
"The association between EGFR and Cbl was markedly reduced in SUM102-Brk cells compared with SUM102-neo cells at 15, 30, and 90 min after EGF stimulation (XREF_FIG)."
22231447
sparser
"Consistent with this idea, Cbl's PTB domain selectively interacts with the EGFR in EGF-stimulated cells (unpublished results)."
9675877
sparser
"Control experiments confirmed retention of EGFR binding by the mutant form of c-Cbl."
10635327
sparser
"The interaction between EGFR and c-Cbl has been shown to depend upon receptor phosphorylation at tyrosine residue 1045, the major docking site for c-Cbl."
16969069
sparser
"Compared with parental DiFi cells that express high levels of EGFR and in which cetuximab induces apoptosis, the cetuximab-resistant DiFi5 cells showed markedly lower protein levels of EGFR, an increased association of EGFR with Cbl, and an increased ubiquitination of EGFR."
17804738
sparser
"We found a significant decrease of c-Cbl bound to the EGFR and of ubiquitinated EGFR in the presence of E5."
15735736
sparser
"Western blot analysis revealed that c-Cbl was able to interact with EGFR and this interaction was unaffected by the presence of the SGR (WT or PA2) ( xref )."
25872741
sparser
"The interaction between CBL and EGFR can also be mediated by other interactors such as the adaptor proteins Grb2 and CIN85."
35159106
biogrid
No evidence text available
19531499
biogrid
No evidence text available
7592693
reach
"Thus, CIN85 tethers EGFR and Cbl complex to the endocytic machinery in an EGF dependent manner [XREF_BIBR]."
25005938
reach
"Furthermore, we analyzed the binding of EGFR to Cbl, a known regulator of this receptor 's ubiquitination [XREF_BIBR, XREF_BIBR]."
27811356
sparser
"To elucidate the mechanism by which Brk inhibits EGFR degradation, we compared the levels of EGFR ubiquitination and the association of EGFR with Cbl, an E3 ubiquitin ligase known for regulating EGFR degradation ( xref ), in SUM102-neo and SUM102-Brk cells after EGF stimulation."
22231447
reach
"The phosphotyrosine interaction site in the c-Cbl TKB domain is basic, and therefore, we expected that the addition of phosphate group (s) on Ser1070 and Ser1071 would have enhanced the interaction between EGFR and c-Cbl."
20877636
reach
"Thus, binding of Cbl to the activated EGFR and recruitment of CIN85 couples EGFR to clathrin mediated endocytosis [XREF_BIBR]."
12559039
sparser
"In summary, our data show a direct interaction between kindlin-1 and EGFR that acts to restrict c-Cbl–EGFR association and thus protect EGFR from lysosomal degradation."
30248333
trips
"Since E5 has been shown to form a complex with the EGFR, we tested the hypothesis that E5 affects the interaction of c-Cbl with the EGFR."
15735736
sparser
"We demonstrated that a physiological concentration of AR induced recycling of the endogenous EGFR to the plasma membrane, which correlated closely with transient association of the EGFR with c-Cbl and transient EGFR ubiquitination."
19173594
sparser
"SGCE loss increases degradation of epidermal growth factor receptor (EGFR) through enhanced interaction between EGFR and its ubiquitination ligase c‐Cbl, providing a potential mechanism for understanding the failure of EGFR‐targeted treatment in breast cancer."
32714745
reach
"EGFRvIII can associate with overexpressed Cbl and this leads to downregulation."
18288481
reach
"23 It has been shown that direct or GRB2 mediated binding of CBL to EGFR is required for multiple mono-ubiquitylation of the activated receptor."
20619386
biogrid
No evidence text available
23799367
sparser
"Other proteins that are capable of binding to Cbl and/or EGFR and implicated in the regulation of EGFR internalization and degradation are: Alix [ xref ], c-Abl tyrosine kinase [ xref ], Sts1/TULA2 [ xref ], Lrig-1 [ xref ], and supressors of cytokine signaling SOCS4/5 [ xref ]."
18793634
sparser
"The CBL bound to the EGFR is also able to ubiquitinate EGFR."
30544639
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
"In this study, we also showed that berberine stimulated ubiquitin ligase Cbl activation and Cbl 's interaction with EGFR, and EGFR ubiquitinylation and down-regulation in these two cell lines in the presence or absence of EGF treatment."
23457600
reach
"Binding of EGFR or PDGFR to Cbl leads to ubiquitination of the receptor and subsequent degradation by the proteosome (Joazeiro et al. 1999)."
11057895
sparser
"It is possible that the combined presence of C225 and ZD1839 may alter the interaction of Cbl with EGFR by a conformational change induced in EGFR."
15756277
reach
"We also found that binding between EGFR and c-Cbl is decreased in the presence of delta-catenin."
29629558
reach
"Interestingly, we observed that PLEK2 inhibited the interaction between EGFR and c-CBL (Fig. 4f)."
31182136
biogrid
No evidence text available
23175185
reach
"In contrast, Cbl binding to EGFR via Grb2 is necessary for receptor internalization."
18288481
sparser
"To investigate whether direct interaction of Cbl with the EGFR is essential for lysosomal sorting, the degradation of wt EGFR and Y1045F EGFR was compared (A)."
15475003
biogrid
No evidence text available
24714105
reach
"However, it has no effect on the indirect binding of c-Cbl to EGFR via Grb2."
29629558
sparser
"The relative contribution of indirect (Grb2-mediated) and direct (TKB-mediated) interactions of Cbl with EGFR may vary in different cell types."
18793634
sparser
"EGFR phosphorylation at Y1068 and Y1086 induces recruitment of the adapter protein Grb2, which then allows binding of c-Cbl to EGFR Y1045."
23633955
sparser
"Overall, increasing amounts of c-Cbl were interacted with EGFR in control cells, while c-Cbl-EGFR interaction levels were reducing in CTEN transfectants during the time course ( xref )."
23774213
sparser
"To further investigate the association between EGFR and c-cbl, co-immunoprecipitation analysis showed the increased association of c-cbl and EGFR by brefeldin-A (figure xref )."
24457597
reach
"During EGFR internalization CIN85 bridges EGFR and Cbl complex, endocytic machinery and fusible membrane through the interactions of CIN85 with c-Cbl, endophilins and phosphatidic acid."
25005938
sparser
"Taken together, these results strongly indicate that 14-3-3σ can inhibit EGF-induced EGFR-Cbl association and subsequent Cbl-mediated EGFR ubiquitination."
33391517
sparser
"Consequently, Spry2 can decrease Cbl-EGFR interactions, thereby inhibiting receptor desensitization processes."
12593795
trips
"Interactions of Cbl with the EGF receptor and multiple downstream signaling proteins suggest a role for this proto-oncogene product in mitogenic signaling through growth factor receptor kinases."
8662998
reach
"delta-Catenin and c-Cbl competitively bind EGFR."
29629558
sparser
"The association of c-Cbl with EGFR is regulated by both protein-protein interactions and tyrosine phosphorylation."
27903975
reach
"Ubiquitylation of EGFR is mediated by the E3 ligase Cbl (c-Cbl and Cbl-b isoforms) that can directly bind to EGFR via phosphorylated Tyr1045 and indirectly through the interaction with the SH2-SH3 adaptor protein Grb2 that binds to phosphorylated Tyr1068 and Tyr1086 in the EGFR [reviewed in]."
26251007
reach
"The recruitment of CIN85 by c-Cbl in EGFR and Cbl complex has been indicated as the initial step for EGFR internalization [XREF_BIBR]."
25005938
reach
"The relevance of cooperativity became evident when we compared simulations of cooperative and noncooperative models, in terms of how Cbl is bound to the EGFR : through pY1045 only (singly bound) or through pY1045 and pY1068 and pY1086 via Grb2 (doubly bound)."
26264748
sparser
"This would probably affect the amount of EGFR-bound Cbl."
21085658
biogrid
No evidence text available
11408594
biogrid
No evidence text available
15677445
reach
"One prominent regulator involved in lyososomal degradation of EGFR is the E3 ubiquitin ligase c-Cbl, which binds to active EGFR and then facilitates its poly-ubiquitination and lysosomal degradation [357,358]."
32796709
reach
"The EGFR has been reported to be multiply monoubiquitinated [57,58], as well as polyubiquitinated [59], and we have previously suggested that direct or indirect binding of Cbl to the EGFR could elicit[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
16859684
reach
"After EGFR internalization, CIN85, associated to EGFR and Cbl complex, appears on endosomal membrane."
25005938
biogrid
No evidence text available
25872741
sparser
"This inhibits the binding of Cbl by the EGF receptor and thus prevents Cbl from catalyzing receptor ubiquitination."
14505571
sparser
"This indicates that the lysosomal sorting of EGFR is inhibited in cells expressing the Y1045F EGFR and is consistent with the view that the direct interaction between activated EGFR and Cbl through ph[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
15475003
sparser
"It has already been established that the E3 ligase c-Cbl is negatively regulated by activated Cdc42, which inhibits interaction of c-Cbl and EGF receptor and prevents c-Cbl-mediated ubiquitination of [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
16084064
sparser
"Src activation has been shown to be increased in a CRC cell line with cetuximab resistance. xref Resistant cells were characterized by markedly lower protein levels of EGFR, an increased association of EGFR with Cbl, and a high level of Src-416 phosphorylation both at baseline and on EGF stimulation."
20378502
sparser
"These results suggest that BASP1 may influence CBL binding to EGFR to prevent its ubiquitination."
33042262
reach
"One such molecule is the ubiquitin ligase Cbl, which binds to the EGFR via a pY mediated mechanism and ubiquitinates the receptor XREF_BIBR."
26264748
reach
"71 Here, E3 ligase Cbl binds phosphotyrosine residues of the activated EGF receptor (EGFR)."
25541750
reach
"As shown in Fig. 4, PLEK2 could suppress the binding between c-CBL and EGFR, and the function of PLEK2 overexpression on EGFR was abolished by c-CBL ectopic expression."
31182136
sparser
"Combining this with the data from Grøvdal et al. [ xref ], who described that a direct association of c-Cbl with EGFR pY1045 was important for MVB sorting of EGFR, we surmised that aberrant EGFR sorting into lysosomes in RBE cells was caused by an impaired association between c-Cbl and EGFR through pY1045."
22591401
sparser
"We then hypothesized that if TRPV1 could recruit the Cbl protein to EGFR, then Cbl binding with EGFR should be enhanced with increasing amounts of TRPV1."
19155296
sparser
"Thus, unlike AR, EGF stimulates c-cbl binding to EGFR, EGFR ubiquitination, and EGFR degradation ( xref )."
19135477
biogrid
No evidence text available
15107835
reach
"Whereas K63 linked polyubiquitin targets the Cbl and EGFR complex to the lysosome, K48- or K29 linked polyubiquitination might deliver the protein to the proteasome for degradation 37."
25081058
sparser
"Taken together with the above results shown in the Western blot analysis (A and B), these results strongly suggest that the internalized EGFR induced by anisomycin are not associated with c-Cbl."
19138820
reach
"A significant finding from the present study is that berberine down-regulates EGFR through activation of Cbl and increasing Cbl interaction with EGFR."
23457600
sparser
"These data strongly suggest that CTEN may regulate the dynamic of c-Cbl-EGFR interaction."
23774213
reach
"A dramatic increase in c-Cbl binding to EGFR in KS cell lysates was observed, with or without treatment with ConA, suggesting that increased constitutive c- Cbl binding in the absence of kindlin-1 may[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
30248333
sparser
"However, the binding between EGFR and δ-catenin was not affected by c-Cbl in the absence of EGF, indicating that c-Cbl binding to EGFR in the presence of EGF decreases the binding between EGFR and δ-catenin."
29629558
sparser
"CTEN reduces ligand-induced ubiquitination of EGFR and modulates c-Cbl-EGFR interaction."
23774213
sparser
"As shown in Figure  xref C, no matter whether the mutants could interact with c-Cbl (CIN85-B4m) or not (CIN85-ΔCC or CIN85-A4m), the presence of CIN85 mutants had no effect on EGFR-Cbl interaction."
25005938
sparser
"Interestingly, we also observed that binding of c-Cbl to EGFR was decreased in the presence of δ-catenin ( xref )."
29629558
biogrid
No evidence text available
16969069
sparser
"In a study about the EGFR-ERK signaling pathway, the reaction rate of c-Cbl and EGFR binding was reduced by a factor of 100 or 1000 by regulating an ODE model to mimic the effects of the endocytosis impairment."
26697484
reach
"As expected, we observed that in the presence of EGF delta-catenin reduced the binding between EGFR and c-Cbl, which in turn led to a decreased ubiquitination and lysosomal degradation of EGFR."
29629558
sparser
"The decrease in ubiquitylation was accompanied by the inhibition of Cbl binding to the EGFR."
16280034
trips
"c-Cbl, a tyrosine phosphorylation substrate shared by several signaling pathways, accelerates desensitization by recruiting EGFR and increasing receptor polyubiquitination."
10428778
reach
"Cbl binds to activated EGFR and recruits CIN85."
21275903
sparser
"C-Cbl can bind to the EGFR either directly or indirectly via Grb2 in an SH3 domain-directed fashion ( xref )."
25872741
reach
"This block to Cbl and EGF-R complex formation and subsequent EGF-R ubiquitination is alleviated through Cbl mediated polyubiquitination of associated Sprouty2, which results in Sprouty2 degradation by[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
16246327
reach
"Cbl proteins can bind to the EGFR via two types of interactions."
12559039
biogrid
No evidence text available
9121472
sparser
"SGCE Knockdown Promotes Interaction between EGFR and c‐Cbl."
32714745
biogrid
No evidence text available
20940296
sparser
"The EGF-activated EGFR is also associated with Cbl in early endosomes, resulting in continued ubiquitination of EGFR (Duan et al. xref ; Longva et al. xref )."
18288481
sparser
"In contrast, the protein level of c-Cbl that binds EGFR was reduced upon CDC34 overexpression, in the absence and presence of EGF ( xref l, left panel; supplementary Fig. 5f)."
32114396
sparser
"We have previously reported that Cbl interacts with EGFR in MECs ( xref )."
20940296
sparser
"Therefore, we suggest that PTK6 negatively affects EGF receptor endocytosis through multiple pathways: through phosphorylation of ARAP1, through phosphorylation and consequent auto-ubiquitination of c[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
23352614
sparser
"Concomitant with increased c-Cbl auto-ubiquitination, H 2 O 2 treatment increased c-Cbl interaction with EGFR along with increased EGFR ubiquitination ( xref ), suggesting that c-Cbl mediates EGFR ubiquitination."
24583314
sparser
"Mechanistically, the EGFR Y1069C mutation disrupted the binding of the ubiquitin ligase c-CBL to EGFR, whereas the ERBB2 E936K mutation selectively enhanced the activity of ERBB heterodimers."
33323455
reach
"The ubiquitin ligase, Cbl, binds to the activated EGFR and promotes monoubiquitylation of the activated EGFR at the plasma membrane."
19155296
sparser
"The modified parameters were the rate constant for the forward reaction of the EGFR phosphorylation ( k 3 ), the binding of EGFR to Cbl ( k 5 ), GAP ( k 7 ), and Shc ( k 8 ) (steps 3, 5, 7, and 8)."
21333004
biogrid
No evidence text available
20877636
reach
"The fact that AR induced c-Cbl phosphorylation lasted longer (XREF_FIG) than AR induced association between c-Cbl and EGFR or EGFR ubiquitination (XREF_FIG, respectively), suggests that deubiquitinating enzymes acted on EGFR prior to dephosphorylation and inactivation of c-Cbl."
19173594
sparser
"Interaction of the EGFR with the ubiquitin ligase c-Cbl is essential for efficient receptor down-regulation."
15519654
sparser
"EGFRvIII can associate with overexpressed Cbl and this leads to downregulation (Davies et al. xref )."
18288481
sparser
"In addition, Cbl proteins (c-Cbl, Cbl-b and Cbl-c) can bind the EGFR directly via their N-terminal tyrosine kinase binding (TKB) domain to EGFR phosphoTyr 1045 and indirectly via Grb2 (vide supra) [[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
19263517
sparser
"Our study found that CTTN expression in CRC cells increased EGFR protein levels, and inhibited the association of EGFR with c-Cbl."
27903975
reach
"In our study, we investigated whether delta-catenin can affect direct or indirect binding of c-Cbl to EGFR."
29629558
reach
"So far through a series of three studies [XREF_BIBR - XREF_BIBR] we found that (1) EGCG alters lipid organization on the plasma membrane, (2) EGCG promote the internalization of nonactivated monomer EGFR into cytosol, thus, inhibiting the activation of EGFR by EGF, (3) as a result, treatment with EGCG causes marked reduction of phosphorylated (activated) EGFRs, that are otherwise preferentially present in lipid rafts, (4) EGCG induced EGFR internalization requires neither the binding of c-Cbl to EGFR nor a phosphorylation of EGFR at tyrosine residue, suggesting that this internalization is mediated by a different mechanism that is observed in EGF treated cells, and (5) phosphorylation of EGFR at serine1046/1047 mediated by p38MAPK is essential for EGCG induced EGFR internalization (XREF_FIG)."
21274257
trips
"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
"Recently, Grøvdal et al. showed that direct binding of Cbl to the EGF receptor is critical for lysosomal sorting of receptors, in contrast to the indirect binding via Grb2 [15] ."
17904548
reach
"On the other hand, the protooncogene Cbl forms a complex only with ErbB1 (Levkowitz et al. 1996)."
10648571
biogrid
No evidence text available
16923119
sparser
"CBL-interacting protein of 85 kDa (CIN85) mediates the interaction between CBL and EGFR and hence is involved in the downregulation of EGFR (Soubeyran et al., xref ; Haglund et al., xref )."
28066764
reach
"We found that delta-catenin had no effect on binding between the EGFR Y1045F mutant and c-Cbl (XREF_FIG), which suggests that delta-catenin decreases the direct binding between c-Cbl and EGFR at phosphorylated Tyr1045."
29629558
reach
"Ruk and CIN85 acts as a scaffolding protein that regulates various biochemical pathways, such as recruiting the Cbl and EGFR complex to endosomes for downregulation of the receptor [21,22], cytoskelet[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
19166927
sparser
"Interestingly, the formation of a complex between SPRY2 and c-Cbl also affects the EGF/EGFR-induced signaling because c-Cbl normally binds to the activated EGFR and promotes its ubiquitylation and degradation xref ."
27539669
sparser
"In conclusion, c-Cbl interacts with EGFR in an inducible manner primarily through an autophosphorylated tyrosine 1045 of the receptor."
10635327
reach
"EGFR and c-Cbl complexes bound to endocytic proteins travel from early endosomes to late endosomes and MVBs, where Vps23 and ESCRT-I recognizes the ubiquitinated EGFR and/or monoubiquitinated CIN85 and/or endocytic proteins."
19489726
sparser
"Consistent with other studies, our previous study demonstrated that the pSpry2 and pEGFR peptides interact with c-Cbl TKB through (1) a positively-charged pocket into which the phosphorylated tyrosine inserts and establishes the majority of the hydrogen bonds, and (2) a hydrophobic cluster, which forms significant interactions with the conserved C-terminal proline residue of the bound peptide."
20877636
sparser
"Lack of tyrosine phosphorylation at residue 1045 of EGFR was associated with the blockade of c-Cbl/EGFR interaction, inhibition of c-Cbl-mediated EGFR internalization, and degradation or EGFR ubiquiti[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
15958209
sparser
"In particular, we observed a reduced phosphorylation of Y1045, Y1086 and Y1068 residues, followed by a decreased Grb2/EGFR interaction and association between EGFR and c-Cbl leading to a reduced ubiqu[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
18358509
sparser
"On the other hand, it has been reported that c-Cbl interacts with EGFR either directly through phosphorylated Tyr1045, or indirectly through Grb2 ( xref )."
29629558
sparser
"The RING-finger E3 ubiquitin ligase CBL binds to EGFR and favors its ubiquitination for lysosomal degradation [ xref ], whereas the E3 ubiquitin ligase CHIP promotes HER2 ubiquitination/degradation [ xref ]."
27203743
biogrid
No evidence text available
14505571
reach
"As can be seen from XREF_FIG, all ligands stimulate c-Cbl binding to EGFR, but the association is more prolonged after EGF and BTC stimulation than the remaining ligands."
19531065
reach
"The inhibition resulted from loss of the recruitment of Cbl to EGFR [XREF_BIBR], and loss of binding of the Src homology (SH) -3 domain of Grb2 to an unidentified protein (s) containing poly-proline motif (s), possibly subunits of the AP2 complex [XREF_BIBR]."
22617029
reach
"These data suggest that the binding of Cbl to epidermal growth factor receptor through Grb2 is necessary and sufficient for Cbl function during clathrin mediated endocytosis."
12839496
reach
"In addition, Cbl can bind indirectly to the EGFR via Grb2 [XREF_BIBR]."
18318691
sparser
"A model compatible with most current data is that c-Cbl binds to kinase-active EGFR, mediates receptor ubiquitination, and then dissociates."
12648467
reach
"In agreement with the autophosphorylation data, c-Cbl and Grb2 interact strongly with EGFR homodimers, and poorly with EGFR : HER2 heterodimers (XREF_FIG)."
23027125
sparser
"23 c-Cbl associates with an activated EGF receptor before endocytosis and mediates its ubiquitination, which serves as docking site for EPS15R and EPS15."
18395097
sparser
"The binding of activated Cdc42 to a βPix-Cbl complex here was thought to sterically interfere with the binding of Cbl to the EGF receptor, thus preventing E3 ligase activity."
16356860
biogrid
No evidence text available
15159412
sparser
"Cbl binds EGFR directly through its TKBD and indirectly through growth factor receptor binding 2-mediated interactions in the region C-terminal to the RING domain [ xref ]."
27609087
sparser
"The role played by Cdc42 in regulating the timing of EGF receptor-Cbl interactions is underscored by the fact that constitutively active Cdc42(F28L), by persistently blocking the binding of Cbl to these receptors, leads to their aberrant accumulation and sustained EGF-stimulated ERK activation, thus resulting in cellular transformation."
14505571
biogrid
No evidence text available
15117950
biogrid
No evidence text available
12803489
sparser
"This is consistent with the notion that direct binding of Cbl to the EGFR is not essential for initial internalization of activated EGFR."
15475003
sparser
"As previously mentioned, the most carboxyl-terminal portion of c-Cbl is also predicted to form a leucine zipper capable of mediating homodimerization of c-Cbl, and the deletion of this region decrease[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
12507554
sparser
"At the same time, we found a correlation between the levels of EGFR-Cbl association and EGFR-14-3-3σ association in HCC cells transfected with increasing amounts of 14-3-3σ constructs."
33391517
reach
"This significant reduction in stable protein complexes suggests a " hit and run " mechanism through which a subset of Cbl truncation mutants can enhance EGF-R ubiquitination during rapid on-off cycles[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
16246327
sparser
"Taken together, these data indicated that the SH3-binding domain of NS5A modulated the ubiquitination status of EGFR, but this was not due to the inhibition of c-Cbl–EGFR binding."
25872741
sparser
"Co-IP experiments also showed that EGF stimulates the interaction between EGFR and CBL."
30544639
sparser
"SGCE stabilizes the level of EGFR by breaking the interaction between c-Cbl and EGFR, activating the PI3K/Akt pathway to foster breast cell stemness [ xref ]."
36230903
biogrid
No evidence text available
18273061
reach
"Catalytic activation of EGFR is also necessary for EGFR and CBL complex formation and CBL dependent ubiquitylation of EGFR."
20421427
sparser
"In CC cells, however, EGFR signaling is sustained because the association of EGFR with c-Cbl is prevented, precluding c-Cbl-mediated EGFR degradation [ xref ]."
32708604
sparser
"A loss of CBL activity, whether by inactivating mutations to CBL or EGFR CBL-binding, would therefore have a more pronounced effect during mitosis, as the EGFR would continue to signal excessively."
30544639
reach
"C-Cbl binds EGFR in the absence or presence of EGF XREF_BIBR."
32114396
reach
"The interaction of CIN85-SH3 with c-Cbl competes off the binding of functional CIN85 to EGFR and Cbl complex."
25005938
sparser
"In this study, we also showed that berberine stimulated ubiquitin ligase Cbl activation and Cbl's interaction with EGFR, and EGFR ubiquitinylation and down-regulation in these two cell lines in the presence or absence of EGF treatment."
23457600
biogrid
No evidence text available
16849543
sparser
"Studies of fibroblasts overexpressing human EGFR showed that transforming Cbl mutant expression was associated with increased EGFR phosphorylation [ xref ]."
23085373
biogrid
No evidence text available
19225046
reach
"Binding between c-Cbl and EGFR was reduced as the amount of delta-catenin was increased (XREF_FIG)."
29629558
sparser
"These findings suggest that low expression of peritumoral Cbl and EGFR were positively associated with tumor size, microvascular invasion and patients survival after hepatectomy, highlighting the key role of peritumoral liver milieu in HCC progression."
26474280
sparser
"Conversely, knockdown of 14-3-3σ in HCC cells markedly increased the levels of EGFR-Cbl association and EGFR ubiquitination (Figure xref F)."
33391517
reach
"Another possibility is the adaptor protein c-Cbl, which preferentially associates with EGFR [29], and which provides a docking site for p85 [30]."
11853876
reach
"A further immuno coprecipitation assay was conducted to examine the binding of EGFR and c-Cbl and EGF, but not anisomycin, induced the EGFR binding to c-Cbl."
19138820
sparser
"In the early steps of EGFR internalization, USP25 could inhibit EGFR degradation by promoting the association of the E3 ubiquitin ligase c-Cbl with EGFR ( xref )."
34249948
sparser
"Cbl binds to EGFRs at the plasma membrane and they remain associated in a complex throughout the endocytic route [11 • ] ."
12648667
sparser
"In the same experiment, the interaction between c-Cbl and EGFR was analyzed."
23774213
sparser
"The E3 RING ligase Cbl, which contains c‐Cbl, Cbl‐b, and Cbl‐c, can directly bind to EGFR. [ xref ] Furthermore, GRB2, as an adaptor protein [ xref , xref ] between Cbl and EGFR, can cause EGFR ubiquitination and lysosomal degradation. [ xref , xref , xref ] Thus, we investigated whether SGCE loss changed the interaction between EGFR and the Cbl family or GRB2."
32714745
sparser
"Cbl proteins can bind to the EGFR via two types of interactions."
12559039
sparser
"Consistent with the transforming effect of blocking EGFR–Cbl interaction, the respective artificial mutants of either Cbl ( Andoniou et al. 1994 ) or EGFR ( Lee et al. 1993; Traverse et al. 1994 ) are[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
10635327
reach
"Therefore, we analyzed the interaction between c-Cbl and EGFR in cells stimulated for 5 min with EGF using an experimental procedure in which immunoprecipitation of cell lysates with anti-EGFR was fol[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
22974559
sparser
"The reduced ubiquitination was expected, given the reported finding that Cbl binds to pTyr1045 in the EGFR ."
15475003
biogrid
No evidence text available
26055326
sparser
"Immunoprecipitation, RNA pull-down, and RNA fluorescence in situ hybridization (RNA-FISH) assays were used to test the interaction of c-Cbl with LINC01485 and EGFR."
32904620
sparser
"We found that δ-catenin binds closely to sites EGFR Y1045 and competes with c-Cbl for EGFR binding leading to reduction in binding between EGFR and c-Cbl."
29629558
reach
"Cbl forms a complex with phospho-EGFR and phospho-Vav2 and facilitates phospho-Vav2 ubiquitinylation."
20940296
biogrid
No evidence text available
20940296
sparser
"In breast cancer cells, ERβ1 inhibits EMT by enhancing the EGFR-c-Cbl interaction, thereby inducing EGFR degradation xref ."
28334634
sparser
"Similarly, depletion of ZNRF1 did not affect the association of EGFR and CBL ( xref )."
33996800
reach
"delta-Catenin decreases the direct binding between c-Cbl and EGFR."
29629558
biogrid
No evidence text available
17486068
reach
"Both direct binding of Cbl to the EGFR and indirect binding of Cbl to the EGFR through Grb2 has been reported to result in ubiquitination of the EGFR [6,11]."
15475003
biogrid
No evidence text available
12604776
biogrid
No evidence text available
7592693
reach
"The 16E5 effect on EGFR levels was similar to that seen by proteosomal inhibition, suggesting that interfering with the EGFR and c-Cbl interaction was an important contributor to E5 activation of EGFR."
25254385
sparser
"Since c-Cbl-CTEN interaction depends on c-Cbl tyrosine phosphorylation, which is relied on its binding to activated EGFR, this may explain the delay disruption of c-Cbl-EGFR interaction by CTEN."
23774213
reach
"However, the deletion mutation of LINC01485 (nucleotides 340-391) partially restored EGFR ubiquitination and the interaction between EGFR and c-Cbl."
32904620
reach
"XREF_BIBR RIN1 QM dominantly blocked ABL kinase activity and enhanced CBL protein recruitment to EGFR, XREF_BIBR supporting a negative role for RIN1 --> ABL signaling during CBL recruitment to EGFR."
24265854
reach
"The experimental analysis of Cbl binding to the EGFR suggested that the interaction between EGFR and Cbl is cooperative with the binding of Grb2 to the receptor XREF_BIBR."
26264748
biogrid
No evidence text available
11239464
reach
"CIN85-DeltaCC, on the other hand, can not interact with c-Cbl and is a bystander to EGFR and Cbl complex."
25005938
reach
"Recruitment of c-Cbl to the EGFR and ubiquitination of the receptor does not correlate after stimulation with AR and HB-EGF, and this could indicate that c-Cbl is not decisive for the ubiquitination of EGFR after stimulation with all ligands."
19531065
sparser
"C-Cbl associates with the EGFR at the plasma membrane and colocalizes in late endosomes and multivesicular bodies (MVBs), suggesting that c-Cbl associates with EGFR throughout the endocytic route ( xref )."
19489726
sparser
"Ligand-induced EGFR forms heterodimers with HER2 ( xref ); in turn, HER2 reduces degradation of EGFR ( xref ) by promoting ligand binding to EGFR and inhibiting binding of EGFR to its ubiquitin ligase Cbl ( xref )."
23948973
biogrid
No evidence text available
9130710
hprd
No evidence text available
8798643
sparser
"Consistent with the reduction in EGFR ubiquitination, the association of EGFR with c-Cbl was obviously decreased in Lv-WT MGC-803 cells than in vector control cells ( xref and xref )."
32904620
sparser
"Biochemical data has demonstrated that mammalian Cbl proteins directly bind to tyrosine-phosphorylated EGFR and ubiquitylates it for endocytosis and lysosomal degradation xref – xref ."
18197257
biogrid
No evidence text available
16246327
sparser
"The EGFR mutants were constitutively associated with the E3 ubiquitin ligase Cbl but did not associate with the adaptor protein CIN85 on the addition of ligand."
16849543
reach
"C-Cbl binds to EGFR either directly to phosphorylated Y1045 XREF_BIBR or through its association with another EGFR interacting protein Grb2 XREF_BIBR."
21949687
reach
"Lack of tyrosine phosphorylation at residue 1045 of EGFR was associated with the blockade of c-Cbl and EGFR interaction, inhibition of c-Cbl-mediated EGFR internalization, and degradation or EGFR ubiq[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
15958209
biogrid
No evidence text available
22976291
sparser
"To describe the dynamics of EGFR ubiquitination, we therefore restricted our analysis to the dynamics of the Cbl:EGFR interaction and assumed that ubiquitination is simply proportional to the amount of Cbl-bound EGFR (Equation 15 in xref )."
26264748
biogrid
No evidence text available
12061819
reach
"Consistence with the previous observation, increasing the amount of PLEK2 gradually inhibited the binding between EGFR and c-CBL (Fig. 4g)."
31182136
trips
"Coupling of the proto-oncogene product c-Cbl to the epidermal growth factor receptor."
7592693
sparser
"It is possible that Kindlin-2 may compete out the binding sites of some E3 ligases, for example, c-Cbl binding to EGFR and reduces c-Cbl action on EGFR."
25790908
reach
"By interacting with EGFR and Cbl complex, endophilins and phosphatidic acid, CIN85 acts as a mediator to bring the receptor, endocytic machinery and fusible membrane together."
25005938
reach
"The results showed that CTTN knockdown increased binding of c-Cbl with EGFR, and rescue expression may interfere with this coupling."
27903975
sparser
"We show that, by acting at the early steps of EGFR internalization, USP25 restrains the degradation of the EGFR by assisting in the association of the E3 ubiquitin ligase c-Cbl with EGFR, thereby modulating the amplitude of ubiquitylation on the receptor."
33202887
reach
"We found that ephrinA5 enhanced c-Cbl binding to EGFR, thus promoted ubiquitylation and degradation of the receptor."
19270726
reach
"TKB domain mediated recruitment of Cbl to EGF-R phosphotyrosine 1045 consistently has been shown to be essential for efficient receptor degradation in various experimental systems [12,14,20,27-29]."
16246327
sparser
"Interactions of Cbl with the EGF receptor and multiple downstream signaling proteins suggest a role for this proto-oncogene product in mitogenic signaling through growth factor receptor kinases."
8662998
reach
"Cbl binds EGFR directly through its TKBD and indirectly through growth factor receptor binding 2 mediated interactions in the region C-terminal to the RING domain [XREF_BIBR]."
27609087
reach
"In this context, Cbl binds to EGFR without the contribution of Grb2."
26264748
sparser
"One prominent regulator involved in lyososomal degradation of EGFR is the E3 ubiquitin ligase c-Cbl, which binds to active EGFR and then facilitates its poly-ubiquitination and lysosomal degradation [ xref , xref ]."
32796709
reach
"However, the binding between EGFR and delta-catenin was not affected by c-Cbl in the absence of EGF, indicating that c-Cbl binding to EGFR in the presence of EGF decreases the binding between EGFR and delta-catenin."
29629558
sparser
"These results also suggested that GRB2 cooperation for indirect CBL-binding to EGFR dramatically increases mitotic EGFR endocytosis."
30544639
reach
"However, the studies do not reach similar conclusions regarding the underlying mechanism, and different models have been presented including lack of Cbl recruitment to activated EGFR, inhibited formation of clathrin coated pits after EGFR stimulation, or reduced targeting of internalized EGFR to lysosomes."
18288481
sparser
"We propose that while indirect binding of Cbl to the EGFR via Grb2 is required for a ubiquitination pattern allowing endocytosis through clathrin-coated pits, direct binding of Cbl to the EGFR is requ[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
15475003
reach
"Results demonstrated obviously enhanced EGFR binding to c-Cbl, but not to Cbl-b or Cbl-c upon SGCE knockdown, whereas the binding was undetected or very weak at normal SGCE expression levels."
32714745
sparser
"For instance, the E3 ligase Cbl associates with EGFR and, upon activation with EGF and the interaction with Cbl, EGFR undergoes lysosomal degradation [ xref ]."
25400118
reach
"C-Cbl can bind to the EGFR either directly or indirectly via Grb2 in an SH3 domain directed fashion."
25872741
biogrid
No evidence text available
23175185
biogrid
No evidence text available
17995934
sparser
"EGFR binds to the E3 ubiquitin ligase c-Cbl in response to EGF, either at the plasma membrane or on early endosomes, which in turn promotes poly-ubiquitination of EGFR resulting in degradation (Duan[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
30248333
biogrid
No evidence text available
14627991
sparser
"In our study, we investigated whether δ-catenin can affect direct or indirect binding of c-Cbl to EGFR."
29629558
sparser
"Therefore, SPROUTY acts as a competitive inhibitor preventing c-CBL interaction with EGFR hence enhancing MAPK signalling pathway ."
28923280
biogrid
No evidence text available
9756944
reach
"We then hypothesized that if TRPV1 could recruit the Cbl protein to EGFR, then Cbl binding with EGFR should be enhanced with increasing amounts of TRPV1."
19155296
reach
"Second, we unraveled a novel interaction between EGFR, Brk, and Cbl."
22231447
biogrid
No evidence text available
10635327
reach
"Due to the lack of C-terminal endophilin interacting domains, CIN85-SH3 can not tether EGFR and Cbl complex with endocytic machinery, blocking endophilin mediated EGFR endocytosis."
25005938
biogrid
No evidence text available
19947936
biogrid
No evidence text available
15668240
sparser
"As described above, binding of the ubiquitin ligase Cbl to EGFR is central in the downregulation."
18288481
reach
"Interestingly, the formation of a complex between SPRY2 and c-Cbl also affects the EGF and EGFR induced signaling because c-Cbl normally binds to the activated EGFR and promotes its ubiquitylation and degradation XREF_BIBR."
27539669
biogrid
No evidence text available
25140053
reach
"C-Cbl binds tyrosine phosphorylated EGFR both directly, through its SH2 domain, and indirectly, via Grb2, and ubiquitinates EGFR."
18765569
reach
"It is possible that Kindlin-2 may compete out the binding sites of some E3 ligases, for example, c-Cbl binding to EGFR and reduces c-Cbl action on EGFR."
25790908
reach
"CBL interacting protein of 85 kDa (CIN85) mediates the interaction between CBL and EGFR and hence is involved in the downregulation of EGFR."
28066764
reach
"In the same experiment, the interaction between c-Cbl and EGFR was analyzed."
23774213
sparser
"These are novel observations and are in contrast to the notion that suggests that erlotinib treatment blocks EGFR and c-CBL binding in cells that express TKI resistant mutant EGFR, thus inhibiting EGFR degradation resulting in TKI resistance."
27612423
reach
"However, Spry2 could inhibit the interaction between c-CBL and EGFR by competitive binding with c-CBL [35]."
31182136
trips
"As previously reported for SHIP2, RNA interference-mediated knockdown of PR130 in COS-7 cells resulted in increased EGF-induced proteasome-dependent EGFR degradation, and an increased interaction of EGFR with the E3 ligase c-Cbl."
19825976
sparser
"Similar findings were obtained when cells were stained with antibodies specific for pY1045, the phosphosite on activated EGFR that binds c-Cbl (unpublished data)."
23051738
sparser
"On the other hand, several other studies suggested that c-Cbl binds with EGFR in the presence of EGF and facilitates EGFR downregulation ( xref ; xref ; xref )."
29629558
hprd
No evidence text available
9890970
sparser
"As it has been established that Cbl is a major E3 ligase responsible for the ubiquitylation of EGFR, we tested whether dynasore-induced EGFR ubiquitylation was associated with increased Cbl interactio[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
30268747
sparser
"The endocytosis of truncated EGFR Δ1044-YFP that does not bind to CBL is completely inhibited in mitosis."
30544639
bel
"Furthermore, we show that activated Abl allows the ligand-activated EGFR to escape Cbl-dependent down-regulation by inhibiting the accumulation of Cbl at the plasma membrane in response to epidermal growth factor stimulation and disrupting the formation of the EGFR.Cbl complex without affecting Cbl protein stability."
16943190
sparser
"These data imply that CTTN may interfere in the association of EGFR with c-Cbl, and inhibits the ubiquitin-mediated degradation of EGFR."
27903975
biogrid
No evidence text available
15282549
sparser
"As expected, the proto-oncogene and RING finger member c-Cbl coimmunoprecipitated with ubiquitinylated EGFR [42,64] and EGF-mediated EGFR phosphorylation caused the en­hanced c-Cbl interactions with a[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
22745586
sparser
"Using co-immunoprecipitation, we found that LGR4 knockout enhanced the levels of EGFR-bound CBL in MDA231-EGFR cells ( xref ), suggesting that LGR4 functions to impair the EGFR-CBL interaction."
34099494
reach
"Several studies have shown that c-Cbl can bind to EGFR either directly to the phosphorylated Tyr1045 residue or indirectly via Grb2."
29629558
reach
"This is because Cbl binding to the EGFR displays a threshold profile very similar to the EGFR ubiquitination curve."
26264748
trips
"We observed that Cbl failed to associate with EGFRvIII as well as an inability of the receptor to undergo ubiquitination and degradation."
16969069
reach
"Downstream of Cbl binding to EGFR, the model did not require additional specific constraints to fully account for the threshold effect."
26264748
reach
"Therefore, we suggest that PTK6 negatively affects EGF receptor endocytosis through multiple pathways : through phosphorylation of ARAP1, through phosphorylation and consequent auto-ubiquitination of [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
23352614
sparser
"Mechanistically, Cbl binds tyrosine-phosphorylated EGFR through its tyrosine kinase binding (TKB) domain xref (see also xref )."
18197257
sparser
"Activated Cdc42 influences the interactions of the ubiquitin- ligase c-Cbl with the EGFR to protect the EGFR from ubiquitin degradation xref ."
23750283
sparser
"While this study was in progress, Li et al. [10,26] reported that PTK6 inhibits EGF receptor degradation by phosphorylation of the EGF receptor, thus blocking association of the EGF receptor and c-C[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
23352614
reach
"C-Cbl binds to EGFR either directly through phosphorylated Tyr1045, or indirectly through Grb2."
29629558
sparser
"Also, it can activate the receptor of epidermal growth factor (EGFR) through the suppression of several phosphatases such as PP2a and SHP-2 and increase the interactions between EGFR and Cbl that are able to induce Cbl tyrosine phosphorylation [ xref ]."
30563141
reach
"Indeed, if the binding of Cbl (in complex with Grb2) to EGFR were to take place with the same affinity (k on / k off) regardless of the binding of Grb2, then EGFR-WT and EGFR-Y1045+ should bind a similar amount of Cbl."
26264748
biogrid
No evidence text available
15735736
biogrid
No evidence text available
12593795
reach
"This indicates that the lysosomal sorting of EGFR is inhibited in cells expressing the Y1045F EGFR and is consistent with the view that the direct interaction between activated EGFR and Cbl through ph[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
15475003
sparser
"This mechanism does not apply to stress-induced degradation of EGFR because no activation of EGFR or Cbl-binding to EGFR is required for stress-induced degradation of EGFR."
27034618
sparser
"To further evaluate the association of EGFR and c-cbl under ER stress, time-lapse confocal microscopy was performed to record the localization of EGFR and c-cbl."
24457597
sparser
"They observed that by substituting these serine residues with alanine, EGF was unable to induce internalization and ubiquitination of the EGFR, even though the Y1045 (Y1069) was still able to be phosphorylated by EGF, and the c-Cbl-EGFR interaction was maintained xref ."
20877636
reach
"Hyperactivated Cdc42 through its effector p85Cool-1 (cloned-out-of-library)/beta-Pix (PAK-interactive exchange factor), directly impedes c-Cbl binding to EGFR, which results in EGFRs escape from catalyzing receptor ubiquitination [XREF_BIBR]."
30754684
reach
"Both direct and indirect binding of Cbl to activated EGFR are reported to result in ubiquitination of the EGFR [1]."
17382318
biogrid
No evidence text available
27059931
sparser
"Based on the high ubiquitination level seen after HB-EGF, it is surprising that we found a low c-Cbl binding to EGFR after this ligand (see discussion)."
19531065
sparser
"The binding of Cbl with phosphorylated Y1045 is not necessary for EGFR endocytosis as it has been shown that the Y1045F mutant of EGFR cannot bind with Cbl directly but still efficiently internalized as the wild-type EGFR [ xref , xref ]."
22239438
biogrid
No evidence text available
12734385
reach
"In particular, AR stimulates a transient c-Cbl binding to EGFR (XREF_FIG)."
19531065
sparser
"Consistent with normal EGF-induced ubiquitination, co-precipitation analysis demonstrated that the S1046/1047A and S1046/1047E double mutants also showed normal binding of c-Cbl to the EGFR, while Cbl[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
19263517
sparser
"Ubiquitination is accomplished by EGFR’s C-terminal interaction with the E3 ubiquitin-protein ligase Cbl (reviewed in [ xref ])."
35158954
biogrid
No evidence text available
8662998
biogrid
No evidence text available
19713535
sparser
"Accordingly, the silencing of cIAP1 slightly reduced the levels and interaction of c-Cbl with EGFR (Fig.  xref ), likely contributing to its increased stability."
29674627
sparser
"We have previously demonstrated that overexpression of N-Cbl, competing out direct and not indirect binding of Cbl to the EGFR, also inhibits lysosomal sorting only ."
15475003
sparser
"The results showed that CTTN knockdown increased binding of c-Cbl with EGFR, and rescue expression may interfere with this coupling (Figure xref )."
27903975
trips
"c-Cbl association with EGFR abolished by AG1478 was not reestablished after tyrphostin cessation."
19947936
reach
"It was reported that PTEN promotes ubiquitylation and downregulation of receptor tyrosine kinases such as epidermal growth factor receptor (EGFR) by enhancing the formation of the EGFR and CBL complex."
22730341
sparser
"With the aid of confocal microscopy and immunogold electron microscopy, we could demonstrate that c-Cbl associates with the EGF receptor at the plasma membrane prior to receptor recruitment into clathrin-coated pits and remains associated throughout the clathrin-mediated endocytic pathway."
11493652
reach
"Also, we studied the association between EGFR and c-Cbl before and after EGF stimulation."
22591401
biogrid
No evidence text available
23799367
sparser
"Consistent with the reduction of EGFR-Cbl association, the level of EGFR ubiquitination was lower in 14-3-3σ-overexpressing cells than in control cells (Figure xref E)."
33391517
hprd
No evidence text available
10799548
sparser
"Identification of the Cbl's docking site enabled us to study the role of Cbl–EGFR interactions in living cells."
10635327
reach
"To further confirm this result, we assessed the binding between EGFR and c-Cbl with a dose dependent increase in delta-catenin."
29629558
reach
"[50] Cbl can directly bind to EGFR, or indirectly bind to EGFR via the adaptor protein Grb2."
32714745
reach
"EGFR degradation by LRIG1 appears to be dependent on the E3 ligase, Cbl, as recruitment of Cbl to either EGFR or LRIG1 is sufficient to induce EGFR ubiquitylation and degradation."
23558895
sparser
"It has been reported that activated Cdc42, through an interaction with its targets/effectors, inhibits the binding of c-Cbl to EGFR and thus prevents c-Cbl from catalyzing EGFR ubiquitination and degr[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
23142484
reach
"Thus, the interactions between EGFR, CBL, ITSN and MIG6 may be overlapping, perhaps to fine tune the temporal signaling through the receptor and to provide redundancy in the system."
25594057
reach
"In marked contrast, the association between c-Cbl and EGFR was more stable in cells treated with EGF, persisting without diminishing for 15 min."
19173594
hprd
No evidence text available
8662998
biogrid
No evidence text available
19578043
reach
"Cbl can bind directly to EGFR by binding to the single phosphorylated tyrosine residue on EGFR (Y1045) or bind indirectly to phosphorylated Y1068 and Y1086 of EGFR via its interacting partner Grb2 [XREF_BIBR, XREF_BIBR]."
22239438
sparser
"The Cbl-EGFR axis undergoes additional levels of regulation."
33432111
reach
"Upon growth factor stimulation, c-Cbl binds to activated EGFR and acts as a multifunctional adaptor protein to recruit additional endocytic regulatory proteins such as Cbl interacting protein of 85 kDa (CIN85), which plays important roles in receptor endocytosis and degradation XREF_BIBR - XREF_BIBR."
21830225
sparser
"δ-Catenin competes with c-Cbl for EGFR binding, which results in a reduction of binding between c-Cbl and EGFR and thus decreases the ubiquitination of EGFR."
29629558
sparser
"Cbl can directly bind the Y1045 residue of EGFR through its SH2 domain."
21340027
reach
"Therefore, we conclude that direct interaction between Cbl and EGFR may not be necessary for ligand-receptor endocytosis in vertebrate and invertebrate cells."
21340027
sparser
"In essence, Cbl may also be recruited to EGFR indirectly by Shc, which forms a complex with Grb2 and binds to phosphosphorylated Y1148 and Y1173 of EGFR ( xref , xref )."
19489726
reach
"On the other hand, the binding of Cbl to EGFR via Grb2 is important for receptor internalization [XREF_BIBR]."
22239438
sparser
"As can be seen from xref , all ligands stimulate c-Cbl binding to EGFR, but the association is more prolonged after EGF and BTC stimulation than the remaining ligands."
19531065
bel
"On EGFR activation, c-Cbl associates with phosphorylated Tyr-1045 and ubiquitinates the receptor, marking it for clathrin-mediated endocytosis and recognition by the lysosomal machinery, which results in receptor degradation and signal termination (3–6)."
17971399
reach
"Taken together, these results indicate that delta-catenin reduces the binding of c-Cbl to EGFR, resulting in decreased EGFR ubiquitination and enhanced EGFR stability in the cell membrane."
29629558
sparser
"Next, we analyzed the interaction between the EGFR and c-Cbl in control and USP25-depleted cells by co-immunoprecipitation experiments."
33202887
sparser
"Nonetheless, CTEN could somehow transiently (≤15 min) but robustly enhance c-Cbl-EGFR interaction."
23774213
reach
"Overexpression of CTTN suppresses the ubiquitin mediated EGFR degradation that is induced with EGF, leading to sustained MAPK signaling by inhibiting the association between EGFR and c-Cbl."
27903975
reach
"C-Cbl contains a phosphotyrosine binding domain at its N-terminus as well as a C3HC4 RING finger [XREF_BIBR] and binds EGFR directly via the phosphorylated EGFR Tyr1045 (Y1045) residue or indirectly via Grb2 [XREF_BIBR - XREF_BIBR]."
18951974