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EGFR binds EGF. 1000 / 4950
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"Based on the 1IVO crystal structure of EGF–EGFR complex reported by Ogiso et al. [ xref ], 48% (10 of 21 residues) were listed in the calcium-binding-like domain region of S. horrens predicted protein i.e., Asn77, Cys79, Phe80, Ser81, Ser82, Pro83, Cys84, Cys90, Cys99 and Thr106."
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"Cetuximab is a chimeric mouse-human immunoglobulin G (IgG) 1 monoclonal antibody (mAb), which can target the extracellular domain of the epidermal growth factor receptor (EGFR) and competitively inhibit the binding of EGFR to ligands such as epidermal growth factor, thus blocking the downstream signal transduction to exert antitumor effects. xref Additionally, cetuximab is an immunomodulating agent that promotes T-cell infiltration into the CRC TME and upregulates ICIs. xref The mechanisms of the anti-tumor effects of cetuximab are depicted in xref , which mainly include: (1) Increased levels of cyclin-dependent kinase inhibitory proteins p21 and p27 and decreased levels of cyclin D1, inhibiting tumor cell proliferation, xref (2) downregulated expression of the apoptosis suppressor B-cell lymphocyte-2 gene and upregulated expression of the proapoptotic Bcl-2-associated X protein gene, activating caspase-8 to induce apoptosis in tumor cells through the caspase cascade reaction, xref and (3) simultaneous binding of cetuximab to the corresponding antigen via its allosteric fragment crystallizable (Fc) segment that binds to the Fc receptors of effector cells (such as natural killer [NK] cells, neutrophils, macrophages, and platelets) to kill tumor cells through antibody-dependent cell-mediated cytotoxicity (ADCC). xref "
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"In cells with physiological receptor expression levels, EGF binding to EGFR also triggers endocytosis through a clathrin-dependent pathway, whereas in EGFR overexpressing cells clathrin-independent pathways have been observed especially in the presence of high EGF concentrations. xref Importantly, the activated EGFR remains dimerized with the phosphorylated tyrosine kinase domain exposed in the cytoplasm after internalization into early endosomes. xref – xref In this fashion, the receptor continues to signal during intracellular trafficking until it is dephosphorylated by a protein tyrosine phosphatase xref , xref , the ligand is removed from the endosome, xref or the phosphorylated EGFR (pEGFR) containing endosome is encapsulated in a multivesicular body. xref The accompanying removal of the phosphorylated receptor tail from the cytoplasm renders the phosphorylated EGFR inaccessible and results in signal termination."
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"A recent study reported that the induction of EGFR mediated carbon monoxide releasing molecule-2 (CORM-2) in human bronchial smooth muscle cells promotes HO-1 expression, whereas in glioblastoma, the phosphoinositide 3-kinase (PI3K) signaling pathway is activated through the binding of EGFR and EGF to induce HO-1 expression [XREF_BIBR, XREF_BIBR, XREF_BIBR]."
| PMC
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"EGFR , one of the members of the epidermal growth factor receptor family ( xref - xref ), specifically binds to ligands such as epidermal growth factor, transforming growth factor, bidirectional regulating protein, B cell factor, liver-binding EGF-like growth factor, and epidermal regulation factor ( xref , xref )."
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"Since Roovers et al. reported (i) an inhibition of EGF-mediated EGFR phosphorylation in the presence of the EGFR-specific Nb 7D12 [ xref ], and (ii) also mentioned a blockage of EGF binding by the Nb 7C12 used in our studies [ xref ] we analyzed the capability of our α-EGFR TMs to mediate EGFR signaling and blocking of EGF binding to EGFR."
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"The presence of excess recombinant human EGF (rhEGF) protein inhibited binding of the EGF-bearing particles at 4°C ( xref ), showing that the particle interactions were dominated by the EGF-EGFR interaction rather than nonspecific associations between the capsid protein and the cell surface."
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"5 A canonical activator of ERK is the epidermal growth factor (EGF)/epidermal growth factor receptor (EGFR) interaction, in which EGF binding to EGFR leads to EGFR homo- and hetero-dimerization, recruitment of Grb2 and son of sevenless (SOS), activation of RAS, and downstream phosphorylation of RAF, MEK, and ultimately ERK."
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"Normally, epidermal growth factor (EGF) binding to EGFR homodimers stimulates receptor downregulation (via internalization), and this depends on recruitment of the E3 ubiquitin ligase, c-Cbl, to the phosphorylated receptors followed by c-Cbl-mediated EGFR ubiquitination and degradation [6]."
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"EGFR is a transmembrane receptor that has intrinsic tyrosine kinase activity and has several specific ligands, such as the epidermal growth factor that binds to EGFR and initiates multiple signaling pathways essential for different cell functions. xref , xref Mutations of the EGFR genes may result in persistent activation of the tyrosine kinase related to EGFR in tumor cells, and may thus promote tumor proliferation, cell survival, and other cancer-related properties. xref , xref , xref TKI binds to the tyrosine kinase domain to inhibit the protein kinase activity of EGFR, and the EGFR mutation may be the most important predictor of responsiveness to TKI. xref , xref , xref , xref , xref In recent years, determination of EGFR gene status has played an extremely important role in TKI selection for advanced lung cancer treatment."
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"Analysis of down-regulated genes in SVF revealed enrichment in signaling pathways such as MAPK, TGF-β, focal adhesion, adipogenesis, androgen receptor signaling, EGF-EGFR, actin cytoskeleton regulation, circadian clock regulation, IL-4 signaling, neural crest development, Wnt, and RANKL-RANK."
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"EGF binds to the epidermal growth factor receptor (EGFR), inducing auto‐phosphorylation to create binding sites for signalling molecules that stimulate proliferation. xref Gangliosides are known inhibitors of this auto‐phosphorylation process and are therefore of interest in oncology research.[ xref , xref ] In a study of a small ganglioside class, GT1b was found to be the most potent inhibitor of EGFR phosphorylation in the human neuroblastoma cell line, NBL‐W. xref The authors postulated that the number and arrangement of Neu5Ac residues were a key contributor to the inhibitory potency."
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"In collaboration with the Michiyuki Matsuda lab, we employed it to investigate the signaling mechanisms controlling collective cell migration. [ xref ] Collective cell migration is vital for embryonic development, wound healing, and cancer metastasis. [ xref , xref ] This process involves leader cells at the migration front, extending lamellipodia and guiding follower cells through Rac‐mediated lamellipodia formation, thereby directing movement. [ xref ] During collective cell migration, ERK activation waves propagate from leader to follower cells via EGF–EGFR signaling; [ xref , xref ] however, the mechanisms of leader cell specification were unclear."
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"In the ligand-dependent mechanism, the stimulation of GPCRs via selective agonists triggers the membrane-bound matrix metalloproteases (MMPs)-mediated proteolytic cleavage of a pro-ligand, generating a cleaved ligand EGF that binds to EGFR and induces signal transduction [ xref , xref , xref ]."
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"To illustrate, Palma et al. designed and synthesized a multi-ligand functionalized, nanoscale particle containing spatially controlled A20FMDV2, an integrin alphaVbeta6 binding motif, and epidermal growth factor (EGF), a protein that binds the epidermal growth factor receptor (EGFR) which is a tyrosine kinase that cooperates closely with integrins XREF_BIBR."
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"The EGFR protein binds the epidermal growth factor (EGF) and plays an important role in regulating cellular growth and function (Traish and Wotiz, 1987; St-Arnaud et al, 1988; Nishi et al, 1996; Itoh et al, 1998; Migliaccio et al, 2006; Bonaccorsi et al, 2004, 2007; Leotoing et al, 2007)."
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"Considering that TNBC and HER2 enriched breast carcinoma cells are highly dependent on the activation of EGFR and HER2, we performed bioluminescence resonance energy transfer (BRET) experiments to determine whether melittin interfered with the binding of EGF to EGFR, leading to the observed suppressed growth factor receptor phosphorylation."
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"The dual-ligand-displaying AaLS/TRAIL/EGFRAfb exhibited a dramatically enhanced cytotoxicity on TRAIL-resistant and EGFR-overexpressing A431 cancer cells in vitro, effectively disrupting the EGF-mediated EGFR survival signaling pathway by blocking EGF/EGFR binding as well as strongly activating both the extrinsic and intrinsic apoptotic pathways synergistically."
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"For the EGFR·EGF-CS-SWCNT-Drug complex, the closer binding pocket (Figure 6(c)) and increased β-sheet formation at residues ~310 and α-helix formation at residues ~470 (Figure 4(c)) promoted the stronger interaction between EGFR and the EGF-conjugated DDS, as clearly seen in Figure 8(a) (red)."
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"Because of its ability to bind EGFR, nimotuzumab can competitively interfere with the binding of EGF to EGFR, resulting in the blockade of downstream signaling pathways, inhibiting tumor cell proliferation, promoting tumor cell apoptosis, and enhancing the efficacy of radio- and/or chemotherapy."
sparser
"The requirement for the WASH complex in segregation of stress-internalized EGFR along with pre-melanosomal factors away from ligand-stimulated EGFR contrasts with the unimpaired lysosomal degradation of EGF-bound EGFR and plasma membrane recycling of TfR in WASH knockouts xref ."
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"Data in xref showed that pre-incubation of the MDA-MB-468 cells with free EGF for 1 h significantly inhibited the cellular uptake of the EGF-GemC18-NPs, but not the OVA-GemC18-NPs, by the MDA-MB-468 cells, demonstrating that the uptake of EGF-GemC18-NPs was mediated by the EGF-EGFR interaction."
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"Epidermal growth factor and transforming growth factor-alpha ligands bind and activate the EGFR receptor, followed by internalization of homodimerized or heterodimerized (EGFR binding HER-2 or ERBB3) receptors, leading to autophosphorylation of the intracellular tyrosine kinase domain and activation of several downstream pro oncogenic signaling pathways [XREF_BIBR]."
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"We have taken advantage of the well characterized trafficking of the EGF and EGFR complex, the dependence of EGF receptor endocytosis on ligand binding, and previously developed cell-free endosome fusion assays, to develop a novel approach for measuring fusion of EGF-EGFR-containing compartments."
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"Our results also suggest that the components of this signaling axis may be potential therapeutic targets for bladder cancer patients undergoing cisplatin chemotherapy.In EGFR signaling pathways, EGF binding to EGFR triggers homodimerization or heterodimerization of this receptor with other ErbB members as well as receptor phosphorylation and activation of downstream effectors, such as RAS-RAF-MEK-ERK-MAPK and PI3K-mTOR, thereby leading to cell proliferation [58]."
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"When protein EGF ( ) is bound to its receptor EGFR phosphorylated on tyrosine ( ), the GRB2-associated-binding protein or phosphorylated on tyrosine is present ( ), the Ras guanyl-releasing protein 3 or protein phosphorylated on tyrosine is present, is present, the protein phosphorylated on tyrosine is present, and the inside of the membrane ( ) contains loaded with guanosine diphosphate , then switches its load to guanosine 5 ′ -triphosphate [ xref ]."
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"The binding of EGF to the EGF receptor (EGFR) on the cell membrane stimulates the phosphorylation of SHC, which complexes with the GEF son of sevenless (SOS) and growth factor receptor-bound protein 2 (GRB2) to promote the binding of GEFs to KRAS, causing KRAS to exist in the activated GTP-bound state xref ."
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"Several mechanisms have been proposed for the inhibition of EGFR by EGCG: (a) interfering with the binding of EGF to EGFR and inhibiting EGFR tyrosine kinase activity [ xref ]; (b) altering lipid organization in the plasma membrane (lipid rafts) and inhibiting EGF binding to EGFR [ xref ]; and (c) inducing EGFR internalization without activation [ xref ]."
sparser
"The binding of EGF to the extracellular domain of EGFR induces dimerization of the receptor and the activation of its intrinsic tyrosine kinase activity, leading to receptor autophosphorylation and the phosphorylation of tyrosine residues in various downstream signaling molecules, including ERK1/2, AKT, STAT3, and PKC [ xref ]."
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"Administration of purified soluble TM inhibited cell proliferation and invasion in murine melanoma. xref Furthermore, recombinant TM suppressed tumor growth by inhibiting thrombin‐induced activation of protease activate receptor‐1 (PAR1) and nuclear factor kappa B (NF‐κB) activation in pancreatic cancer cells. xref Kuo et al reported that the lectin‐like domain recognized and adhered the Lewis‐Y antigen of the EGF receptor (EGFR) on the surface of the cancer cell and subsequently inhibited the binding of EGF to EGFR and suppressed cell proliferation. xref On the contrary, our study showed no correlation between tumor size and differentiation and TM expression."
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"Decorin can competitively inhibit the receptor-ligand binding of EGF and EGFR, and based on the mechanisms described, Decorin can block the phosphorylation of FER and SHP2, thus inhibiting the formation of early endosomes, their transition to late endosomes, and the recycling function of recycling endosomes."
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"This may be because the intestinal mucosal surface was completely saturated with EGFR as when EGFR is fully bound to EGF, even if there is excess EGF, it cannot perform its biological functions due to the lack of corresponding receptors.Transcriptome sequencing can detect all the transcript information of tissue in different physiological states (39), providing a new technical means for examining the pathogenesis of NEC and the mechanism of EGF."
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"EGF binds to its cognate receptor EGFR, leading to the phosphorylation of numerous tyrosine residues on its cytoplasmic domain [23], which induce activation of downstream signal transduction components and regulate receptor trafficking, including internalization, recycling and degradation [24]."
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"The reduced expression of HER1 suggests that AB1 might interfere with the binding of EGFR with EGF preventing its activation, and hence the dimerization and tyrosine autophosphorylation would not take place and the cell proliferation would stop [57], which supports the cell-cycle arrest at the G1 phase."
sparser
"This is qualitatively consistent with our previously reported simulations xref , in which the ligand-bound conformation was not stable without the EGF ligands, and it suggests that the favorable EGF-EGFR interaction is approximately canceled out by EGFR adopting the unfavorable ligand-bound conformation."
sparser
"Recently, human lung adenocarcinoma cells (A549 cell line), when exogenously treated with SP-D, showed suppressed epidermal growth factor (EGF) signaling by reducing the EGF binding to EGFR, which subsequently reduced the cell proliferation, invasion, and migration of cancer cells ( xref )."
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"The filter mats were then allowed to dry, inserted into sample bags, scintillation fluid (10ml) was added and incorporated 'H-thymidine determined using an LKB 1205 liquid scintillation counter.
THE INTERACTION BETWEEN EGF AND sEGFR
17
RESULTS
Purification and Characterisationof sEGFR
Large (mg) quantities of homogenous, well characterised and quantified, biologically active sEGFR are required to perform both kinetic and stoichiometric studies."
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"Furthermore, the kinase activity can be significantly stabilized by reconstituting purified EGF-bound EGFR dimers in phospholipid nanodiscs or vesicles, suggesting that the environment around the hydrophobic transmembrane and amphipathic juxtamembrane domains is important for stabilizing the tyrosine kinase activity in vitro ."
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"Furthermore, the kinase activity can be significantly stabilized by reconstituting purified EGF-bound EGFR dimers in phospholipid bilayer nanodiscs or vesicles, suggesting that the environment around the hydrophobic transmembrane and amphipathic juxtamembrane domains is important for stabilizing the tyrosine kinase activity in vitro ."
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"The N glycosylation of the glycosyl group next to the EGF binding site in EGFR could cause its noncovalent interactions with the EGFR extracellular domain, stabilizing the EGF binding site, leading to a stronger interaction between EGF and EGFR; N glycosylation also helps maintain the binding of the EGFR dimer and plays a special role in the binding of antibodies and the extracellular domain of EGFR XREF_BIBR."
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"Comprehensive genomic profiling (CGP) based on next-generation sequencing has enabled the detection of uncommon EGFR variants in clinical practice, including kinase domain duplications (KDDs) and rearrangements. xref In 2015, EGFR -KDD was reported as a novel oncogenic driver of alterations in patients with NSCLC. xref , xref Preclinical studies reported that EGFR -KDD formed asymmetric epidermal growth factor (EGF)-independent and -dependent intramolecular and intermolecular dimers that constitutively activate downstream mitogen-activated protein kinase (MAPK) signaling. xref Moreover, downstream MAPK signaling was inhibited by EGFR-TKIs such as afatinib and osimertinib in cells with EGFR -KDD. xref Recently, many retrospective clinical studies have addressed the clinical benefit of EGFR-TKIs in advanced NSCLC harboring EGFR -KDD. xref Herein, we report the antitumor effect of EGFR-TKIs on advanced CRC harboring EGFR -KDD with ex vivo analysis and a literature review."
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"If the EGFR remains ubiquitinated or is re-ubiquitinated in early or late endosomes, then a distinct coat protein complex, the endosomal sorting complex required for transport (ESCRT) complex, interacts with the EGF and EGFR complex, to generate multivesicular bodies containing the EGF and EGFR complex."
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"The EGF signal diminished due to the degradation of the EGFR-EGF complex within endolysosomal compartments, a key step in regulating EGFR signaling and ensuring proper signal termination ( xref B). xref The fluorescent signal for transferrin, conjugated to an iron-binding fluorescent dye, reflects its interaction with the transferrin receptor (TfR), which triggers the internalization of the iron-transferrin-TfR complex via clathrin-mediated endocytosis."
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"The corresponding average fraction of EGFR that is bound by EGF (α ) in the same cell was obtained by normalizing the average ratiometric fluorescence of EGF‐Alexa647/EGFR‐mCitrine at the PM for each cumulative EGF dose to that at saturating EGF‐Alexa647 dose (Reynolds et al, 2003; Stanoev et al, 2018; Fig 2D)."
sparser
"These findings indicate the importance of the hydrophobic interaction of EGF with EGFR on site 3 interface to activate the mitogenic EGFR signalling, and open up the possibility to insert new amino acid changes that could increase EGFt affinity for EGFR and its blocking activity."
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"In the meantime though, while one study reported that in U87 glioma cells EGF induced tyrosine phosphorylation of nuclear β-catenin and increased β-catenin transcription activity, little is known about the intranuclear mechanisms via which β-catenin activity is regulated by EGF–EGFR signaling."
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"Chen et al [ xref ] and She et al [ xref ] developed hollow MSNs functionalized with epidermal growth factor (EGF) which were used as nanocarriers for 5-FU delivery to CRC cells and CRC acquired drug resistance cells, and demonstrated efficient and high specificity, and excellent targeting performance via the EGF–EGFR interaction."
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"Numerous prior studies have concluded that EGF and TF are internalized through clathrin coated pits into similar endocytic vesicles, which fuse with a sorting endosome from which Tf/TfR complexes are removed to undergo recycling, and EGF and EGFR complexes undergo inward vesiculation and targeting to late endosomes and lysosomes."
sparser
"Interestingly, SHCBP1 had been previously found to specifically interact with the SH2 domain of SHC1 [ xref ], and of note, while most of these SHC1 binding partners displayed enhanced affinity with SHC1 following EGF stimulation, SHCBP1 was the only molecule dissociated from SHC1 in response to EGFR activation, raising the possibility that the released SHCBP1 might play a thus far unknown role distinct from other SHC1 binding partners in the transduction and regulation of EGF–EGFR signaling [ xref ]."
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"In the case of EGFR, the following scheme can be hypothesized: (1) binding of EGF to the extracellular domain of EGFR promotes a conformational change in its kinase domain (opening of the activation segment); (2) Y845 in the activation segment becomes exposed to the outer surface of the EGFR kinase domain (display of Y845); (3) exposed Y845 becomes accessible to Src, thereby being phosphorylated; and (4) the phosphorylated Y845 and its surrounding amino acid sequence provide a docking site for the Src homology 2 domain of Src and phosphotyrosine-binding domains of other signaling molecules (e.g., STAT3, CoxII), leading to the physical interaction of EGFR and these molecules."
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"To understand whether the increase in autophagic markers observed in MPS VI cells is due to the deficient ability of lysosomes to recycle metabolites, we compared the Epidermal Growth Factor (EGF)/EGF Receptor (EGFR) turnover in MPS VI and NR fibroblasts based on the knowledge that binding of EGF to EGFR induces ubiquitination, rapid internalization and degradation of both ligand and receptor via the lysosomal pathway [XREF_BIBR, XREF_BIBR]."
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"43 In vitro experiments have indicated that SP-A can inhibit EGF-induced phosphorylation of EGFR, ERK, and Akt in a dose-dependent way, thereby inhibiting cell proliferation and motility.43,108 Additionally, SP-A-deficient mice show heightened sensitivity to MMF exposure, and the pharmacological inhibition of EGFR before MMF stimulation significantly decreases mucin production and neutrophil infiltration in SP-A-deficient mice.109 Mechanistically, SP-A may interact with EGFR via the neck region of the CRD, effectively blocking the binding of EGF to EGFR and suppressing mucin production."
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"We have previously shown that tethering EGF to polymeric substrates to physically inhibit endocytosis of the EGF and EGFR complex elicits sustained EGFR activity XREF_BIBR, XREF_BIBR and increased osteogenic differentiation of MSCs compared to control surfaces when induced by osteogenic media XREF_BIBR."
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"Initial experiments in 1483 cells stimulated with Alexa Fluor-488 conjugated EGF for 30 min indicated that EGF and EGFR complexes were present throughout the vertical dimension of the cell when analyzed by whole cell confocal analysis, demonstrating internalization of activated EGFR in this system (XREF_FIG)."
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"Two notable examples are discussed here : (1) In canonical receptor tyrosine kinase (RTK) pathways, binding of the epidermal growth factor (EGF) to its receptor EGFR and ErbB1 at the cell surface triggers receptor dimerization and cross phosphorylation of the EGFR intracellular kinase domains; phosphorylated domains then recruit and activate effectors such as the small GTPase Ras and the lipid kinase PI3K."
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"We present a model whereby the tetraspanin resident EGFR is preferentially able to bind EGF, followed by rapid relocalization of ligand-bound EGFR out of tetraspanin nanodomains to other regions of the plasma membrane including clathrin nanodomains, supporting robust signal transduction."
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"Attempts were made to sort EGFR-positive MSCs but high EGFR levels were not maintained in culture and the populations reverted to variable EGFR expression (data not shown), which may be related to an autocrine EGF-EGFR negative feedback response and ligand-induced internalisation of the EGFR [ xref ]."
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"Collectively, this suggests that CD81 and possibly other tetraspanins regulate two aspects of EGFR signaling: (i) enhancement of direct EGFR binding to EGF, likely restricted to the confined fraction of EGFR in larger-scale tetraspanin assemblies and (ii) suppression of formation of signaling oligomers of EGFR, perhaps because of small-scale EGFR-tetraspanin assemblies that are more mobile."
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"Based on (1) cigarette smoking reduces the junctional barrier integrity of the airway epithelium, partially mediated by the EGF-EGFR signaling [ xref , xref ], to allow the particles/proteins to go across the barrier junctions of the airway epithelium, (2) our observation that BMP4 is expressed abundantly in the airway epithelium of smokers, we hypothesized that up-regulated BMP4 passes through the damaged barrier junctions of the airway epithelium, and interacts with BC to switch the normal BC self-renewal and differentiation toward smoking relevant abnormal airway epithelium."
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"Plasma, serum, and saliva have low EGF concentrations (1–2 ng/mL), whereas bile and urine have much higher concentrations (50–500 ng/mL).2 At low EGF concentrations (i.e., <10 ng/mL), EGF binds to EGFR and the ligand-receptor complex is mainly internalized through clathrin-mediated endocytosis, however, at relative high doses of EGF (i.e., ≥10 ng/mL), clathrin-independent endocytosis also takes place."
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"The results were published in full in 2023.NSCLC is the most common type of lung cancer, but is often not diagnosed until the cancer has spread beyond the lungs described as 'metastastic' or 'advanced' disease.Epidermal growth factor (EGF) binds to the EGFR (epidermal growth factor receptor) and leads to signaling events that control how cells grow and divide.Healthy cells transform into cancer cells when changes (mutations) occur in the EGFR gene, in NSCLC this is known as EGFR-mutated NSCLC."
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"This can transition from a free cytosolic form to membrane‐bound fractions and be targeted to receptors through vesicles, a process activated by the phosphorylation of tyrosine residues in the receptor, like the interaction between epidermal growth factor and epidermal growth factor receptor. xref Various subcellular compartmentations are recognised and defined by specific biomarkers at a two‐dimensional level, which partly shows the spatialization and temporalization of compartments and molecular relocations in stereological cells (Figure xref )."
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"Mucin-1 plays important roles in cancer development and metastasis by inhibiting the anti-tumor immune response [ xref ], promoting the growth of cancer cells by binding to EGFR in an epidermal growth factor-dependent manner [ xref ], preventing cell death by inhibition of p53-mediated apoptosis and promotion of p53-mediated cell cycle arrest [ xref ], and promoting cancer metastasis [ xref - xref ]."
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"When epidermal growth factor ligands bind to the EGFR , they activate a signalling pathway cascade, mediated by downstream effectors of the mitogen-activated protein kinase ( MAPK ) pathway and other pathways including the phosphoinositide-3-kinase ( PIK3CA )/ AKT signalling pathway."
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"Our finding of ligand-independent EGFR activation and concurrent CTX resistance as a consequence of mutations in or near the EGF binding pocket highlights the potentially profound impact and molecular mimicry small missense mutations can have on protein dynamics and function: restricting adoption of a fully closed, inactive EGFR conformation while not permitting association of EGFR with EGF; and, in parallel, restricting accessibility for domain III to interact with CTX, thereby leading to CTX resistance in our model ( xref )."
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"Recently, human lung adenocarcinoma cells (A549 cell line), when exogenously treated with SP-D, showed suppressed epidermal growth factor (EGF) signaling by reducing the EGF binding to EGFR, which subsequently reduced the cell proliferation, invasion, and migration of cancer cells."
sparser
"Because of its ability to bind EGFR, nimotuzumab can competitively interfere with the binding of EGF to EGFR, resulting in the blockade of downstream signaling pathways, inhibiting tumor cell proliferation, promoting tumor cell apoptosis, and enhancing the efficacy of radio- and/or chemotherapy."
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"Inhibition of K V 1 channels with 4-aminopyridine or treatment with the epidermal growth factor receptor agonist heparin binding EGF (HB-EGF), which promotes K V 1 channel endocytosis, reduced K V current density and restored myogenic responses in PAs from TgNotch3R169C mice, whereas pharmacological inhibition of other major vasodilatory influences had no effect."
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"While at this point we can not completely exclude membrane depolarization to be a contributing factor, we suggest that an increase in intracellular sodium is a component of an auto-regulatory loop that regulates termination of EGFR signaling through trafficking of the EGF and EGFR complex and includes HDAC6 and tubulin acetylation."
sparser
"The model represents ErbB1 synthesis and degradation; EGF ligand binding to ErbB1; receptor dimerization and activation; activation of the signaling pathways associated with the binary interactions between ErbB1 + Shc, Shc + Grb2, ErbB1 + Shc-Grb2, ErbB1 + Grb2, and Grb2 + Sos; deactivation of ErbB1 following PTP + ErbB1 interactions; and dissociation of active Shc from ErbB1."
sparser
"EGF binding to EGFR triggers the activation of the receptor's intrinsic kinase activity, in turn eliciting the recruitment of many secondary signaling proteins and activation of downstream signals, such as the activation of phosphatidylinositol-3-kinase (PI3K) and Akt, a process requiring the phosphorylation of Gab1."
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"Further evidences point out that EGF signalling is important for prostate cancer cell proliferation : (i) EGFR is over-expressed in prostate cancer cells XREF_BIBR, XREF_BIBR (ii) overexpression of EGFR stimulates cell growth in vitro and in vivo, XREF_BIBR, (iii) in the TRAMP (TRansgenic Adenocarcinoma of the Mouse Prostate) mouse model, the activation of the MAPK pathway involving the ERK1/2 transducers downstream of the EGF and EGFR complex promotes prostate epithelial cell proliferation and tumour progression XREF_BIBR, (iv) ERK1/2 promotes the degradation of extracellular matrix proteins thus favouring tumour invasion XREF_BIBR."
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"This response consisted of a downregulation by miR-223 of the local expression of epidermal growth factor (EGF), leading to a decreased activation of the EGF receptor (EGFR) on target cells as a consequence of the positive EGF–EGFR autocrine/paracrine effect induced by the post-surgical wound-healing response."
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"To demonstrate that the sialylation of NRP1 could increase the binding affinity between NRP1 and the EGF/EGFR complex (Fig. 3C), recombinant EGF was coupled to MagPlex beads and then incubated with EGFR overnight, followed by incubation with increasing concentrations of biotinylated HA-NRP1."
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"Honjo, K., Munakata, S., Tashiro, Y., Salama, Y., Shimazu, H., Eiamboonsert, S., Dhahri, D., Ichimura, A., Dan, T., Miyata, T., Takeda, K., Sakamoto, K., Hattori, K., & Heissig, B. Plasminogen activator inhibitor-1 regulates macrophage-dependent postoperative adhesion by enhancing EGF-HER1 signaling in mice."
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"EGF selectively binds to EGFR and triggers the receptor to form a dimer that activates RAS which can transmit signals from the activated transmembrane receptor EGFR to effectors in the MAPK and PI3K/AKT signaling pathways in the cytoplasm, regulating cell survival and proliferation ( xref )."
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"Likewise, monoclonal antibodies directed against the extracellular domain of ERBB1/EGFR, such as cetuximab block the binding of EGF and other ligands, such as amphiregulin (AREG), to the ERBB1/EGFR receptor and inhibit the ERBB1/EGFR signaling pathway that contributes to the survival and proliferation of EGFR-positive malignant cells [57,60]."
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"The model represents ErbB1 synthesis and degradation; EGF ligand binding to ErbB1; receptor dimerization and activation; activation of the signaling pathways associated with the binary interactions between ErbB1 + Shc, Shc + Grb2, ErbB1 + Shc-Grb2, ErbB1 + Grb2, and Grb2 + Sos; deactivation of ErbB1 following PTP + ErbB1 interactions; and dissociation of active Shc from ErbB1."
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"To characterize the effects of ligand binding on the conformations of the EGFR dimers, we compared structures generated during simulation runs to previously solved x-ray structures of EGFR bound to TGF-alpha and EGF, and the recently solved structure of another ErbB4 and ligand complex XREF_BIBR, XREF_BIBR, XREF_BIBR."
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"Treatment of cells with PI3K inhibitor LY294002 prevented upregulation of MMP-2 and MMP-9 indicating that EGFR-mediated signalling for MMP regulation occurs through PI3K. As increased EGFR activity has been observed in highly invasive breast cancers, targeting EGFR-EGF interactions might render such cancers less invasive by inhibiting EGFR-mediated upregulation of MMP-2 and MMP-9 and therefore could be of importance in their clinical management."
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"Since Roovers et al. reported (i) an inhibition of EGF mediated EGFR phosphorylation in the presence of the EGFR specific Nb 7D12 [XREF_BIBR], and (ii) also mentioned a blockage of EGF binding by the Nb 7C12 used in our studies [XREF_BIBR] we analyzed the capability of our alpha-EGFR TMs to mediate EGFR signaling and blocking of EGF binding to EGFR."
sparser
"The different mechanisms that have been proposed for the inhibition of EGFR by EGCG include 1) interfering with the binding of EGF to EGFR and inhibiting EGFR tyrosine kinase activity [ xref ], 2) altering lipid organization in the plasma membrane (lipid rafts) and inhibiting EGF binding to EGFR [ xref ], and 3) inducing EGFR internalization without activation [ xref ]."
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"Preclinical experiments indicate that concentrations of ∼0.9 nM block the interaction of EGF and EGFR to 50%, and that single agent treatment with necitumumab at doses of 4–6 mg/kg every second week, corresponding to trough serum levels of ∼40 μg/mL, showed significant antitumor activity in non‐small cell lung (NSCLC), pancreatic, colon, and squamous cervical cancer xenograft tumor models. xref , xref "
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"Seribantumab also reduced HRG1-mediated Akt and ERK phosphorylation whereas EGF-stimulated ERK activity was not affected, indicating that seribantumab’s effect was specific to HRG1/ErbB3 binding and not EGF/EGFR binding.Since cisplatin increases HRG1 levels and subsequently leads to increased Akt and ERK phosphorylation, we investigated whether seribantumab prevent these effects."
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"EGFR receptors become activated by homo- or heterodimerization of
the receptors after epidermal growth factor (EGF) binding. xref Dimerization of receptors can further activate
a series of downstream signaling pathways that regulate numerous biological
processes including cellular proliferation, apoptosis, and tumor progression. xref Therefore, precise visualization of the interaction
between EGF and EGFR can not only contribute to understanding the
molecular mechanism in various biological processes but also help
reveal the progression of tumor development. xref Yan’s team designed EGFR aptamers modified with Cy3 fluorescent
dye as imager probes and then visualized the interaction between EGF
and EGFR using dSTORM imaging at the single-molecule level. xref The super-resolution images showed that EGFR
formed protein clusters of different sizes on the COS-7 cell membrane."
sparser
"When human epidermal growth factor (EGF) binds to EGFR, EGFR and its relatives, the ERBB family members, have mutations or increased expression, which will trigger a cascade reaction of upstream and downstream signaling pathways in the ERBB signaling pathway, especially the intracellular tyrosine kinase signaling pathway, eventually becoming various malignant tumors [ xref ]."
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"EGF induced activation of EGFR and subsequent tyrosine phosphorylation leads to endocytosis of the EGF and EGFR complex into late endosomes, which is followed by lysosomal fusion and degradation of the receptor, thus decreasing EGFR expression on the cell membrane and ultimately downregulating EGFR signaling XREF_BIBR, XREF_BIBR."
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"With respect to pre-EMT carcinoma cells, STAT3 is predominantly activated by the binding of EGF to EGFR (i.e., EGF dependent; XREF_FIG, left), and to a lesser extent, by the binding of FN to a complex comprised of alphavbeta3 integrin and EGFR (i.e., EGF independent; XREF_FIG, middle)."
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"HER ligands are divided into three groups; those which bind specifically to EGFR (epidermal growth factor, amphiregulin and transforming growth factor-alpha), those conferring dual specificity to EGFR and HER4 (betacellulin, heparin binding EGF, and epiregulin), and those which bind to HER3 and HER4 (neuregulins and heregulins) 14."
sparser
"These results demonstrated that mn-STESS promoted the expression of EGFR through self-powered ES to improve pharmacodynamics, thereby enhancing the binding of EGF to EGFR, promoting the phosphorylation of EGFR, and accelerating cell migration and proliferation by activating the EGFR signaling pathway."
reach
"Instead, binding of EGF to the EGFR was confined to other membrane populations, and correlation of ligand interaction with the laterobasal membranes (LBM) was nearly perfect (p less than 0.001) across a special equilibrium gradient enriched in brush border and LBM but devoid of intracellular membranes."
reach
"XREF_BIBR, XREF_BIBR By binding to the extracellular domain of the human EGFR, cetuximab competitively inhibits the binding of epidermal growth factor (EGF) and other ligands to EGFR, blocking receptor phosphorylation and activation of receptor associated kinases, thereby inhibiting downstream signal transduction and resulting in the inhibition of cell proliferation, induction of apoptosis, and reduction in angiogenesis."
reach
"The unitary association processes mirrored the EGF and ErbB1 interactions in HeLa cells [Teramura Y, et al. (2006) EMBO J 25:4215-4222], suggesting that the predimerization of the receptors, followed by intermediate formation (between the first and second ligand binding events to a receptor dimer), accelerated the formation of doubly liganded signaling dimers of the receptor molecules."
sparser
"One difference in how these studies were conducted is temperature: those which reported AP-2 siRNA to have an effect on EGFR entry were performed at 37° C; ( xref ), while in the two which claimed no role for AP-2 in EGFR endocytosis EGF binding was performed at 4° C ( xref ; xref )."
sparser
"MMF are predominantly identified via TLR1, TLR2, and TLR6. xref MMF can bind to these receptors and activate downstream signaling pathways including NF-κB, xref mitogen-activated protein kinases (MAPKs), xref and the epidermal growth factor receptor (EGFR). xref EGFR has long been recognized as a prominent receptor that regulates mucin production through endogenous and exogenous ligand signaling cascades, including the Ras/ERK or PI3K/Akt pathways. xref Previous reports indicated that SP-A exhibits a high affinity for live M. pneumoniae and MMF. xref In the absence or downregulation of SP-A, MMF induces increased activation of the EGFR signaling pathway, resulting in enhanced mucin production. xref In vitro experiments have indicated that SP-A can inhibit EGF-induced phosphorylation of EGFR, ERK, and Akt in a dose-dependent way, thereby inhibiting cell proliferation and motility. xref , xref Additionally, SP-A-deficient mice show heightened sensitivity to MMF exposure, and the pharmacological inhibition of EGFR before MMF stimulation significantly decreases mucin production and neutrophil infiltration in SP-A-deficient mice. xref Mechanistically, SP-A may interact with EGFR via the neck region of the CRD, effectively blocking the binding of EGF to EGFR and suppressing mucin production. xref These findings indicate that SP-A may contribute to the negative regulation of pulmonary inflammation to a certain degree."
reach
"XREF_BIBR, XREF_BIBR In a normal tissue, the ligand EGF binds to the EGF receptor (EGFR), inducing a dimerization of one or several members of the EGF receptor family (ErbB 1-4), activating several tyrosine kinases and other downstream signal molecules promoting transcription in the cell nucleus."
sparser
"Since human EGF can bind to murine EGFR with an affinity that is even stronger than that of human EGFR, xref this is pertinent to the safety concerns of targeting EGFR, which is a tumor-associated antigen. xref These results demonstrate the potency without overt toxicity of PVAQ."
sparser
"Under the conditions of the FA experiments, isolated sEGFR (without zipper or Fc fusion) remains monomeric; the FA assay contains just 60 nM EGF, so the maximum concentration of EGF-bound sEGFR is also limited to 60 nM – which is over 20-fold lower than the K D for dimerization of the EGF/sEGFR complex ( xref ; xref )."
sparser
"The K D value for EGF binding to dimeric sEGFR wild-type was essentially the same (within 2-fold) as that for sEGFR Y251A/R285S ( xref and xref ), arguing that the favorable Gibbs Free Energy (ΔG) of liganded sEGFR dimerization (−5.5 to −8 kcal/mol) does not contribute significantly (< 0.4 kcal/mol) to enhanced ligand-binding."
sparser
"Moreover, direct comparison of ITC and FA experiments shows that EGF binds sEGFR wild-type with very similar affinities regardless of whether it does (in ITC experiments) or does not (in FA experiments) dimerize ( xref , xref ) – also arguing that ligand binding and dimerization are not linked."
sparser
"Such a mechanism is consistent with our hypothesis that pre-incubation of 32D/EGFR cells with increasing concentrations of NRG2β/Q43L progressively (but incompletely) inhibits subsequent binding of radiolabelled EGF ( xref ) by stimulating EGFR degradation and depletion from the cell surface."
sparser
"In this study, we found that (1) CIN85 significantly facilitates EGFR internalization without apparently altering the levels of phosphorylated EGFR protein (i.e., EGFR signal intensity), consistent with the theory that TGF- α bound EGFRs are mainly sorted to the recycling-back pathway escaping from degradation, while a majority of EGF-bound EGFRs are processed via the degradation pathway [ xref ], (2) TGF- α bound EGFR receptor signals in the cytosol as well as on plasma membrane, activating ras-MAPK cascade (ras-enriched small cytosolic nanoparticles, “rasosomes,” might contribute to this signaling [ xref ]), (3) CIN85 silencing, therefore, inhibits EGFR internalization and activation of ras-MAPK cascade, and (4) CIB85 overexpression observed in 40% of HNSCC tumor samples contributes to the development of EGFR/ras-MAPK activation loop (Figures xref and xref )."
reach
"EGFR, as a transmembrane tyrosine kinase receptor, specifically binds to epidermal growth factor (EGF) or transforming growth factor-alpha (TGF-alpha), causing tyrosine kinase auto-phosphorylation, which in turn activates the phosphatidylinositol 3-kinase pathway (PI3K and Akt pathway) and ras-raf-mitogen-activated protein kinase pathway (Ras/Raf/MAPK pathway) XREF_BIBR."
sparser
"44, 839-848, March 28, 1988, Copyright 0 1986 by Cell Press
Protein Kinase C Phosphorylation at Thr 654 of the Unoccupied EGF Receptor and EGF Binding Regulate Functional Receptor Loss by Independent Mechanisms
Chijen R. Lin,’ William S. Chen,‘t Cheri S. Lazar, Clifford D. Carpenter; Gordon N. Gill, Ronald M. Evans,*9 and Michael G. Rosenfeld*§ l Eukaryotic Regulatory Biology Program University of California, San Diego La Jolla, California 92093 t Department of Chemistry University of California, San Diego La Jolla, California 92093 +Molecular Biology and Virology Laboratory The Salk Institute La Jolla, California 92138 5Howard Hughes Medical Institute La Jolla, California 92093
Summary
To test the functional consequence of phosphorylation of the EGF receptor at Thr 654 by protein kinase C, the normal Thr 654 human EGF receptor cDNA or a mutant encoding an Ala 654 were expressed in heterologous cells."
reach
"Fan et al. (4) using a mouse model, showed that at week 4, gene expressions of epidermal growth factor receptor (EGFR, a cell surface protein that binds to epidermal growth factor) and Suppressor of Mothers against Decapentaplegi-2 (smad 2) were higher in the Radiesse group compared to control; no difference in Smad 3 and fibrillin expression was found."
reach
"After incubation in HEPES buffer (pH 7.0) for 1h to facilitate an efficient interaction between the EGFR and EGF, the fractions of cytoplasm and cell wall of yeast cells were prepared, and then analyzed with anti-EGFR phosphotyrosine (pY) antibodies against pY-1068, pY-1148 and pY-1173 (XREF_FIG)."
reach
"These include : EGF, TGFalpha and amphiregulin (AREG), which bind specifically to EGFR; heparin binding EGF like growth factor, betacellulin and epiregulin which bind to both EGFR and ErbB4 [XREF_BIBR]; and the neuregulins and heregulins (HRGs), which are specific for ErbB3 and ErbB4 [XREF_BIBR]."
sparser
"EGF binds to Epidermal Growth Factor Receptor (EGFR) and show several growth promoting actions such as improved cell proliferation, cell growth and cell differentiation, improved ECM synthesis and ECM remodeling, increased protein synthesis and protein phosphorylation, and increased cell migration ( xref ; xref ; xref )."
reach
"The binding of EGF to the corresponding EGF receptor (EGFR), found to be over expressed in a number of cancers including breast cancer, stimulates the secretion of CSF-1, which further drives macrophages along the pro tumor pathway in a positive feedback loop with nearby tumor cells [XREF_BIBR, XREF_BIBR]."
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"Furthermore, blocking this interaction markedly decreased the overall metabolism in the heterospheroid systems but not the other cancer cell containing systems, confirming that the EGF and EGFR interaction is at least partly responsible for the early and sustained increased metabolic activity as noted by a decrease in oxygen level with the heterospheroids (XREF_FIG)."
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"We discovered that binding of the growth factor EGF to the EGFR extracellular domain induced the formation of a discrete anti-parallel coiled coil within the juxtamembrane-A (JM-A) segment, whereas binding of the alternative growth factor TGF-alpha induced an alternative, helical interface whose structure was not established (XREF_FIG)."
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"Because the antitumour mechanism of nimotuzumab is mainly attributed to its ability to interrupt the signal transduction cascade triggered by EGF and EGFR interaction, we have hypothesized that an aglycosylated form of this antibody, produced by mutating the N (297) position in the IgG (1) Fc region gene, would have similar biochemical and biological properties as the mammalian-cell-produced glycosylated counterpart."
sparser
"Similarly, Lidke and colleagues demonstrated that Qdot-conjugated EGF binds and activates the EGF receptor erbB1, being rapidly internalized into endosomes that exhibit active trafficking and extensive fusion in A431 cells (epidermal carcinoma) and CHO cells (chinese hamster ovary) xref ."
sparser
"The EGF:EGFR co-crystal structure ( xref ) was further studied to identify four residues (M21, A30, I38, and W49) on EGF that contact Domain I such that mutations to them would be predicted to disrupt the interface, either eliminating hydrophobic interactions or introducing steric hindrance."
sparser
"EGF binding to EGFR leads to receptor dimerization and autophosphorylation of many tyrosine residues in its C-terminal domain, allowing direct or indirect recruitment of proteins as growth factor receptor-bound protein 2 (Grb2), Gab1, the E3 ubiquitin ligase CBL, the phosphoinositide 3-kinase (PI3K) complex and Src kinase."
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"The previous study identified that the epidermal growth factor (EGF) promoted DNA synthesis and HCC cell regeneration, multiple inflammatory factor production and accumulation[24], and bound to EGFR to form EGF–EGFR pathway, which contributes to the formation of inflammation, angiogenesis, and distant HCC metastasis[25,26]."
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"Thus, in this regard HER2/HER4 heterodimers are more similar to known structures of HER homodimers (NRG1β-bound HER4 and EGF-bound EGFR homodimers) than to heterodimers.These similarities are also reflected in the interactions that the tips of both dimerization arms at the HER2/HER4 interface make with domains I of their respective dimerization partners."
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"Considering that inhibition of ligand binding to therapeutically block an oncogenic signal is one of the known MOAs with the anti-EGFR antibodies used in clinical treatment,6 we chose 14C07 as the lead antibody for further investigation.Histidine (H) has been repeatedly demonstrated to contribute to the binding between pH-dependent antibodies and their antigens.30 48 A previously reported crystal structure of EGFR/EGF complex revealed that two histidines (H370 and H433) in EGFR’s domain III (residues Lys335-Lys538) participate in the EGFR-EGF interaction."
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"It was evident that binding of EGF to EGFR triggered a series of biochemical events including autophosphorylation of specific tyrosine residues (like Tyr 1045, Tyr 992, Tyr 975, Tyr 1068, Tyr 1173 etc) in its kinase domain XREF_BIBR i.e activated EGFR protein level will be elevated without changing total EGFR protein level XREF_BIBR, XREF_BIBR."
sparser
"It was evident that binding of EGF to EGFR triggered a series of biochemical events including autophosphorylation of specific tyrosine residues (like Tyr 1045, Tyr 992, Tyr 975, Tyr 1068, Tyr 1173 etc) in its kinase domain xref i.e activated EGFR protein level will be elevated without changing total EGFR protein level xref , xref ."
sparser
"Although there are cross-interactions between EGF family and their receptors from human and mouse based on the structural similarity xref , xref , such as human EGF binding the mouse EGF receptor xref and mouse EGF binding the human EGF receptor xref , we confirmed that the human EGF peptide of the EGF-SEA fusion protein bound the EGFR of S180 cells by showing the interaction of anti-SEA antibody with EGFR-interacting EGF-SEA molecules ( xref ) and performing FACS analysis ( xref )."
sparser
"2D NS-EM class averages revealed heart-shaped particles, resembling those previously seen for the EGF-bound extracellular EGFR dimer, providing first structural characterization of the HER2/HER3 heterodimers, and showing, for the first time, that HER3 adopts an extended conformation upon ligand binding (discussed in detail in ( xref ))."
sparser
"Moreover, NMR studies of a 60-residue peptide containing the TM and part of the JM region solubilized in lipid bicelles led them to conclude that specific TM dimerization through an N-terminal GxxxG motif stabilizes formation of an antiparallel coiled-coil between the two JM fragments in the dimer – the same JM coiled coil shown in xref that was investigated in the bipartite tetracysteine display studies of intact EGF-bound EGFR described above [ xref , xref ]."
sparser
"From the structural and energetic analysis, it can be stated that when EGF binds to EGFR in the tethered form, the interactions between EGF and the binding pocket domains I (mainly) and III will begin, and this then narrows the binding pocket and finally expands the EGFR structure by pulling domain II out from its interaction with domain IV (Ferguson et al., 2003)."
sparser
"Furthermore, since the ERK pathway is initiated by the binding of epidermal growth factor (EGF) to the epidermal growth factor receptor (EGFR), we speculate that H-LIPEF could have an interaction with EGFR and cause the conformation change of EGFR, thus triggering the ERK pathway."
sparser
"Furthermore, introduction of additional dimerization-disrupting mutants, the receiver-impairing P699G mutant and activator-impairing M952R mutant, into the Ex20Ins background ( xref ) did not significantly reduce colony formation by Ex20Ins mutants ( xref ) but did abolish colony formation by wild-type EGFR with exogenous EGF ( xref )."
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"When clathrin dependent endocytosis is inhibited in HeLa cells by overexpression of a K44A (Lys (44) --> Ala) mutant of the GTPase dynamin, high-affinity binding of epidermal growth factor (EGF) to the EGF receptor (EGFR) is disrupted [Ringerike, Stang, Johannessen, Sandnes, Levy and Madshus (1998) J. Biol."
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"The binding of epidermal growth factor (EGF) to the EGF receptor triggers a rapid succession of intermolecular binding and phosphorylation steps that induce and amplify the signal to ultimately drive procession through cell cycle checkpoints, transcription factor activation of gene expression modules, assembly of macromolecules to promote protein translation, and alterations in choice of nutrient utilization programs (XREF_FIG)."
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"This can also be ligand specific with transforming growth factor alpha (TGFalpha) dissociating from the epidermal growth factor (EGF) receptor (EGFR) in the acidic environment of late endosomes allowing its prompt return to the plasma membrane by recycling endosomes, while the more stable EGF and EGFR complex is delivered to the lysosome compartment for degradation and attenuation of signaling [XREF_BIBR]."
sparser
"This model accurately recreated the pro-invasive Rac1 to RhoA switch observed in vitro [ xref ] and highlighted the importance of the Rac1 activator/inhibitor hierarchy a priori : the simulations suggested that either Rac1 activity simply gives way to RhoA activity following increased EGF–EGFR binding if RacGAP1 dominates the activity of Rac1 above all activators or, more interestingly, a steady state with RhoA-dominated Rac–RhoA pseudo-oscillations is reached if the Sos1-Eps8-Abi1 Rac1-specific activating complex [ xref ] preferentially acts upon Rac1 over the otherwise dominant RacGAP1."
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"EGF binding to EGFR triggers the activation of the receptor 's intrinsic kinase activity, in turn eliciting the recruitment of many secondary signaling proteins and activation of downstream signals, such as the activation of phosphatidylinositol-3-kinase (PI3K) and Akt, a process requiring the phosphorylation of Gab1."
sparser
"These kinases were chosen due to their known importance to schistosome biology: a) epidermal growth factor receptor (EGFR, SER), which binds human EGF and induces signalling in the worm [ xref , xref ]; b) PKCβ, which plays an important role in schistosome larval development and possibly regulates pairing and egg release of adults [ xref , xref ]; c) extracellular signal-regulated kinase 2 (ERK2), which together with ERK1, regulates the maintenance of the ovaries and thus egg production [ xref ]; d) Akt, which plays an important role in glucose uptake in adult worms [ xref ]; and e) PKA, which is important in schistosome motor activity and survival [ xref , xref ]."
sparser
"In this paper, taken into consideration abovementioned differences, we have focused on the behavior of vesicles bearing EEA1 and have demonstrated that (i) these vesicles are detected in HeLa and A549 cells in absence of external growth factors; (ii) the level of membrane-associated EEA1 did not change after stimulation of endocytosis with EGF and formation of comparable number of EGF/EGFR-loaded vesicles; (iii) newly formed endocytic vesicles loaded with EGF/EGFR complexes directly fuse with pre-existing EEA1-positive vesicles forming hybrid structures with domain organization of united membrane, (iv) fusions results in effective increase of EGFR- positive domains area, that makes it possible to form ILVs and sort there EGF/EGFR."