The epidermal growth factor receptor (EGFR) is one member of the ERBB family of transmembrane glycoprotein tyrosine receptor kinases (RTK). Binding of EGFR to its ligands induces conformational change that unmasks the dimerization interface in the extracellular domain of EGFR, leading to receptor homo- or heterodimerization at the cell surface. Dimerization of the extracellular regions of EGFR triggers additional conformational change of the cytoplasmic EGFR regions, enabling the kinase domains of two EGFR molecules to achieve the catalytically active conformation. Ligand activated EGFR dimers trans-autophosphorylate on tyrosine residues in the cytoplasmic tail of the receptor. Phosphorylated tyrosines serve as binding sites for the recruitment of signal transducers and activators of intracellular substrates, which then stimulate intracellular signal transduction cascades that are involved in regulating cellular proliferation, differentiation, and survival. Recruitment of complexes containing GRB2 and SOS1 to phosphorylated EGFR dimers either directly, through phosphotyrosine residues that serve as GRB2 docking sites, or indirectly, through SHC1 recruitment, promotes GDP to GTP exchange on RAS, resulting in the activation of RAF/MAP kinase cascade. Binding of complexes of GRB2 and GAB1 to phosphorylated EGFR dimers leads to formation of the active PI3K complex, conversion of PIP2 into PIP3, and activation of AKT signaling. Phospholipase C-gamma1 (PLCG1) can also be recruited directly, through EGFR phosphotyrosine residues that serve as PLCG1 docking sites, which leads to PLCG1 phosphorylation by EGFR and activation of DAG and IP3 signaling. EGFR signaling is downregulated by the action of ubiquitin ligase CBL. CBL binds directly to the phosphorylated EGFR dimer through the phosphotyrosine Y1045 in the C-tail of EGFR, and after CBL is phosphorylated by EGFR, it becomes active and ubiquitinates phosphorylated EGFR dimers, targeting them for degradation. For a recent review of EGFR signaling, please refer to Avraham and Yarden, 2011.
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Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, Singh B, Heelan R, Rusch V, Fulton L, Mardis E, Kupfer D, Wilson R, Kris M, Varmus H.; ''EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib.''; PubMedEurope PMCScholia
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Bache KG, Raiborg C, Mehlum A, Stenmark H.; ''STAM and Hrs are subunits of a multivalent ubiquitin-binding complex on early endosomes.''; PubMedEurope PMCScholia
Chardin P, Camonis JH, Gale NW, van Aelst L, Schlessinger J, Wigler MH, Bar-Sagi D.; ''Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2.''; PubMedEurope PMCScholia
Cantwell-Dorris ER, O'Leary JJ, Sheils OM.; ''BRAFV600E: implications for carcinogenesis and molecular therapy.''; PubMedEurope PMCScholia
Kazazic M, Bertelsen V, Pedersen KW, Vuong TT, Grandal MV, Rødland MS, Traub LM, Stang E, Madshus IH.; ''Epsin 1 is involved in recruitment of ubiquitinated EGF receptors into clathrin-coated pits.''; PubMedEurope PMCScholia
Songyang Z, Margolis B, Chaudhuri M, Shoelson SE, Cantley LC.; ''The phosphotyrosine interaction domain of SHC recognizes tyrosine-phosphorylated NPXY motif.''; PubMedEurope PMCScholia
Lombardo CR, Consler TG, Kassel DB.; ''In vitro phosphorylation of the epidermal growth factor receptor autophosphorylation domain by c-src: identification of phosphorylation sites and c-src SH2 domain binding sites.''; PubMedEurope PMCScholia
Plotnikov A, Zehorai E, Procaccia S, Seger R.; ''The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation.''; PubMedEurope PMCScholia
Meisenhelder J, Suh PG, Rhee SG, Hunter T.; ''Phospholipase C-gamma is a substrate for the PDGF and EGF receptor protein-tyrosine kinases in vivo and in vitro.''; PubMedEurope PMCScholia
Wu WJ, Tu S, Cerione RA.; ''Activated Cdc42 sequesters c-Cbl and prevents EGF receptor degradation.''; PubMedEurope PMCScholia
Brown MD, Sacks DB.; ''Protein scaffolds in MAP kinase signalling.''; PubMedEurope PMCScholia
Lock LS, Frigault MM, Saucier C, Park M.; ''Grb2-independent recruitment of Gab1 requires the C-terminal lobe and structural integrity of the Met receptor kinase domain.''; PubMedEurope PMCScholia
Schlessinger J.; ''Ligand-induced, receptor-mediated dimerization and activation of EGF receptor.''; PubMedEurope PMCScholia
Ren Y, Meng S, Mei L, Zhao ZJ, Jove R, Wu J.; ''Roles of Gab1 and SHP2 in paxillin tyrosine dephosphorylation and Src activation in response to epidermal growth factor.''; PubMedEurope PMCScholia
Lee JC, Vivanco I, Beroukhim R, Huang JH, Feng WL, DeBiasi RM, Yoshimoto K, King JC, Nghiemphu P, Yuza Y, Xu Q, Greulich H, Thomas RK, Paez JG, Peck TC, Linhart DJ, Glatt KA, Getz G, Onofrio R, Ziaugra L, Levine RL, Gabriel S, Kawaguchi T, O'Neill K, Khan H, Liau LM, Nelson SF, Rao PN, Mischel P, Pieper RO, Cloughesy T, Leahy DJ, Sellers WR, Sawyers CL, Meyerson M, Mellinghoff IK.; ''Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain.''; PubMedEurope PMCScholia
Gual P, Giordano S, Williams TA, Rocchi S, Van Obberghen E, Comoglio PM.; ''Sustained recruitment of phospholipase C-gamma to Gab1 is required for HGF-induced branching tubulogenesis.''; PubMedEurope PMCScholia
Secondary mutation T790M in EGFR E746_A750del mutant confers TKI resistance and results in cancer progression in patients initially responsive to TKI therapy (Balak et al. 2006).
L858R, a substitution of leucine 858 with arginine, accounts for ~40% of EGFR mutations in the non-small-cell lung cancer. L858R, encoded by exon 21, localizes to the N-terminal portion of the activation loop (A loop) of the kinase domain of EGFR. By locking the EGFR in its active conformation, L858R mutation results in constitutive catalytic activity of EGFR which is ~50-fold higher than the activity of the wild-type enzyme (Yun et al. 2007). The L858R EGFR mutant is inhibited by binding of small EGFR-specific tyrosine kinase inhibitors from the 4-anilinoquinazoline group, erlotinib and gefitinib, as well as the pyrrolopyrimidine compound AEE788. Gefitinib is ~100-fold more potent against the L858R mutant than against the wild-type EGFR kinase (Yun et al. 2007). Erlotinib (Pao et al. 2004) and AEE788 (Yun et al. 2007) are also more efficient in inhibiting the L858R mutant than the wild-type EGFR.
Secondary mutation T790M in EGFR L858R mutant confers TKI resistance and results in cancer progression in patients initially responsive to TKI therapy (Balak et al. 2006).
L861Q, a substitution of leucine 861 with glutamine, is a documented EGFR mutation in the non-small-cell lung cancer (NSCLC). Leu861, encoded by exon 21, localizes to the N-terminal portion of the activation loop (A loop) of the kinase domain of EGFR and together with Leu858 participates in hydrophobic interactions that keep the kinase in the inactive conformation (Zhang et al. 2006). Replacement of Leu861 with glutamine is expected to destabilize the inactive conformation of EGFR and result in constitutive catalytic activity (Zhang et al. 2006). NSCLCs harboring L861Q mutation in EGFR are responsive to small EGFR-specific tyrosine kinase inhibitors from the 4-anilinoquinazoline group gefitinib (Lynch et al. 2004) and are expected to be responsive to the related drug, erlotinib.
EGFR V30_R297delinsG mutant of EGFR, commonly known as EGFRvIII, is found in ~25% high-grade glioblastomas and can also be found in squamous cell carcinoma of the lung. EGFRvIII lacks the ligand biding domain and is constitutively active.
EGFR V30_R297delinsG mutant of EGFR, commonly known as EGFRvIII, is found in ~25% high-grade glioblastomas and can also be found in squamous cell carcinoma of the lung. EGFRvIII lacks the ligand biding domain and is constitutively active.
Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007.
The RAS-RAF-MEK-ERK pathway regulates processes such as proliferation, differentiation, survival, senescence and cell motility in response to growth factors, hormones and cytokines, among others. Binding of these stimuli to receptors in the plasma membrane promotes the GEF-mediated activation of RAS at the plasma membrane and initiates the three-tiered kinase cascade of the conventional MAPK cascades. GTP-bound RAS recruits RAF (the MAPK kinase kinase), and promotes its dimerization and activation (reviewed in Cseh et al, 2014; Roskoski, 2010; McKay and Morrison, 2007; Wellbrock et al, 2004). Activated RAF phosphorylates the MAPK kinase proteins MEK1 and MEK2 (also known as MAP2K1 and MAP2K2), which in turn phophorylate the proline-directed kinases ERK1 and 2 (also known as MAPK3 and MAPK1) (reviewed in Roskoski, 2012a, b; Kryiakis and Avruch, 2012). Activated ERK proteins may undergo dimerization and have identified targets in both the nucleus and the cytosol; consistent with this, a proportion of activated ERK protein relocalizes to the nucleus in response to stimuli (reviewed in Roskoski 2012b; Turjanski et al, 2007; Plotnikov et al, 2010; Cargnello et al, 2011). Although initially seen as a linear cascade originating at the plasma membrane and culminating in the nucleus, the RAS/RAF MAPK cascade is now also known to be activated from various intracellular location. Temporal and spatial specificity of the cascade is achieved in part through the interaction of pathway components with numerous scaffolding proteins (reviewed in McKay and Morrison, 2007; Brown and Sacks, 2009). The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).
In the cytoplasm of unstimulated cells, SOS1 is found in a complex with GRB2. The interaction occurs between the carboxy terminal domain of SOS1 and the Src homology 3 (SH3) domains of GRB2.
Benzoquinoid ansamycins (geldanamycin, herbimycin, and geldanamycin derivatives 17-AAG, 17-DMAG and IPI-504) are antitumor antibiotics that inactivate HSP90 by binding to its substrate-binding pocket.
EGFR kinase domain mutants need continuous association with HSP90 chaperone protein for proper functioning. CDC37 is a co-chaperone of HSP90 that acts as a scaffold and regulator of interaction between HSP90 and its protein kinase clients. CDC37 binds a protein kinase through its N-terminal domain and HSP90 through its C-terminal domain, arresting ATP-ase activity of HSP90 and enabling the loading of a client kinase. CDC37 is frequently over-expressed in cancers involving mutant kinases and acts as an oncogene (reviewed by Gray Jr. et al. 2008). Association of EGFR extracellular domain point mutants with HSP90 chaperone has not been tested.
Non-covalent (reversible) tyrosine kinase inhibitors (TKIs), erlotinib, gefitinib, lapatinib and vandetanib, selectively inhibit EGFR-stimulated tumor cell growth by blocking EGFR mutant autophosphorylation through competitive inhibition of ATP binding to the kinase domain. A number of EGFR kinase domain mutants and extracellular domain point mutants show increased senistivity to non-covalent TKIs compared with the wild-type EGFR. EGFR kinase domain mutants may be resistant to non-covalent TKIs due to primary or secondary mutations in the kinase domain that increase the affinity of the kinase domain for ATP, such as small insertions within exon 20, and substituion of threonine 790 with methionine (T790M).
Covalent (irreversible) tyrosine kinase inhibitors (TKIs), pelitinib, WZ4002, HKI-272, canertinib and afatinib, form a covalent bond with the EGFR cysteine residue C397 and inhibit trans-autophosphorylation of mutants resistant to non-covalent TKIs. However, effective concentrations of covalent TKIs also inhibit wild type EGFR, resulting in severe side effects. Hence, covalent TKIs have not shown much promise as therapeutics.
EGFR ligand-responsive mutants dimerize spontaneously, without ligand binding, although ligand binding ability is preserved. This was experimentally demonstrated for EFGR L858R mutant and is presumed to happen in other constitutively active EGFR kinase domain mutants and EGFR extracellular domain point mutants.
Covalent (irreversible) TKIs, pelitinib, WZ4002, HKI-272, canertinib and afatinib, inhibit the wild-type EGFR through formation of the covalent bond with the cysteine residue C397.
EGFRvIII mutant lacks the ligand binding domain and is therefore unable to bind EGFR ligands, but is able to dimerize spontaneously. Self-dimerization may be dependent on N-linked glycosylation.
Cetuximab binds to the extracellular domain of EGFR and blocks ligand binding, leading to receptor inactivation, internalization and degradation. Cetuximab is approved for combination therapy and monotherapy of metastatic colorectal cancer and advanced squamous cell carcinoma of head and neck in patients whose tumors over-express wild-type EGFR protein, usually due to amplification of EGFR gene.
EGF and other growth factors induce oligomerization of their specific receptors. Inactive EGFR monomers are in equilibrium with active EGFR dimers and binding of the EGF ligand stabilizes the active dimeric form.
SHP2 can dephosphorylate paxillin, which leads to Csk dissociation from the paxillin-Src complex and Src activation. Src is an SHP2 effector in EGF-stimulated Erk activation and cell migration.
Phosphorylated GAB1 can bind PI3 kinase by its regulatory alpha subunit. SHP2 dephosphorylation of the tyrosine residues 447, 472 and 589 on GAB1 means PI3 kinase can no longer bind to the complex in the plasma membrane and cannot be activated.
SHC1 (Src homology 2 domain-containing) transforming protein can bind to either phosphorylated tyrosine 1148 (p-Y1148) and/or tyrosine 1173 (p-Y1173) sites on the EGF receptor. The N-terminal phosphotyrosine binding domain (PBD) of SHC1, also known as the phosphotyrosine interaction (PI) domain, binds to phosphorylated p-Y1148 of EGFR, which is part of the NPXpY motif. The SH2 domain of SHC1 binds to p-Y1173 of EGFR (Batzer et al. 1995, Songyang et al. 1995, Sakaguchi et al. 1998).
Dephosphorylation of CBP/PAG negatively regulates the recruitment of the Src inhibiting kinase, Csk. Src is not negatively regulated by phosphorylation by Csk.
The Src homology 2 (SH2) domain of the phosphatidylinositol 3-kinase (PIK3) regulatory subunit (PIK3R1, i.e. PI3Kp85) binds to GAB1 in a phosphorylation-independent manner. GAB1 serves as a docking protein which recruits a number of downstream signalling proteins. PIK3R1 can bind to either GAB1 or phosphorylated GAB1.
The cytoplasmic domain of EGFR contains tyrosine, serine and threonine phosphorylation sites. Dimerization of EGFR activates its intrinsic protein kinase activity and results in autophosphorylation of 6 tyrosine residues in the cytoplasmic tail of EGFR. Tyrosine autophosphorylation is crucial for normal receptor signalling. Five of these tyrosine residues (Y992, Y1068, Y1086, Y1148 and Y1173) serve as specific binding sites for cytosolic target proteins involved in signal transmission, while the tyrosine residue Y1045 is involved in recruitment of CBL ubiquitin ligase and downregulation of EGFR signaling through degradation of activated EGFR.
The tyrosine-protein phosphatase SHP2 is a positive effector of EGFR signalling. SHP2 inhibits the tyrosine-dependent translocation of RasGAP (catalyses Ras inactivation) to the plasma membrane, thereby keeping it away from Ras-GTP (its substrate). This inhibition is achieved by the dephosphorylation of a RasGAP binding site on the EGF receptor.
Besides autophosphorylation, EGFR can become tyrosine-phosphorylated by the action of the proto-oncogene tyrosine-protein kinase, c-src. This Src homology 2 (SH2) domain-containing protein is one of many such proteins which bind to phosphorylated sites on EGFR to affect signal transmission into the cell.
The guanine nucleotide exchange factor SOS1 interacts with EGFR through the adaptor protein, GRB2. Upon formation of this complex, SOS activates RAS by promoting GDP release and GTP binding.
The regulatory subunit of PIK3 mediates the association of GAB1 and receptor protein-tyrosine kinases such as the EGF receptor, which can phosphorylate GAB1. It appears that the PIK3 regulatory subunit acts as an adaptor protein allowing GAB1 to serve as a substrate for several tyrosine kinases.
The prototypic receptor tyrosine kinase (RTK) EGFR is composed of 3 major domains; an extracellular domain linked via a single membrane-spanning domain to a cytoplasmic domain. EGF binds to the extracellular domain from where the signal is transmitted to the cytoplasmic domain.
Cytoplasmic target proteins containing the SH2 domain can bind to activated EGFR. One such protein, growth factor receptor-bound protein 2 (GRB2), can bind activated EGFR with its SH2 domain whilst in complex with SOS through its SH3 domain. GRB2 can bind at either Y1068 and/or Y1086 tyrosine autophosphorylation sites on the receptor.
The SH2 domains repress phosphatase activity of SHP2. Binding of these domains to phosphotyrosine-containing proteins relieves this autoinhibition, possibly by inducing a conformational change in the enzyme.
SOS1 is the guanine nucleotide exchange factor (GEF) for RAS. SOS1 activates RAS nucleotide exchange from the inactive form (bound to GDP) to an active form (bound to GTP).
Ligands of the epidermal growth factor receptor (EGFR) are shed from the plasma membrane by metalloproteases. Identification of the sheddases for EGFR ligands using mouse embryonic cells lacking candidate sheddases (a disintegrin and metalloprotease; ADAM) has revealed that ADAM10, -12 and -17 are the sheddases of the EGFR ligands in response to various shedding stimulants such as GPCR agonists, growth factors, cytokines, osmotic stress, wounding and phorbol ester. Among the EGFR ligands, heparin-binding EGF-like growth factor (HB-EGF), EGF and TGF-alpha are the best characterized.
The pleckstrin homology (PH) domain of GAB1 binds to PIP3 and can target GAB1 to the plasma membrane in response to EGF stimulation. This mechanism provides a positive feedback loop with respect to PI3K activation, to enhance EGFR signalling.
EGF (and indeed FGF, PDGF and NGF) stimulation results in CBL phosphorylation on Tyr-371. Phosphorylation is necessary for CBL to exhibit ubiquitin ligase activity.
The adaptor protein CIN85 is monoubiquitinated by CBL after EGF stimulation. Monoubiquitination is thought to regulate receptor internalization and endosomal sorting.
The NEYTEG motif is very similar to the CBL binding motif around Tyr-1045 in EGFR. Tyrosine-phosphorylated Sprouty (hSpry) binds to CBL, which then cannot ubiquitinate EGFR. Sprouty acts as a decoy to lure CBL away from EGFR and targets it for degradation.
Sprouty can constitutively interact with two SH3 domains of CIN85 whereas the third SH3 domain of CIN85 can still associate with CBL on cell activation with EGF. This allows Sprouty to block CIN85-mediated clustering of CBL molecules, stablization of CBL-EGFR interactions and efficient ubiquitination and down-regulation of EGFR.
CBL down-regulates receptor tyrosine kinases by conjugating ubiquitin to them. This leads to receptor internalization and degradation. The ubiquitin protein ligase activity of CBL (abbreviated as E3 activity) is mediated by its RING finger domain.
CBL-CIN85-Endophilin complex mediates ligand-induced down-regulation of the EGF receptor. The BAR domain of endophilin induces membrane curvature. The three SH3 domains of CIN85 bind to atypical proline-arginine motifs (PxxxPR) present in the carboxyl termini of CBL and CBL-b. In this way, CIN85 clusters CBL molecules, which is crucial for efficient EGFR endocytosis and degradation (Soubeyran et al. 2002).
High concentrations of active CDC42 (bound to GTP) and Beta-Pix may promote the binding of Beta-Pix to CBL, pushing out the usually preferred binding partner CIN85 (SH3KBP1) from the CBL complex. This competitive mechanism could block the CIN85-imposed clustering phenomenon on CBL that is required for tighter binding (Schmidt et al. 2006).
The NEYTEG motif is very similar to the CBL binding motif around Tyr-1045 in EGFR. Tyrosine-phosphorylated Sprouty (hSpry) binds to CBL, which then cannot ubiquitinate EGFR. Sprouty acts as a decoy to lure CBL away from EGFR and targets it for degradation.
CBL down-regulates receptor tyrosine kinases by conjugating ubiquitin to them. This leads to receptor internalization and degradation. The ubiquitin protein ligase activity of CBL (abbreviated as E3 activity) is mediated by its RING finger domain.
Sprouty is ubiquitinated by CBL in an EGF-dependent manner. EGF stimulation induces the tyrosine phosphorylation of Sprouty, which in turn enhances the interaction of Sprouty with CBL. The CBL-mediated ubiquitination of Sprouty targets the protein for degradation by the 26S proteasome.
CBL binds multiple signalling proteins including GRB2. The CBL:GRB2 complex translocates to the plasma membrane where it can bind to GRB2-specific docking sites on the EGF receptor.
Phosphorylation at tyrosine Y1045 of EGFR creates a major docking site for E3 ubiquitin-protein ligase, CBL (Casitas B-lineage lymphoma proto- oncogene) and is required to sort the EGFR to lysosomes for degradation. The E3 ligase CBL plays a crucial role in these events as it dually participates in early events of internalization via a CIN85-endophilin dependent mechanism and endocytic sorting by mediating multiple monoubiquitylation of the receptor.
EGF (and indeed FGF, PDGF and NGF) stimulation results in CBL phosphorylation on Tyr-371. Phosphorylation is necessary for CBL to exhibit ubiquitin ligase activity.
At higher concentrations of ligand, a substantial fraction of the receptor (>50%) is endocytosed through a clathrin independent, lipid-raft-dependent route as the receptor becomes Y1045 phosphorylated and ubiquitnated. Eps15 and Epsin are found in caveolae. Eps15 and Epsin are immunoprecipated with the EGF receptor. Non-clathrin internalization of ubiquitinated EGFR depends on its interaction with proteins harbouring the UIM Ub-interacting motif, as shown through the ablation of three Ub-interacting motif-containing proteins, Eps15, Eps15R and Epsin.
Beta-Pix (Cool-1) associates with CBL, which appears to be a critical step in CDC42-mediated inhibition of EGFR ubiquitylation and downregulation. The SH3 domain of Beta-Pix specifically interacts with a proline-arginine motif (PxxxPR) present within CBL, which mediates ubiquitylation and subsequent degradation of Beta-Pix.
Sprouty is ubiquitinated by CBL in an EGF-dependent manner. EGF stimulation induces the tyrosine phosphorylation of Sprouty, which in turn enhances the interaction of Sprouty with CBL.The CBL-mediated ubiquitination of Sprouty targets the protein for degradation by the 26S proteosome.
Activated CDC42 binds to Beta-Pix (p85Cool-1), a protein that directly associates with CBL. This inhibits the binding of CBL to the EGF receptor and thus prevents CBL from catalyzing receptor ubiquitination.
PTPN12 protein tyrosine phosphatase dephosphorylates activated EGFR at tyrosine residue Y1148 (Y1148 corresponds to Y1172 in the nascent EGFR sequence which includes the 24 amino acid long signal peptide at the N-terminus). PTPN12-mediated dephosphorylation of activated EGFR inhibits SHC1 recruitment to the p-Y1148 docking site, thus attenuating downstream RAS activation (Sun et al. 2011). The recruitment of SHC1 to p-Y1148 of EGFR is mediated by the N-terminal phosphotyrosine interaction domain (PID) of SHC1 (Batzer et al. 1995, Songyang et al. 1995).
EPS15 is phosphorylated at Y849 by activated EGFR (Confalonieri et al, 2000). While the roles of phosphorylation and ubiquitination in EGFR endocytosis are unclear, emerging evidence suggests that EPS15 phosphorylation may target the activated EGFR complex for endocytosis through a clathrin-mediated route, while dephosphorylation at Y849 may direct the receptor complex into a clathrin-independent route (Confalonieri et al, 2002; de Melker et al, 2004; Li et al, 2015; reviewed in van Bergen en Henegouwen, 2009).
EH-containing proteins such as EPS15, EPN1 and EPS15L1 are required for the endocytosis of ligand-activated EGFR (Confalonieri et al, 2000; Huang et al, 2004; reviewed in van Bergen en Henegouwen, 2009). EPS15 and EPN1 bind components of the clathrin coated pit through DPF motifs and likely bind to EGFR through the ubiquitin interacting motifs (UIMs). In this way EH proteins may help cluster activated EGFR into nascent clathrin-coated pits (Kazazic et al, 2009; Benmerah et al, 2000; reviewed in van Bergen en Henegouwen, 2009). Note, however, that EH-containing proteins are also involved in the clathrin-independent endocytosis of EGFR (Sigismund et al, 2005)
While the roles of EGFR and EPS15 phosphorylation and ubiquitination are not completely clear, recent evidence supports the idea that EGFR-mediated phosphorylation of EPS15 promotes the clustering of the activated receptor into clathrin-coated pits, while the dephosphorylated EPS15 targets EGFR for endocytosis through a caveolin-and lipid raft-dependent route (reviewed in van Bergen en Henegouwen, 2009). Consistent with this, overexpression of the phosphatase PTPN3, which dephosphorylates EPS15 in vitro and in vivo, promotes the internalization of EGFR into caveolin-enriched structures and targets it for lysosomal degradation (Li et al, 2015).
High concentrations of active CDC42 (bound to GTP) and Beta-Pix may promote the binding of Beta-Pix to CBL, pushing out the usually preferred binding partner CIN85 (SH3KBP1) from the CBL complex. This competitive mechanism could block the CIN85-imposed clustering phenomenon on CBL that is required for tighter binding (Schmidt et al. 2006).
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ligand-responsive
EGFR mutantstyrosine kinase
inhibitorsDimer:Covalent EGFR
TKIsdephosphorylated at
Y1148 (Y1172)EGFR
mutants:HSP90:CDC37tyrosine kinase
inhibitorsThe importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).
ligand-responsive EGFR mutants:Covalent
EGFR TKIsligand-responsive
EGFR mutantsligand-responsive EGFR
mutants:Non-covalent EGFR TKIsAnnotated Interactions
ligand-responsive
EGFR mutantstyrosine kinase
inhibitorstyrosine kinase
inhibitorsDimer:Covalent EGFR
TKIsdephosphorylated at
Y1148 (Y1172)EGFR
mutants:HSP90:CDC37EGFR
mutants:HSP90:CDC37tyrosine kinase
inhibitorsligand-responsive EGFR mutants:Covalent
EGFR TKIsligand-responsive
EGFR mutantsligand-responsive
EGFR mutantsligand-responsive EGFR
mutants:Non-covalent EGFR TKIs