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.
Roskoski R.; ''RAF protein-serine/threonine kinases: structure and regulation.''; PubMedEurope PMCScholia
Yang S, Qu S, Perez-Tores M, Sawai A, Rosen N, Solit DB, Arteaga CL.; ''Association with HSP90 inhibits Cbl-mediated down-regulation of mutant epidermal growth factor receptors.''; PubMedEurope PMCScholia
Zhang SQ, Yang W, Kontaridis MI, Bivona TG, Wen G, Araki T, Luo J, Thompson JA, Schraven BL, Philips MR, Neel BG.; ''Shp2 regulates SRC family kinase activity and Ras/Erk activation by controlling Csk recruitment.''; PubMedEurope PMCScholia
Soubeyran P, Kowanetz K, Szymkiewicz I, Langdon WY, Dikic I.; ''Cbl-CIN85-endophilin complex mediates ligand-induced downregulation of EGF receptors.''; PubMedEurope PMCScholia
Kyriakis JM, Avruch J.; ''Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update.''; PubMedEurope PMCScholia
Hall AB, Jura N, DaSilva J, Jang YJ, Gong D, Bar-Sagi D.; ''hSpry2 is targeted to the ubiquitin-dependent proteasome pathway by c-Cbl.''; PubMedEurope PMCScholia
Walton GM, Chen WS, Rosenfeld MG, Gill GN.; ''Analysis of deletions of the carboxyl terminus of the epidermal growth factor receptor reveals self-phosphorylation at tyrosine 992 and enhanced in vivo tyrosine phosphorylation of cell substrates.''; PubMedEurope PMCScholia
Joazeiro CA, Wing SS, Huang H, Leverson JD, Hunter T, Liu YC.; ''The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-dependent ubiquitin-protein ligase.''; PubMedEurope PMCScholia
Cseh B, Doma E, Baccarini M.; ''"RAF" neighborhood: protein-protein interaction in the Raf/Mek/Erk pathway.''; PubMedEurope PMCScholia
Panchamoorthy G, Fukazawa T, Miyake S, Soltoff S, Reedquist K, Druker B, Shoelson S, Cantley L, Band H.; ''p120cbl is a major substrate of tyrosine phosphorylation upon B cell antigen receptor stimulation and interacts in vivo with Fyn and Syk tyrosine kinases, Grb2 and Shc adaptors, and the p85 subunit of phosphatidylinositol 3-kinase.''; PubMedEurope PMCScholia
Kassenbrock CK, Anderson SM.; ''Regulation of ubiquitin protein ligase activity in c-Cbl by phosphorylation-induced conformational change and constitutive activation by tyrosine to glutamate point mutations.''; PubMedEurope PMCScholia
Schmidt MHH, Husnjak K, Szymkiewicz I, Haglund K, Dikic I.; ''Cbl escapes Cdc42-mediated inhibition by downregulation of the adaptor molecule betaPix.''; PubMedEurope PMCScholia
McKay MM, Morrison DK.; ''Integrating signals from RTKs to ERK/MAPK.''; PubMedEurope PMCScholia
Helin K, Beguinot L.; ''Internalization and down-regulation of the human epidermal growth factor receptor are regulated by the carboxyl-terminal tyrosines.''; PubMedEurope PMCScholia
Red Brewer M, Choi SH, Alvarado D, Moravcevic K, Pozzi A, Lemmon MA, Carpenter G.; ''The juxtamembrane region of the EGF receptor functions as an activation domain.''; PubMedEurope PMCScholia
Sakaguchi K, Okabayashi Y, Kido Y, Kimura S, Matsumura Y, Inushima K, Kasuga M.; ''Shc phosphotyrosine-binding domain dominantly interacts with epidermal growth factor receptors and mediates Ras activation in intact cells.''; PubMedEurope PMCScholia
de Melker AA, van der Horst G, Borst J.; ''Ubiquitin ligase activity of c-Cbl guides the epidermal growth factor receptor into clathrin-coated pits by two distinct modes of Eps15 recruitment.''; PubMedEurope PMCScholia
Pao W, Chmielecki J.; ''Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer.''; PubMedEurope PMCScholia
Kapoor GS, Zhan Y, Johnson GR, O'Rourke DM.; ''Distinct domains in the SHP-2 phosphatase differentially regulate epidermal growth factor receptor/NF-kappaB activation through Gab1 in glioblastoma cells.''; PubMedEurope PMCScholia
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA.; ''Mutations of the BRAF gene in human cancer.''; PubMedEurope PMCScholia
Sherrill JM, Kyte J.; ''Activation of epidermal growth factor receptor by epidermal growth factor.''; PubMedEurope PMCScholia
Turjanski AG, Vaqué JP, Gutkind JS.; ''MAP kinases and the control of nuclear events.''; PubMedEurope PMCScholia
Rodrigues GA, Falasca M, Zhang Z, Ong SH, Schlessinger J.; ''A novel positive feedback loop mediated by the docking protein Gab1 and phosphatidylinositol 3-kinase in epidermal growth factor receptor signaling.''; PubMedEurope PMCScholia
Wahl MI, Nishibe S, Kim JW, Kim H, Rhee SG, Carpenter G.; ''Identification of two epidermal growth factor-sensitive tyrosine phosphorylation sites of phospholipase C-gamma in intact HSC-1 cells.''; PubMedEurope PMCScholia
Fukumoto T, Kubota Y, Kitanaka A, Yamaoka G, Ohara-Waki F, Imataki O, Ohnishi H, Ishida T, Tanaka T.; ''Gab1 transduces PI3K-mediated erythropoietin signals to the Erk pathway and regulates erythropoietin-dependent proliferation and survival of erythroid cells.''; PubMedEurope PMCScholia
Burtness B, Goldwasser MA, Flood W, Mattar B, Forastiere AA, Eastern Cooperative Oncology Group.; ''Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study.''; PubMedEurope PMCScholia
Roe SM, Ali MM, Meyer P, Vaughan CK, Panaretou B, Piper PW, Prodromou C, Pearl LH.; ''The Mechanism of Hsp90 regulation by the protein kinase-specific cochaperone p50(cdc37).''; PubMedEurope PMCScholia
Grøvdal LM, Stang E, Sorkin A, Madshus IH.; ''Direct interaction of Cbl with pTyr 1045 of the EGF receptor (EGFR) is required to sort the EGFR to lysosomes for degradation.''; PubMedEurope PMCScholia
Lock LS, Royal I, Naujokas MA, Park M.; ''Identification of an atypical Grb2 carboxyl-terminal SH3 domain binding site in Gab docking proteins reveals Grb2-dependent and -independent recruitment of Gab1 to receptor tyrosine kinases.''; PubMedEurope PMCScholia
Fan YX, Wong L, Deb TB, Johnson GR.; ''Ligand regulates epidermal growth factor receptor kinase specificity: activation increases preference for GAB1 and SHC versus autophosphorylation sites.''; PubMedEurope PMCScholia
Roskoski R.; ''MEK1/2 dual-specificity protein kinases: structure and regulation.''; PubMedEurope PMCScholia
Batzer AG, Blaikie P, Nelson K, Schlessinger J, Margolis B.; ''The phosphotyrosine interaction domain of Shc binds an LXNPXY motif on the epidermal growth factor receptor.''; PubMedEurope PMCScholia
Carpenter G, Ji Q.; ''Phospholipase C-gamma as a signal-transducing element.''; PubMedEurope PMCScholia
Cargnello M, Roux PP.; ''Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases.''; PubMedEurope PMCScholia
Li MY, Lai PL, Chou YT, Chi AP, Mi YZ, Khoo KH, Chang GD, Wu CW, Meng TC, Chen GC.; ''Protein tyrosine phosphatase PTPN3 inhibits lung cancer cell proliferation and migration by promoting EGFR endocytic degradation.''; PubMedEurope PMCScholia
Patterson RL, van Rossum DB, Nikolaidis N, Gill DL, Snyder SH.; ''Phospholipase C-gamma: diverse roles in receptor-mediated calcium signaling.''; PubMedEurope PMCScholia
Sun T, Aceto N, Meerbrey KL, Kessler JD, Zhou C, Migliaccio I, Nguyen DX, Pavlova NN, Botero M, Huang J, Bernardi RJ, Schmitt E, Hu G, Li MZ, Dephoure N, Gygi SP, Rao M, Creighton CJ, Hilsenbeck SG, Shaw CA, Muzny D, Gibbs RA, Wheeler DA, Osborne CK, Schiff R, Bentires-Alj M, Elledge SJ, Westbrook TF.; ''Activation of multiple proto-oncogenic tyrosine kinases in breast cancer via loss of the PTPN12 phosphatase.''; PubMedEurope PMCScholia
Montagner A, Yart A, Dance M, Perret B, Salles JP, Raynal P.; ''A novel role for Gab1 and SHP2 in epidermal growth factor-induced Ras activation.''; PubMedEurope PMCScholia
Huang F, Khvorova A, Marshall W, Sorkin A.; ''Analysis of clathrin-mediated endocytosis of epidermal growth factor receptor by RNA interference.''; PubMedEurope PMCScholia
Lavictoire SJ, Parolin DA, Klimowicz AC, Kelly JF, Lorimer IA.; ''Interaction of Hsp90 with the nascent form of the mutant epidermal growth factor receptor EGFRvIII.''; PubMedEurope PMCScholia
Paez JG, Jänne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M.; ''EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy.''; PubMedEurope PMCScholia
Zhang X, Gureasko J, Shen K, Cole PA, Kuriyan J.; ''An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor.''; PubMedEurope PMCScholia
Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA.; ''Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib.''; PubMedEurope PMCScholia
Greulich H, Chen TH, Feng W, Jänne PA, Alvarez JV, Zappaterra M, Bulmer SE, Frank DA, Hahn WC, Sellers WR, Meyerson M.; ''Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants.''; PubMedEurope PMCScholia
Waterman H, Katz M, Rubin C, Shtiegman K, Lavi S, Elson A, Jovin T, Yarden Y.; ''A mutant EGF-receptor defective in ubiquitylation and endocytosis unveils a role for Grb2 in negative signaling.''; PubMedEurope PMCScholia
Benmerah A, Poupon V, Cerf-Bensussan N, Dautry-Varsat A.; ''Mapping of Eps15 domains involved in its targeting to clathrin-coated pits.''; PubMedEurope PMCScholia
Carpenter G.; ''Employment of the epidermal growth factor receptor in growth factor-independent signaling pathways.''; PubMedEurope PMCScholia
Wellbrock C, Karasarides M, Marais R.; ''The RAF proteins take centre stage.''; PubMedEurope PMCScholia
Wong ES, Fong CW, Lim J, Yusoff P, Low BC, Langdon WY, Guy GR.; ''Sprouty2 attenuates epidermal growth factor receptor ubiquitylation and endocytosis, and consequently enhances Ras/ERK signalling.''; PubMedEurope PMCScholia
Lehr S, Kotzka J, Herkner A, Klein E, Siethoff C, Knebel B, Noelle V, Brüning JC, Klein HW, Meyer HE, Krone W, Müller-Wieland D.; ''Identification of tyrosine phosphorylation sites in human Gab-1 protein by EGF receptor kinase in vitro.''; PubMedEurope PMCScholia
Cunnick JM, Mei L, Doupnik CA, Wu J.; ''Phosphotyrosines 627 and 659 of Gab1 constitute a bisphosphoryl tyrosine-based activation motif (BTAM) conferring binding and activation of SHP2.''; PubMedEurope PMCScholia
Shimamura T, Lowell AM, Engelman JA, Shapiro GI.; ''Epidermal growth factor receptors harboring kinase domain mutations associate with the heat shock protein 90 chaperone and are destabilized following exposure to geldanamycins.''; PubMedEurope PMCScholia
Sigismund S, Woelk T, Puri C, Maspero E, Tacchetti C, Transidico P, Di Fiore PP, Polo S.; ''Clathrin-independent endocytosis of ubiquitinated cargos.''; PubMedEurope PMCScholia
Agazie YM, Hayman MJ.; ''Molecular mechanism for a role of SHP2 in epidermal growth factor receptor signaling.''; PubMedEurope PMCScholia
van Bergen En Henegouwen PM.; ''Eps15: a multifunctional adaptor protein regulating intracellular trafficking.''; PubMedEurope PMCScholia
Confalonieri S, Salcini AE, Puri C, Tacchetti C, Di Fiore PP.; ''Tyrosine phosphorylation of Eps15 is required for ligand-regulated, but not constitutive, endocytosis.''; PubMedEurope PMCScholia
Roberts PJ, Der CJ.; ''Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer.''; PubMedEurope PMCScholia
Haglund K, Schmidt MHH, Wong ES, Guy GR, Dikic I.; ''Sprouty2 acts at the Cbl/CIN85 interface to inhibit epidermal growth factor receptor downregulation.''; PubMedEurope PMCScholia
Patterson J, Palombella VJ, Fritz C, Normant E.; ''IPI-504, a novel and soluble HSP-90 inhibitor, blocks the unfolded protein response in multiple myeloma cells.''; PubMedEurope PMCScholia
Yun CH, Boggon TJ, Li Y, Woo MS, Greulich H, Meyerson M, Eck MJ.; ''Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity.''; PubMedEurope PMCScholia
Stebbins CE, Russo AA, Schneider C, Rosen N, Hartl FU, Pavletich NP.; ''Crystal structure of an Hsp90-geldanamycin complex: targeting of a protein chaperone by an antitumor agent.''; PubMedEurope PMCScholia
Margolis B, Bellot F, Honegger AM, Ullrich A, Schlessinger J, Zilberstein A.; ''Tyrosine kinase activity is essential for the association of phospholipase C-gamma with the epidermal growth factor receptor.''; PubMedEurope PMCScholia
Margolis BL, Lax I, Kris R, Dombalagian M, Honegger AM, Howk R, Givol D, Ullrich A, Schlessinger J.; ''All autophosphorylation sites of epidermal growth factor (EGF) receptor and HER2/neu are located in their carboxyl-terminal tails. Identification of a novel site in EGF receptor.''; PubMedEurope PMCScholia
Li N, Batzer A, Daly R, Yajnik V, Skolnik E, Chardin P, Bar-Sagi D, Margolis B, Schlessinger J.; ''Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling.''; PubMedEurope PMCScholia
Batzer AG, Rotin D, Ureña JM, Skolnik EY, Schlessinger J.; ''Hierarchy of binding sites for Grb2 and Shc on the epidermal growth factor receptor.''; PubMedEurope PMCScholia
Rubin C, Litvak V, Medvedovsky H, Zwang Y, Lev S, Yarden Y.; ''Sprouty fine-tunes EGF signaling through interlinked positive and negative feedback loops.''; PubMedEurope PMCScholia
Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, Chau I, Van Cutsem E.; ''Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer.''; PubMedEurope PMCScholia
Galisteo ML, Dikic I, Batzer AG, Langdon WY, Schlessinger J.; ''Tyrosine phosphorylation of the c-cbl proto-oncogene protein product and association with epidermal growth factor (EGF) receptor upon EGF stimulation.''; PubMedEurope PMCScholia
Li S, Schmitz KR, Jeffrey PD, Wiltzius JJ, Kussie P, Ferguson KM.; ''Structural basis for inhibition of the epidermal growth factor receptor by cetuximab.''; PubMedEurope PMCScholia
Marmor MD, Yarden Y.; ''Role of protein ubiquitylation in regulating endocytosis of receptor tyrosine kinases.''; PubMedEurope PMCScholia
Onishi-Haraikawa Y, Funaki M, Gotoh N, Shibuya M, Inukai K, Katagiri H, Fukushima Y, Anai M, Ogihara T, Sakoda H, Ono H, Kikuchi M, Oka Y, Asano T.; ''Unique phosphorylation mechanism of Gab1 using PI 3-kinase as an adaptor protein.''; PubMedEurope PMCScholia
Zhou W, Ercan D, Chen L, Yun CH, Li D, Capelletti M, Cortot AB, Chirieac L, Iacob RE, Padera R, Engen JR, Wong KK, Eck MJ, Gray NS, Jänne PA.; ''Novel mutant-selective EGFR kinase inhibitors against EGFR T790M.''; PubMedEurope PMCScholia
Fernandes H, Cohen S, Bishayee S.; ''Glycosylation-induced conformational modification positively regulates receptor-receptor association: a study with an aberrant epidermal growth factor receptor (EGFRvIII/DeltaEGFR) expressed in cancer cells.''; PubMedEurope PMCScholia
Holgado-Madruga M, Moscatello DK, Emlet DR, Dieterich R, Wong AJ.; ''Grb2-associated binder-1 mediates phosphatidylinositol 3-kinase activation and the promotion of cell survival by nerve growth factor.''; PubMedEurope PMCScholia
Klapisz E, Sorokina I, Lemeer S, Pijnenburg M, Verkleij AJ, van Bergen en Henegouwen PM.; ''A ubiquitin-interacting motif (UIM) is essential for Eps15 and Eps15R ubiquitination.''; PubMedEurope PMCScholia
VanderKuur J, Allevato G, Billestrup N, Norstedt G, Carter-Su C.; ''Growth hormone-promoted tyrosyl phosphorylation of SHC proteins and SHC association with Grb2.''; PubMedEurope PMCScholia
Okutani T, Okabayashi Y, Kido Y, Sugimoto Y, Sakaguchi K, Matuoka K, Takenawa T, Kasuga M.; ''Grb2/Ash binds directly to tyrosines 1068 and 1086 and indirectly to tyrosine 1148 of activated human epidermal growth factor receptors in intact cells.''; PubMedEurope PMCScholia
Soler C, Alvarez CV, Beguinot L, Carpenter G.; ''Potent SHC tyrosine phosphorylation by epidermal growth factor at low receptor density or in the absence of receptor autophosphorylation sites.''; PubMedEurope PMCScholia
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
Balak MN, Gong Y, Riely GJ, Somwar R, Li AR, Zakowski MF, Chiang A, Yang G, Ouerfelli O, Kris MG, Ladanyi M, Miller VA, Pao W.; ''Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors.''; PubMedEurope PMCScholia
Haglund K, Shimokawa N, Szymkiewicz I, Dikic I.; ''Cbl-directed monoubiquitination of CIN85 is involved in regulation of ligand-induced degradation of EGF receptors.''; PubMedEurope PMCScholia
Yun CH, Mengwasser KE, Toms AV, Woo MS, Greulich H, Wong KK, Meyerson M, Eck MJ.; ''The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP.''; PubMedEurope PMCScholia
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
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.
Erlotinib (OSI-774, Tarceva) is an EGFR-specific tyrosine kinase inhibitor (TKI) from the anilinoquinazoline class of TKIs, developed by OSI/Genentech. Erlotinib competitively inhibits binding of ATP to kinase domain of EGFR, thereby preventing EGFR autophosphorylation and downstream signaling, which halts proliferation of EGFR-dependent tumor cells (Moyer et al. 1997 , Stamos et al. 2002).
Gefitinib (ZD1839, Iressa) is a low-molecular-weight EGFR tyrosine kinase inhibitor (TKI) from the anilinoquinazoline class of TKIs, developed by AstraZeneca Pharmaceuticals. Gefitinib selectively inhibits EGFR-stimulated tumor cell growth and blocks EGFR autophosphorylation in tumor cells by competitive inhibition of ATP binding to kinase domain of EGFR (Wakeling et al. 2002, Yun et al. 2007).
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 MAP kinase cascade describes a sequence of phosphorylation events involving serine/threonine-specific protein kinases. Used by various signal transduction pathways, this cascade constitutes a common 'module' in the transmission of an extracellular signal into the nucleus.
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.
Recruitment of GRB2:SOS1 complex by SHC1 bound to phosphorylated dimers of EGFR cancer mutants has not been directly tested, but is assumed to happen in the same way it happens with the SHC1 bound to the phosphorylated homodimer of wild-type EGFR.
Direct binding of GRB2:GAB1:PIK3R1 complex to phosphorylated homodimers of EGFR cancer mutants has not been tested. This complex is recruted to EGFR via GRB2 binding to phosphorylated tyrosine residues Y1068 and Y1086 (corresponding to Y1092 and Y1110, respectively, when counting from the first amino acid of the EGFR precursor, prior to cleavage of the 24-amino acid signal peptide at the N-terminus). Phosphorylation of Y1068 (i.e. Y1092) has been directly demonstrated in the following EGFR cancer mutants: EGFR L858R mutant (Sordella et al. 2004, Lynch et al. 2004, Greulich et al. 2005, Yang et al. 2006, Choi et al. 2007); EGFR G719S mutant (Greulich et al. 2005, Choi et al. 2007); EGFR L747_P753insS mutant (Sordella et al. 2004, Lynch et al. 2004, Choi et al. 2007); EGFR L747_A750delinsP (Greulich et al. 2005); EGFR L747_S752del mutant (Pao et al. 2004); EGFR L861Q mutant (Lee et al. 2006, Yang et al. 2006); EGFRvIII mutant (Huang et al. 2007); EGFR A289V mutant (Lee et al. 2006); EGFR G598V mutant (Lee et al. 2006); EGFR R108K mutant (Lee et al. 2006); EGFR T263P mutant (Lee et al. 2006); EGFR D770_N771insNPG mutant (Greulich et al. 2005, Xu et al. 2007); EGFR D770_N771insNPH mutant (Xu et al. 2007); EGFR V738_K739insKIPVAI mutant (Xu et al. 2007); EGFR M766_A767insASV mutant (Xu et al. 2007).
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).
Upon dimerization, EGFRvIII mutants trans-autophosphorylate on tyrosine residues Y992, Y1068, Y0186, Y1143 and Y1173 while the tyrosine residue Y1045, a docking site for CBL, remains either unphosphorylated or hypophosphorylated, allowing EGFRvIII to activate downstream signaling cascades while escaping downregulation.
CBL binds to phosphorylated tyrosine Y1045 residue of EGFR cancer mutants. Phosphorylation of Y1045 (corresponding to Y1069 when counting from the first amino acid of the EGFR precursor, prior to cleavage of the 24-amino acid signal peptide at the N-terminus) has been directly demonstrated in the following EGFR cancer mutants: EGFR L858R mutant (Greulich et al. 2005, Choi et al. 2007); EGFR G719S mutant (Sordella et al. 2004, Greulich et al. 1005, Choi et al. 2007); EGFR L747_P753delinsS mutant (Sordella et al. 2004, Choi et al. 2007); EGFR L747_A750delinsP mutant (Greulich et al. 2005); EGFR L861Q mutant (Choi et al. 2007); EGFR A289V mutant (Lee et al. 2006); EGFR G598V mutant (Lee et al. 2006); EGFR R108K mutant (Lee et al. 2006); EGFR D770_N771insNPG mutant (Greulich et al. 2005; Xu et al. 2007); EGFR V738_K739insKIPVAI mutant (Xu et al. 2007); EGFR M766_A767insASV mutant (Xu et al. 2007). Very little if any phosphorylation of Y1045 was shown in EGFR T263P mutant (Lee et al. 2006) and EGFR D770_N771insNPH mutant (Xu et al. 2007). Direct binding of CBL was demonstrated for the EGFR L858R mutant (Yang et al. 2006, Padron et al. 2007) and EGFR E746_A750del mutant (Padron et al. 2007). In EGFRvIII mutant, Y1045 (Y1069) is not phosphorylated (Han et al. 2006, Grandal et al. 2007). Han et al. detected no CBL binding to EGFRvIII mutant (Han et al. 2006), while Grandal et al. detected very little binding, which they explained by indirect recruitment of CBL to EGFRvIII through GRB2 (Grandal et al. 2007).
Phosphorylated CBL does not ubiquitinate EGFR kinase domain mutants efficiently, which enables mutant proteins to escape degradation. There are indications that phosphorylated CBL shows decreased affinity for EGFR kinase domain mutants compared to wild-type EGFR proteins, and quickly dissociates, before ubiquitination is completed. This decreased affinity may be due to altered structure of EGFR kinase domain mutants or to the presence of the chaperone protein HSP90 in complex with the mutant protein. Weaker afinity for phosphorylated CBL was directly demonstrated for EGFR L858R mutant (Yang et al. 2006), and poor ubiquitination inspite of CBL binding was shown for EGFR L858R and EGFR E746_A750del mutants (Yang et al. 2006, Padron et al. 2007).
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.
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.
Tyrosine residue Y992, a docking site for PLC-gamma 1 (PLCG1), is phosphorylated in EGFR cancer mutants and expected to recruit PLC-gamma 1 in the same way as the wild-type EGFR receptor. Phosphorylation of Y992 (corresponding to Y1016 when counting from the first amino acid of the EGFR precursor, prior to cleavage of the 24-amino acid signal peptide at the N-terminus) has been directly demonstrated for the following EGFR cancer mutants: EGFR L858R mutant (Sordella et al. 2004, Choi et al. 2007); EGFR G719S mutant (Choi et al. 2007); EGFR L747_P753delinsS mutant (Sordella et al. 2004, Choi et ak, 2007); EGFR L861Q mutant (Choi et al. 2007); EGFRvIII mutant (Grandal et al. 2007); EGFR A289V mutant (Lee et al. 2006); EGFR D770_N771insNPG mutant (Xu et al. 2007); EGFR D770_N771insNPH mutant (Xu et al. 2007); EGFR V738_K739insKIPVAI mutant (Xu et al. 2007); EGFR M766_A767insASV mutant (Xu et al. 2007).
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.
The cytoplasmic domain of EGFR contains tyrosine, serine and threonine phosphorylation sites. Activation of ligand-responsive EGFR mutants through spontaneous or EGF-induced dimerization results in trans-autophosphorylation of 5 tyrosine residues (Y992, Y1068, Y1086, Y1148 and Y1173), which enables constitutive receptor signaling as it provides specific binding sites for cytosolic target proteins involved in signal transduction (Zhang et al. 2006, Yun et al. 2007, Sordella et al. 2004, Lee et al. 2006). Tyrosine residue Y1045, involved in EGFR down-regulation, is usually phosphorylated in ligand-responsive EGFR mutants (Sordella et al. 2004, Lee et al. 2006). The exact phosphorylation pattern has not been examined for each mutant, but is assumed to closely follow, based on existing experimental evidence, the trans-autophosphorylation pattern of the wild-type EGFR.
EGFR L858R mutant was shown to directly phosphorylate CBL on tyrosine residue Y371. Other EGFR cancer mutants with phosphorylation of tyrosine Y1045 (Y1069) are assumed to bind and phosphorylate CBL in a manner similar to the wild-type EGFR.
SOS1 is the guanine nucleotide exchange factor (GEF) for RAS. SOS1, recruited by GRB2 bound to p-SHC1:p-EGFR mutants, is assumed to activate RAS nucleotide exchange from the inactive form (bound to GDP) to an active form (bound to GTP). Although this reaction has not been shown to occur directly for EGFR cancer mutants, activation of RAF/MAP kinase cascade, through detection of phosphorylated ERK1/2, has been demonstrated in cells expressing EGFR L858R mutant (Sordella et al. 2004, Paez et al. 2004, Shimamura et al. 2005), EGFR E746_A750 mutant (Sordella et al. 2004, Shimamura et al. 2005), EGFR L747_P753delinS mutant (Sordella et al. 2004), and EGFR E746_A750del;T790M double mutant (Shimamura et al. 2005).
Constitutive phosphorylation of SHC1 was directly demonstrated in cells expressing EGFR L858R mutant (Greulich et al. 2005). Other EGFR cancer mutants were not directly tested for their ability to phosphorylate SHC1, but are assumed to interact with SHC1 in the same way as the wild-type EGFR protein.
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.
The kinase activity of PI3K mediates the phosphorylation of PIP2 to form PIP3. It is assumed that EGFR cancer mutants induce PI3K/AKT signaling in a manner similar to wild-type EGFR. Phosphorylation of AKT on serine residue S473, and therby activation of PI3K/AKT signaling cascade, has been directly demonstrated in cells expressing the following EGFR cancer mutants: EGFR L858R mutant (Sordella et al. 2004, Paez et al. 2004, Greulich et al. 2005, Shimamura et al. 2005); EGFR G719S mutant (Greulich et al. 2005); EGFR E746_A750del mutant (Sordella et al. 2004, Shimamura et al. 2005); EGFR L747_P753insS mutant (Sordella et al. 2004); EGFR L747_A750delinsP mutant (Greulich et al. 2005); EGFR L861Q mutant (Lee et al. 2006); EGFR D770_N771insNPG mutant (Greulich et al. 2005, Xu et al. 2007); EGFR D770_N771insNPH mutant (Xu et al. 2007); EGFR V738_K739insKIPVAI mutant (Xu et al. 2007); EGFR M766_A767insASV mutant (Xu et al. 2007); EGFR E746_A750del;T790M double mutant (Shimamura et al. 2005).
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.
Once phosphorylated, PLC-gamma 1 is expected to dissociate from phosphorylated EGFR cancer mutants and induce downstream signaling in the same way it does when activated by the wild-type EGFR. However, except for the phosphorylation of PLCG1 binding site in EGFR cancer mutants, other events involved in activation of PLCG1 signaling have not been studied in cells expressing EGFR cancer mutants.
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.
The 110 kDa catalytic subunit of PI3K (PIK3CA) binds to the 85 kDa regulatory subunit of PI3K (PIK3R1) to create the active PI3K. EGFR cancer mutants are assumed to mediate the assembly of active PI3K in a manner similar to wild-type EGFR.
SHC1 (Src homology 2 domain-containing transforming protein) is known to bind two phosphorylated tyrosine docking sites of EGFR: Y1148 and Y1173 (corresponding to Y1172 and Y1197 when counting from the first amino acid of EGFR precursor, before the cleavage of the 24-amino acid signal peptide at the N-terminus takes place). Phosphorylation of Y1173 tyrosine residue was directly demonstrated in the following EGFR cancer mutants: EGFR L858R mutant (Sordella et al. 2004, Greulich et al. 2005); EGFR G719S mutant (Greulich et al. 2005); EGFR L747_P753delinsS mutant (Sordella et al. 2004); EGFR L747_A750delinsP (Greulich et al. 2005); EGFRvIII mutant (Han et al. 2006, Grandal et al. 2007); EGFR D770_N771insNPG mutant (Greulich et al. 2005, Xu et al. 2007); EGFR D770_N771insNPH mutant (Xu et al. 2007); EGFR V738_K739insKIPVAI mutant (Xu et al. 2007); EGFR M766_A767insASV mutant (Xu et al. 2007). Phosphorylation of Y1148 was shown in EGFRvIII mutant (Huang et al. 2007).
Besides EGFR L858R mutant, which was directly shown to bind SHC1 (Greulich et al. 2005), binding of SHC1 was not tested in other EGFR cancer mutants. Nonetheless, it is assumed that SHC1 binds EGFR cancer mutants in the same way it binds wild-type EGFR.
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.
Direct binding of GRB2:SOS1 complex to phosphorylated homodimers of EGFR cancer mutants has not been tested. GRB2 binds to phosphorylated tyrosine residues Y1068 and Y1086 (corresponding to Y1092 and Y1110, respectively, when counting from the first amino acid of the EGFR precursor, prior to cleavage of the 24-amino acid signal peptide at the N-terminus). Phosphorylation of Y1068 (i.e. Y1092) has been directly demonstrated in the following EGFR cancer mutants: EGFR L858R mutant (Sordella et al. 2004, Lynch et al. 2004, Greulich et al. 2005, Yang et al. 2006, Choi et al. 2007); EGFR G719S mutant (Greulich et al. 2005, Choi et al. 2007); EGFR L747_P753insS mutant (Sordella et al. 2004, Lynch et al. 2004, Choi et al. 2007); EGFR L747_A750delinsP (Greulich et al. 2005); EGFR L747_S752del mutant (Pao et al. 2004); EGFR L861Q mutant (Lee et al. 2006, Yang et al. 2006); EGFRvIII mutant (Huang et al. 2007); EGFR A289V mutant (Lee et al. 2006); EGFR G598V mutant (Lee et al. 2006); EGFR R108K mutant (Lee et al. 2006); EGFR T263P mutant (Lee et al. 2006); EGFR D770_N771insNPG mutant (Greulich et al. 2005, Xu et al. 2007); EGFR D770_N771insNPH mutant (Xu et al. 2007); EGFR V738_K739insKIPVAI mutant (Xu et al. 2007); EGFR M766_A767insASV mutant (Xu et al. 2007).
Based on the wild-type EGFR signaling, it is assumed that the guanine nucleotide exchange factor SOS1 interacts with phosphorylated EGFR mutants through the adaptor protein, GRB2. Upon formation of this complex, SOS1 activates RAS by promoting GDP release and GTP binding. Although this reaction has not been directly confirmed for EGFR cancer mutants, activation of RAF/MAP kinase cascade has been demonstrated, through detection of phosphorylated ERK1/2, in cells expressing EGFR L858R mutant (Sordella et al. 2004, Paez et al. 2004, Shimamura et al. 2005), EGFR E746_A750del mutant (Sordella et al. 2004, Shimamura et al. 2005), EGFR L747_P753delinsS mutant (Sordella et al. 2004) and EGFR E746_A750del;T790M double mutant (Shimamura et al. 2005).
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.
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.
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.
Dephosphorylation of CBP/PAG negatively regulates the recruitment of the Src inhibiting kinase, Csk. Src is not negatively regulated by phosphorylation by Csk.
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.
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).
High concentrations of active CDC42 and Beta-Pix may promote the binding of Beta-Pix to CBL, pushing out the usually preferred binding partner CIN85 from the CBL complex. This competitive mechanism could block the CIN85-imposed clustering phenomenon on CBL that is required for tighter binding.
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 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.
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.
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.
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.
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.
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.
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 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.
The adaptor protein CIN85 is monoubiquitinated by CBL after EGF stimulation. Monoubiquitination is thought to regulate receptor internalization and endosomal sorting.
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.
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.
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.
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.
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.
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 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.
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.
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.
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.
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.
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.
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.
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 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.
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DataNodes
CDC42
GTPBeta-Pix CDC42
GTPEGFR Dimer
Covalent EGFR TKIsLigand-responsive EGFR mutants HSP90
CDC37Ub-p-6Y-EGFR p-Y371-CBL
GRB2Ub-p-6Y-EGFR
p-Y371-CBLp-5Y-EGFR GRB2 p-5Y-GAB1
SHP2p-6Y-EGFR CBL Beta-Pix CDC42
GTPp-6Y-EGFR CBL
CIN85p-6Y-EGFR CBL
GRB2p-6Y-EGFR CBL
Ub-p-Y53/55-SPRY1/2p-6Y-EGFR CBL
p-Y53/55-SPRY1/2p-6Y-EGFR
CBLp-6Y-EGFR GRB2 GAB1
PIK3R1p-6Y-EGFR GRB2 GAB1
PIK3p-6Y-EGFR GRB2
GAB1p-6Y-EGFR GRB2
SOS1p-6Y-EGFR GRB2 p-5Y-GAB1
SHP2p-6Y-EGFR GRB2
p-5Y-GAB1p-6Y-EGFR GRB2 p-Y627,659-GAB1
SHP2p-6Y-EGFR
PLCG1p-6Y-EGFR
SHC1p-6Y-EGFR p-Y349,350-SHC1 GRB2
SOS1p-6Y-EGFR
p-Y349,350-SHC1p-6Y-EGFR p-Y371-CBL CIN85 Endophilin Epsin Eps15R
Eps15p-6Y-EGFR p-Y371-CBL CIN85 SPRY1/2 Endophilin Epsin Eps15R
Eps15p-6Y-EGFR p-Y371-CBL GRB2 CIN85 Endophilin Epsin Eps15R Eps15
Clathrinp-6Y-EGFR p-Y371-CBL GRB2 CIN85
Endophilinp-6Y-EGFR p-Y371-CBL
GRB2p-6Y-EGFR p-Y371-CBL Ub-CIN85 Endophilin Epsin Eps15R
Eps15p-6Y-EGFR
p-Y371-CBLp-6Y-EGFR
p-Y472,771,783,1254-PLCG1HSP90
CDC37HGS
STAMGAB1
PIK3R1GAB1
PIP3HSP90
CDC37CSK
SRCCDC42
GTPGRB2 GAB1
PI3KGRB2 GAB1
PIK3R1GRB2
SOS1p-Y349,350-SHC1 GRB2
SOS1Annotated Interactions
CDC42
GTPp-5Y-EGFR GRB2 p-5Y-GAB1
SHP2p-6Y-EGFR CBL Beta-Pix CDC42
GTPp-6Y-EGFR CBL Beta-Pix CDC42
GTPp-6Y-EGFR CBL Beta-Pix CDC42
GTPp-6Y-EGFR CBL
CIN85p-6Y-EGFR CBL
GRB2p-6Y-EGFR CBL
GRB2p-6Y-EGFR CBL
p-Y53/55-SPRY1/2p-6Y-EGFR CBL
p-Y53/55-SPRY1/2p-6Y-EGFR
CBLp-6Y-EGFR
CBLp-6Y-EGFR
CBLp-6Y-EGFR GRB2 GAB1
PIK3R1p-6Y-EGFR GRB2 GAB1
PIK3p-6Y-EGFR GRB2
GAB1p-6Y-EGFR GRB2
GAB1p-6Y-EGFR GRB2
GAB1p-6Y-EGFR GRB2
SOS1p-6Y-EGFR GRB2 p-5Y-GAB1
SHP2p-6Y-EGFR GRB2 p-5Y-GAB1
SHP2p-6Y-EGFR GRB2 p-5Y-GAB1
SHP2p-6Y-EGFR GRB2 p-5Y-GAB1
SHP2p-6Y-EGFR GRB2 p-5Y-GAB1
SHP2p-6Y-EGFR GRB2 p-5Y-GAB1
SHP2p-6Y-EGFR GRB2
p-5Y-GAB1p-6Y-EGFR GRB2
p-5Y-GAB1p-6Y-EGFR GRB2 p-Y627,659-GAB1
SHP2p-6Y-EGFR
PLCG1p-6Y-EGFR
PLCG1p-6Y-EGFR
SHC1p-6Y-EGFR
SHC1p-6Y-EGFR p-Y349,350-SHC1 GRB2
SOS1p-6Y-EGFR
p-Y349,350-SHC1p-6Y-EGFR
p-Y349,350-SHC1p-6Y-EGFR p-Y371-CBL CIN85 Endophilin Epsin Eps15R
Eps15p-6Y-EGFR p-Y371-CBL CIN85 Endophilin Epsin Eps15R
Eps15p-6Y-EGFR p-Y371-CBL CIN85 Endophilin Epsin Eps15R
Eps15p-6Y-EGFR p-Y371-CBL GRB2 CIN85
Endophilinp-6Y-EGFR p-Y371-CBL
GRB2p-6Y-EGFR p-Y371-CBL
GRB2p-6Y-EGFR p-Y371-CBL
GRB2p-6Y-EGFR p-Y371-CBL
GRB2p-6Y-EGFR
p-Y371-CBLp-6Y-EGFR
p-Y371-CBLp-6Y-EGFR
p-Y371-CBLp-6Y-EGFR
p-Y371-CBLp-6Y-EGFR
p-Y371-CBLp-6Y-EGFR
p-Y371-CBLp-6Y-EGFR
p-Y472,771,783,1254-PLCG1HGS
STAMHGS
STAMGAB1
PIK3R1GAB1
PIK3R1GAB1
PIP3HSP90
CDC37CSK
SRCBesides EGFR L858R mutant, which was directly shown to bind SHC1 (Greulich et al. 2005), binding of SHC1 was not tested in other EGFR cancer mutants. Nonetheless, it is assumed that SHC1 binds EGFR cancer mutants in the same way it binds wild-type EGFR.
CDC42
GTPGRB2 GAB1
PI3KGRB2 GAB1
PIK3R1GRB2
SOS1p-Y349,350-SHC1 GRB2
SOS1