ENTRY hsa04012 Pathway NAME ErbB signaling pathway - Homo sapiens (human) DESCRIPTION The ErbB family of receptor tyrosine kinases (RTKs) couples binding of extracellular growth factor ligands to intracellular signaling pathways regulating diverse biologic responses, including proliferation, differentiation, cell motility, and survival. Ligand binding to the four closely related members of this RTK family -epidermal growth factor receptor (EGFR, also known as ErbB-1 or HER1), ErbB-2 (HER2), ErbB-3 (HER3), and ErbB-4 (HER4)-induces the formation of receptor homo- and heterodimers and the activation of the intrinsic kinase domain, resulting in phosphorylation on specific tyrosine residues (pY) within the cytoplasmic tail. Signaling effectors containing binding pockets for pY-containing peptides are recruited to activated receptors and induce the various signaling pathways. The Shc- and/or Grb2-activated mitogen-activated protein kinase (MAPK) pathway is a common target downstream of all ErbB receptors. Similarly, the phosphatidylinositol-3-kinase (PI-3K) pathway is directly or indirectly activated by most ErbBs. Several cytoplasmic docking proteins appear to be recruited by specific ErbB receptors and less exploited by others. These include the adaptors Crk, Nck, the phospholipase C gamma (PLCgamma), the intracellular tyrosine kinase Src, or the Cbl E3 ubiquitin protein ligase. CLASS Environmental Information Processing; Signal transduction PATHWAY_MAP hsa04012 ErbB signaling pathway NETWORK nt06210 ERK signaling (cancer) nt06214 PI3K signaling (cancer) nt06260 Colorectal cancer nt06261 Gastric cancer nt06263 Hepatocellular carcinoma nt06265 Bladder cancer nt06270 Breast cancer nt06464 Amyotrophic lateral sclerosis nt06543 NRG-ERBB signaling ELEMENT N00021 EGF-ERBB2-RAS-ERK signaling pathway N00231 TGFA-EGFR-PI3K signaling pathway N01163 NRG-ERBB4-PI3K signaling pathway N01874 NRG-ERBB2/ERBB3 pathway (RAS-ERK signaling) N01875 NRG-ERBB2/ERBB3 pathway (P13K signaling) N01877 ERBB4 mutation to GF-RTK-PI3K signaling pathway DRUG D01977 Gefitinib (JP18/USAN/INN) D02714 Everolimus (JAN/USAN/INN) D03252 Bosutinib (USAN) D03257 Trastuzumab (USAN/INN) D03350 Canertinib dihydrochloride (USAN) D03455 Cetuximab (USAN/INN) D03658 Dasatinib (JAN/INN) D04023 Erlotinib hydrochloride (JAN/USAN) D04024 Lapatinib ditosylate (USAN) D04025 Mubritinib (USAN/INN) D04862 Masoprocol (USAN/INN) D05350 Panitumumab (USAN/INN) D05399 Pelitinib (USAN/INN) D05446 Pertuzumab (USAN/INN) D06068 Temsirolimus (JAN/USAN/INN) D06272 Sorafenib tosylate (USAN) D06407 Vandetanib (JAN/USAN/INN) D06413 Nilotinib hydrochloride hydrate (JAN) D06414 Dasatinib (USAN) D06610 Lapuleucel-T (USAN) D07907 Erlotinib (INN) D08108 Lapatinib (INN) D08279 Tozasertib (USAN) D08344 Tozasertib lactate (USAN) D08524 Sorafenib (USAN/INN) D08950 Neratinib (USAN/INN) D08953 Nilotinib (USAN/INN) D09660 Rindopepimut (USAN) D09664 Saracatinib (USAN/INN) D09665 Saracatinib difumarate (USAN) D09666 Selumetinib (USAN/INN) D09689 Varlitinib (USAN/INN) D09690 Varlitinib tosylate (USAN) D09724 Afatinib (USAN/INN) D09728 Bosutinib hydrate (JAN) D09733 Afatinib dimaleate (USAN) D09883 Dacomitinib (INN) D09980 Trastuzumab emtansine (USAN/INN) D09996 Vemurafenib (JAN/USAN/INN) D10018 Necitumumab (USAN/INN) D10024 Selumetinib sulfate (JAN/USAN) D10031 Zalutumumab (USAN/INN) D10064 Dabrafenib (USAN) D10104 Dabrafenib mesylate (USAN) D10175 Trametinib (USAN) D10176 Trametinib dimethyl sulfoxide (JAN/USAN) D10405 Cobimetinib (USAN/INN) D10426 Pimasertib (USAN/INN) D10446 Margetuximab (USAN/INN) D10486 Pimasertib hydrochloride (USAN) D10514 Dacomitinib (USAN) D10615 Cobimetinib fumarate (USAN) D10766 Osimertinib mesylate (USAN) D10858 Rociletinib (USAN/INN) D10859 Olmutinib (USAN/INN) D10898 Neratinib maleate D10943 Istiratumab (USAN/INN) D10958 Naquotinib (USAN/INN) D11053 Encorafenib (JAN/USAN/INN) D11115 Olmutinib hydrochloride (USAN) D11141 Tucatinib (USAN/INN) D11239 Lumretuzumab (USAN/INN) D11410 Lifirafenib (USAN/INN) D11411 Lifirafenib maleate (USAN) D11430 Nazartinib (USAN/INN) D11434 Nazartinib mesylate (USAN) D11529 Trastuzumab deruxtecan (USAN/INN) D11675 Mirdametinib (USAN) D11750 Duligotuzumab (USAN) D11777 Seribantumab (USAN/INN) D11803 Cetuximab sarotalocan (USAN/INN) D11805 Cetuximab sarotalocan sodium (genetical recombination) (JAN) D11869 Paxalisib (USAN/INN) D11872 Serclutamab (USAN/INN) D11874 Serclutamab talirine (USAN/INN) D11969 Mobocertinib succinate (JAN) D11980 Lazertinib (USAN/INN) D11991 Zenocutuzumab (USAN/INN) D12001 Mobocertinib (USAN/INN) D12011 Zanidatamab (USAN/INN) D12184 Patritumab deruxtecan (USAN/INN) D12185 Patritumab (USAN/INN) D12229 Poziotinib (USAN/INN) D12230 Poziotinib hydrochloride (USAN) D12236 Runimotamab (USAN/INN) D12245 Lazertinib mesylate (USAN) D12258 Aumolertinib (USAN/INN) D12259 Aumolertinib mesylate (USAN) D12343 Fepixnebart (TN) D12416 Petosemtamab (USAN/INN) D12444 Nilotinib hydrochloride dihydrate (JAN) D12457 Tuxobertinib (USAN/INN) D12506 Sunvozertinib (USAN/INN) D12515 Avutometinib (USAN/INN) D12534 Avutometinib potassium (USAN) D12730 Tigozertinib (USAN) D12859 Pebezertinib (USAN) D12879 Zongertinib (JAN/USAN/INN) D12947 Claturafenib (USAN) D12956 Firmonertinib (USAN/INN) D12957 Firmonertinib mesylate (USAN) D13008 Nilotinib D-tartrate (USAN) D13039 Nedometinib (USAN/INN) D13052 Izalontamab (USAN/INN) D13062 Zipalertinib (JAN/USAN/INN) D13097 Polfurmetinib (USAN) D13098 Sevabertinib (USAN) ORGANISM Homo sapiens (human) [GN:hsa] GENE 10000 AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1] 1026 CDKN1A; cyclin dependent kinase inhibitor 1A [KO:K06625] 1027 CDKN1B; cyclin dependent kinase inhibitor 1B [KO:K06624] 10298 PAK4; p21 (RAC1) activated kinase 4 [KO:K05734] [EC:2.7.11.1] 106821730 BUB1B-PAK6; BUB1B-PAK6 readthrough [KO:K05735] [EC:2.7.11.1] 10718 NRG3; neuregulin 3 [KO:K05457] 110117499 P3R3URF-PIK3R3; P3R3URF-PIK3R3 readthrough [KO:K02649] 1398 CRK; CRK proto-oncogene, adaptor protein [KO:K04438] 1399 CRKL; CRK like proto-oncogene, adaptor protein [KO:K04438] 145957 NRG4; neuregulin 4 [KO:K05458] 1839 HBEGF; heparin binding EGF like growth factor [KO:K08523] 1950 EGF; epidermal growth factor [KO:K04357] 1956 EGFR; epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1] 1978 EIF4EBP1; eukaryotic translation initiation factor 4E binding protein 1 [KO:K07205] 2002 ELK1; ETS transcription factor ELK1 [KO:K04375] 2064 ERBB2; erb-b2 receptor tyrosine kinase 2 [KO:K05083] [EC:2.7.10.1] 2065 ERBB3; erb-b2 receptor tyrosine kinase 3 [KO:K05084] [EC:2.7.10.1] 2066 ERBB4; erb-b2 receptor tyrosine kinase 4 [KO:K05085] [EC:2.7.10.1] 2069 EREG; epiregulin [KO:K09784] 207 AKT1; AKT serine/threonine kinase 1 [KO:K04456] [EC:2.7.11.1] 208 AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:2.7.11.1] 2475 MTOR; mechanistic target of rapamycin kinase [KO:K07203] [EC:2.7.11.1] 25 ABL1; ABL proto-oncogene 1, non-receptor tyrosine kinase [KO:K06619] [EC:2.7.10.2] 2549 GAB1; GRB2 associated binding protein 1 [KO:K09593] 25759 SHC2; SHC adaptor protein 2 [KO:K17447] 27 ABL2; ABL proto-oncogene 2, non-receptor tyrosine kinase [KO:K08887] [EC:2.7.10.2] 2885 GRB2; growth factor receptor bound protein 2 [KO:K04364] 2932 GSK3B; glycogen synthase kinase 3 beta [KO:K03083] [EC:2.7.11.26] 3084 NRG1; neuregulin 1 [KO:K05455] 3265 HRAS; HRas proto-oncogene, GTPase [KO:K02833] 369 ARAF; A-Raf proto-oncogene, serine/threonine kinase [KO:K08845] [EC:2.7.11.1] 3725 JUN; Jun proto-oncogene, AP-1 transcription factor subunit [KO:K04448] 374 AREG; amphiregulin [KO:K09782] 3845 KRAS; KRAS proto-oncogene, GTPase [KO:K07827] 399694 SHC4; SHC adaptor protein 4 [KO:K17449] 4609 MYC; MYC proto-oncogene, bHLH transcription factor [KO:K04377] 4690 NCK1; NCK adaptor protein 1 [KO:K07365] 4893 NRAS; NRAS proto-oncogene, GTPase [KO:K07828] 5058 PAK1; p21 (RAC1) activated kinase 1 [KO:K04409] [EC:2.7.11.1] 5062 PAK2; p21 (RAC1) activated kinase 2 [KO:K04410] [EC:2.7.11.1] 5063 PAK3; p21 (RAC1) activated kinase 3 [KO:K05733] [EC:2.7.11.1] 5290 PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153] 5291 PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153] 5293 PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153] 5295 PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649] 5296 PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649] 5335 PLCG1; phospholipase C gamma 1 [KO:K01116] [EC:3.1.4.11] 53358 SHC3; SHC adaptor protein 3 [KO:K17448] 5336 PLCG2; phospholipase C gamma 2 [KO:K05859] [EC:3.1.4.11] 5578 PRKCA; protein kinase C alpha [KO:K02677] [EC:2.7.11.13] 5579 PRKCB; protein kinase C beta [KO:K19662] [EC:2.7.11.13] 5582 PRKCG; protein kinase C gamma [KO:K19663] [EC:2.7.11.13] 5594 MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24] 5595 MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24] 5599 MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24] 5601 MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24] 5602 MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24] 5604 MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2] 5605 MAP2K2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2] 5609 MAP2K7; mitogen-activated protein kinase kinase 7 [KO:K04431] [EC:2.7.12.2] 56924 PAK6; p21 (RAC1) activated kinase 6 [KO:K05735] [EC:2.7.11.1] 57144 PAK5; p21 (RAC1) activated kinase 5 [KO:K05736] [EC:2.7.11.1] 572 BAD; BCL2 associated agonist of cell death [KO:K02158] 5747 PTK2; protein tyrosine kinase 2 [KO:K05725] [EC:2.7.10.2] 5894 RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1] 6198 RPS6KB1; ribosomal protein S6 kinase B1 [KO:K04688] [EC:2.7.11.1] 6199 RPS6KB2; ribosomal protein S6 kinase B2 [KO:K04688] [EC:2.7.11.1] 6416 MAP2K4; mitogen-activated protein kinase kinase 4 [KO:K04430] [EC:2.7.12.2] 6464 SHC1; SHC adaptor protein 1 [KO:K06279] 6654 SOS1; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO:K03099] 6655 SOS2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO:K03099] 6714 SRC; SRC proto-oncogene, non-receptor tyrosine kinase [KO:K05704] [EC:2.7.10.2] 673 BRAF; B-Raf proto-oncogene, serine/threonine kinase [KO:K04365] [EC:2.7.11.1] 6776 STAT5A; signal transducer and activator of transcription 5A [KO:K11223] 6777 STAT5B; signal transducer and activator of transcription 5B [KO:K11224] 685 BTC; betacellulin [KO:K09783] 7039 TGFA; transforming growth factor alpha [KO:K08774] 815 CAMK2A; calcium/calmodulin dependent protein kinase II alpha [KO:K04515] [EC:2.7.11.17] 816 CAMK2B; calcium/calmodulin dependent protein kinase II beta [KO:K04515] [EC:2.7.11.17] 817 CAMK2D; calcium/calmodulin dependent protein kinase II delta [KO:K04515] [EC:2.7.11.17] 818 CAMK2G; calcium/calmodulin dependent protein kinase II gamma [KO:K04515] [EC:2.7.11.17] 8440 NCK2; NCK adaptor protein 2 [KO:K19862] 8503 PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649] 867 CBL; Cbl proto-oncogene [KO:K04707] [EC:2.3.2.27] 868 CBLB; Cbl proto-oncogene B [KO:K22517] [EC:2.3.2.27] 9542 NRG2; neuregulin 2 [KO:K05456] COMPOUND C00076 Calcium cation C00165 Diacylglycerol C01245 D-myo-Inositol 1,4,5-trisphosphate C05981 Phosphatidylinositol-3,4,5-trisphosphate REFERENCE PMID:14967450 AUTHORS Marmor MD, Skaria KB, Yarden Y. TITLE Signal transduction and oncogenesis by ErbB/HER receptors. JOURNAL Int J Radiat Oncol Biol Phys 58:903-13 (2004) DOI:10.1016/j.ijrobp.2003.06.002 REFERENCE PMID:11252954 AUTHORS Yarden Y, Sliwkowski MX. TITLE Untangling the ErbB signalling network. JOURNAL Nat Rev Mol Cell Biol 2:127-37 (2001) DOI:10.1038/35052073 REFERENCE PMID:16829981 AUTHORS Citri A, Yarden Y. TITLE EGF-ERBB signalling: towards the systems level. JOURNAL Nat Rev Mol Cell Biol 7:505-16 (2006) DOI:10.1038/nrm1962 REFERENCE PMID:17000658 AUTHORS Scaltriti M, Baselga J. TITLE The epidermal growth factor receptor pathway: a model for targeted therapy. JOURNAL Clin Cancer Res 12:5268-72 (2006) DOI:10.1158/1078-0432.CCR-05-1554 REFERENCE PMID:16377102 AUTHORS Normanno N, De Luca A, Bianco C, Strizzi L, Mancino M, Maiello MR, Carotenuto A, De Feo G, Caponigro F, Salomon DS. TITLE Epidermal growth factor receptor (EGFR) signaling in cancer. JOURNAL Gene 366:2-16 (2006) DOI:10.1016/j.gene.2005.10.018 REFERENCE PMID:14744244 AUTHORS Holbro T, Hynes NE. TITLE ErbB receptors: directing key signaling networks throughout life. JOURNAL Annu Rev Pharmacol Toxicol 44:195-217 (2004) DOI:10.1146/annurev.pharmtox.44.101802.121440 REFERENCE PMID:12851486 AUTHORS Liang J, Slingerland JM. TITLE Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression. JOURNAL Cell Cycle 2:339-45 (2003) DOI:10.4161/cc.2.4.433 REFERENCE PMID:15864276 AUTHORS Hynes NE, Lane HA. TITLE ERBB receptors and cancer: the complexity of targeted inhibitors. JOURNAL Nat Rev Cancer 5:341-54 (2005) DOI:10.1038/nrc1609 REFERENCE PMID:16729045 AUTHORS Oda K, Matsuoka Y, Funahashi A, Kitano H. TITLE A comprehensive pathway map of epidermal growth factor receptor signaling. JOURNAL Mol Syst Biol 1:2005.0010 (2005) DOI:10.1038/msb4100014 REFERENCE PMID:16729043 AUTHORS Schulze WX, Deng L, Mann M. TITLE Phosphotyrosine interactome of the ErbB-receptor kinase family. JOURNAL Mol Syst Biol 1:2005.0008 (2005) DOI:10.1038/msb4100012 REFERENCE PMID:10880430 AUTHORS Olayioye MA, Neve RM, Lane HA, Hynes NE. TITLE The ErbB signaling network: receptor heterodimerization in development and cancer. JOURNAL EMBO J 19:3159-67 (2000) DOI:10.1093/emboj/19.13.3159 REFERENCE PMID:9872057 AUTHORS McCarty JH. TITLE The Nck SH2/SH3 adaptor protein: a regulator of multiple intracellular signal transduction events. JOURNAL Bioessays 20:913-21 (1998) DOI:10.1002/(SICI)1521-1878(199811)20:11<913::AID-BIES6>3.0.CO;2-T REFERENCE PMID:15863494 AUTHORS Clark DE, Williams CC, Duplessis TT, Moring KL, Notwick AR, Long W, Lane WS, Beuvink I, Hynes NE, Jones FE. TITLE ERBB4/HER4 potentiates STAT5A transcriptional activity by regulating novel STAT5A serine phosphorylation events. JOURNAL J Biol Chem 280:24175-80 (2005) DOI:10.1074/jbc.M414044200 REFERENCE PMID:10490623 AUTHORS Muthuswamy SK, Gilman M, Brugge JS. TITLE Controlled dimerization of ErbB receptors provides evidence for differential signaling by homo- and heterodimers. JOURNAL Mol Cell Biol 19:6845-57 (1999) DOI:10.1128/MCB.19.10.6845 REFERENCE PMID:9642287 AUTHORS Hashimoto Y, Katayama H, Kiyokawa E, Ota S, Kurata T, Gotoh N, Otsuka N, Shibata M, Matsuda M. TITLE Phosphorylation of CrkII adaptor protein at tyrosine 221 by epidermal growth factor receptor. JOURNAL J Biol Chem 273:17186-91 (1998) DOI:10.1074/jbc.273.27.17186 REL_PATHWAY hsa04010 MAPK signaling pathway hsa04020 Calcium signaling pathway hsa04110 Cell cycle hsa04150 mTOR signaling pathway hsa04151 PI3K-Akt signaling pathway hsa05212 Pancreatic cancer hsa05213 Endometrial cancer hsa05214 Glioma hsa05223 Non-small cell lung cancer KO_PATHWAY ko04012 ///