KEGG   PATHWAY: hsa04012Help
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
BRITE hierarchy
Pathway map
ErbB signaling pathway
hsa04012

All organismsOrtholog table
Disease
H00539  
PTEN hamartoma tumor syndrome (PHTS)
H00865  
Lethal congenital contractural syndrome (LCCS)
H00931  
Growth hormone insensitivity with immunodeficiency
H01102  
Pituitary adenomas
Drug
D01977  
Gefitinib (JAN/USAN/INN)
D03252  
Bosutinib (USAN)
D03257  
Trastuzumab (genetical recombination) (JAN)
D03350  
Canertinib dihydrochloride (USAN)
D03455  
Cetuximab (genetical recombination) (JAN)
D03658  
Dasatinib (INN)
D04023  
Erlotinib hydrochloride (JAN/USAN)
D04024  
Lapatinib tosilate hydrate (JAN)
D04025  
Mubritinib (USAN/INN)
D05350  
Panitumumab (genetical recombination) (JAN)
D05399  
Pelitinib (USAN/INN)
D05446  
Pertuzumab (genetical recombination) (JAN)
D06068  
Temsirolimus (JAN/USAN/INN)
D06272  
Sorafenib tosilate (JAN)
D06407  
Vandetanib (JAN/USAN/INN)
D06413  
Nilotinib hydrochloride hydrate (JAN)
D06414  
Dasatinib hydrate (JAN)
D07907  
Erlotinib (INN)
D08108  
Lapatinib (INN)
D08524  
Sorafenib (USAN/INN)
D08950  
Neratinib (INN/USAN)
D08953  
Nilotinib (USAN/INN)
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 maleate (JAN)
D09883  
Dacomitinib (USAN/INN)
D09980  
Trastuzumab emtansine (genetical recombination) (JAN)
D10018  
Necitumumab (USAN/INN)
D10024  
Selumetinib sulfate (USAN)
D10031  
Zalutumumab (USAN/INN)
D10064  
Dabrafenib (USAN)
D10104  
Dabrafenib mesilate (JAN)
D10175  
Trametinib (USAN)
D10176  
Trametinib dimethyl sulfoxide (JAN/USAN)
D10426  
Pimasertib (USAN/INN)
D10486  
Pimasertib hydrochloride (USAN)
D10514  
Dacomitinib hydrate (JAN)
Organism
Homo sapiens (human) [GN:hsa]
Gene
1950  
EGF; epidermal growth factor [KO:K04357]
7039  
TGFA; transforming growth factor, alpha [KO:K08774]
374  
AREG; amphiregulin [KO:K09782]
1956  
EGFR; epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
2064  
ERBB2; v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 [KO:K05083] [EC:2.7.10.1]
5335  
PLCG1; phospholipase C, gamma 1 [KO:K01116] [EC:3.1.4.11]
5336  
PLCG2; phospholipase C, gamma 2 (phosphatidylinositol-specific) [KO:K05859] [EC:3.1.4.11]
815  
CAMK2A; calcium/calmodulin-dependent protein kinase II alpha [KO:K04515] [EC:2.7.11.17]
817  
CAMK2D; calcium/calmodulin-dependent protein kinase II delta [KO:K04515] [EC:2.7.11.17]
816  
CAMK2B; calcium/calmodulin-dependent protein kinase II beta [KO:K04515] [EC:2.7.11.17]
818  
CAMK2G; calcium/calmodulin-dependent protein kinase II gamma [KO:K04515] [EC:2.7.11.17]
5578  
PRKCA; protein kinase C, alpha [KO:K02677] [EC:2.7.11.13]
5579  
PRKCB; protein kinase C, beta [KO:K02677] [EC:2.7.11.13]
5582  
PRKCG; protein kinase C, gamma [KO:K02677] [EC:2.7.11.13]
23624  
CBLC; Cbl proto-oncogene C, E3 ubiquitin protein ligase [KO:K04707] [EC:6.3.2.19]
867  
CBL; Cbl proto-oncogene, E3 ubiquitin protein ligase [KO:K04707] [EC:6.3.2.19]
868  
CBLB; Cbl proto-oncogene B, E3 ubiquitin protein ligase [KO:K04707] [EC:6.3.2.19]
6776  
STAT5A; signal transducer and activator of transcription 5A [KO:K11223]
6777  
STAT5B; signal transducer and activator of transcription 5B [KO:K11224]
6714  
SRC; SRC proto-oncogene, non-receptor tyrosine kinase [KO:K05704] [EC:2.7.10.2]
5747  
PTK2; protein tyrosine kinase 2 [KO:K05725] [EC:2.7.10.2]
1398  
CRK; v-crk avian sarcoma virus CT10 oncogene homolog [KO:K04438]
1399  
CRKL; v-crk avian sarcoma virus CT10 oncogene homolog-like [KO:K04438]
25  
ABL1; ABL proto-oncogene 1, non-receptor tyrosine kinase [KO:K06619] [EC:2.7.10.2]
27  
ABL2; ABL proto-oncogene 2, non-receptor tyrosine kinase [KO:K08887] [EC:2.7.10.2]
4690  
NCK1; NCK adaptor protein 1 [KO:K07365]
8440  
NCK2; NCK adaptor protein 2 [KO:K07365]
5058  
PAK1; p21 protein (Cdc42/Rac)-activated kinase 1 [KO:K04409] [EC:2.7.11.1]
5062  
PAK2; p21 protein (Cdc42/Rac)-activated kinase 2 [KO:K04410] [EC:2.7.11.1]
5063  
PAK3; p21 protein (Cdc42/Rac)-activated kinase 3 [KO:K05733] [EC:2.7.11.1]
10298  
PAK4; p21 protein (Cdc42/Rac)-activated kinase 4 [KO:K05734] [EC:2.7.11.1]
56924  
PAK6; p21 protein (Cdc42/Rac)-activated kinase 6 [KO:K05735] [EC:2.7.11.1]
57144  
PAK7; p21 protein (Cdc42/Rac)-activated kinase 7 [KO:K05736] [EC:2.7.11.1]
6416  
MAP2K4; mitogen-activated protein kinase kinase 4 [KO:K04430] [EC:2.7.12.2]
5609  
MAP2K7; mitogen-activated protein kinase kinase 7 [KO:K04431] [EC:2.7.12.2]
5599  
MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
5602  
MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
5601  
MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
3725  
JUN; jun proto-oncogene [KO:K04448]
2002  
ELK1; ELK1, member of ETS oncogene family [KO:K04375]
685  
BTC; betacellulin [KO:K09783]
1839  
HBEGF; heparin-binding EGF-like growth factor [KO:K08523]
2069  
EREG; epiregulin [KO:K09784]
2065  
ERBB3; v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3 [KO:K05084] [EC:2.7.10.1]
3084  
NRG1; neuregulin 1 [KO:K05455]
9542  
NRG2; neuregulin 2 [KO:K05456]
2066  
ERBB4; v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 4 [KO:K05085] [EC:2.7.10.1]
6464  
SHC1; SHC (Src homology 2 domain containing) transforming protein 1 [KO:K06279]
25759  
SHC2; SHC (Src homology 2 domain containing) transforming protein 2 [KO:K17447]
53358  
SHC3; SHC (Src homology 2 domain containing) transforming protein 3 [KO:K17448]
399694  
SHC4; SHC (Src homology 2 domain containing) family, member 4 [KO:K17449]
2885  
GRB2; growth factor receptor-bound protein 2 [KO:K04364]
6654  
SOS1; son of sevenless homolog 1 (Drosophila) [KO:K03099]
6655  
SOS2; son of sevenless homolog 2 (Drosophila) [KO:K03099]
3265  
HRAS; Harvey rat sarcoma viral oncogene homolog [KO:K02833]
3845  
KRAS; Kirsten rat sarcoma viral oncogene homolog [KO:K07827]
4893  
NRAS; neuroblastoma RAS viral (v-ras) oncogene homolog [KO:K07828]
369  
ARAF; A-Raf proto-oncogene, serine/threonine kinase [KO:K08845] [EC:2.7.11.1]
673  
BRAF; B-Raf proto-oncogene, serine/threonine kinase [KO:K04365] [EC:2.7.11.1]
5894  
RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1]
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]
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]
4609  
MYC; v-myc avian myelocytomatosis viral oncogene homolog [KO:K04377]
2549  
GAB1; GRB2-associated binding protein 1 [KO:K09593]
10718  
NRG3; neuregulin 3 [KO:K05457]
145957  
NRG4; neuregulin 4 [KO:K05458]
5290  
PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha [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]
5291  
PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
5294  
PIK3CG; phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit gamma [KO:K00922] [EC:2.7.1.153]
5295  
PIK3R1; phosphoinositide-3-kinase, regulatory subunit 1 (alpha) [KO:K02649]
23533  
PIK3R5; phosphoinositide-3-kinase, regulatory subunit 5 [KO:K02649]
5296  
PIK3R2; phosphoinositide-3-kinase, regulatory subunit 2 (beta) [KO:K02649]
8503  
PIK3R3; phosphoinositide-3-kinase, regulatory subunit 3 (gamma) [KO:K02649]
207  
AKT1; v-akt murine thymoma viral oncogene homolog 1 [KO:K04456] [EC:2.7.11.1]
208  
AKT2; v-akt murine thymoma viral oncogene homolog 2 [KO:K04456] [EC:2.7.11.1]
10000  
AKT3; v-akt murine thymoma viral oncogene homolog 3 [KO:K04456] [EC:2.7.11.1]
2475  
MTOR; mechanistic target of rapamycin (serine/threonine kinase) [KO:K07203]
6198  
RPS6KB1; ribosomal protein S6 kinase, 70kDa, polypeptide 1 [KO:K04688] [EC:2.7.11.1]
6199  
RPS6KB2; ribosomal protein S6 kinase, 70kDa, polypeptide 2 [KO:K04688] [EC:2.7.11.1]
1978  
EIF4EBP1; eukaryotic translation initiation factor 4E binding protein 1 [KO:K07205]
572  
BAD; BCL2-associated agonist of cell death [KO:K02158]
2932  
GSK3B; glycogen synthase kinase 3 beta [KO:K03083] [EC:2.7.11.26]
1026  
CDKN1A; cyclin-dependent kinase inhibitor 1A (p21, Cip1) [KO:K06625]
1027  
CDKN1B; cyclin-dependent kinase inhibitor 1B (p27, Kip1) [KO:K06624]
Compound
C00076  
Calcium cation
C00165  
Diacylglycerol
C01245  
D-myo-Inositol 1,4,5-trisphosphate
C05981  
Phosphatidylinositol-3,4,5-trisphosphate
Reference
  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)
Reference
  Authors
Yarden Y, Sliwkowski MX.
  Title
Untangling the ErbB signalling network.
  Journal
Nat Rev Mol Cell Biol 2:127-37 (2001)
Reference
  Authors
Citri A, Yarden Y.
  Title
EGF-ERBB signalling: towards the systems level.
  Journal
Nat Rev Mol Cell Biol 7:505-16 (2006)
Reference
  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)
Reference
  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)
Reference
  Authors
Holbro T, Hynes NE.
  Title
ErbB receptors: directing key signaling networks throughout life.
  Journal
Annu Rev Pharmacol Toxicol 44:195-217 (2004)
Reference
  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)
Reference
  Authors
Hynes NE, Lane HA.
  Title
ERBB receptors and cancer: the complexity of targeted inhibitors.
  Journal
Nat Rev Cancer 5:341-54 (2005)
Reference
  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)
Reference
  Authors
Schulze WX, Deng L, Mann M.
  Title
Phosphotyrosine interactome of the ErbB-receptor kinase family.
  Journal
Mol Syst Biol 1:2005.0008 (2005)
Reference
  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)
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)
Reference
  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)
Reference
  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)
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)
KO pathway
 

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