KEGG   PATHWAY: dre04012
dre04012                    Pathway                                

ErbB signaling pathway - Danio rerio (zebrafish)
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.
Environmental Information Processing; Signal transduction
Pathway map
dre04012  ErbB signaling pathway

Danio rerio (zebrafish) [GN:dre]
403045  egf; pro-epidermal growth factor isoform 1 precursor [KO:K04357]
100034402  tgfa; protransforming growth factor alpha precursor [KO:K08774]
378478  egfra; epidermal growth factor receptor precursor [KO:K04361] [EC:]
571431  epidermal growth factor receptor-like [KO:K04361] [EC:]
386966  erbb2; receptor tyrosine-protein kinase erbB-2 precursor [KO:K05083] [EC:]
373867  plcg1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 [KO:K01116] [EC:]
561747  plcg2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 [KO:K05859] [EC:]
436815  camk2d2; calcium/calmodulin-dependent protein kinase type II delta 2 chain [KO:K04515] [EC:]
445208  camk2d1; calcium/calmodulin-dependent protein kinase type II delta 1 chain isoform 1 [KO:K04515] [EC:]
550436  camk2a; calcium/calmodulin-dependent protein kinase type II subunit alpha [KO:K04515] [EC:]
562064  camk2b1; calcium/calmodulin-dependent protein kinase (CaM kinase) II beta 1 [KO:K04515] [EC:]
793359  camk2g2; calcium/calmodulin-dependent protein kinase type II subunit gamma isoform X26 [KO:K04515] [EC:]
798222  camk2b; calcium/calmodulin-dependent protein kinase type II subunit beta isoform X4 [KO:K04515] [EC:]
791855  camk2g1; calcium/calmodulin-dependent protein kinase (CaM kinase) II gamma 1 [KO:K04515] [EC:]
497384  prkcaa; protein kinase C, alpha, a [KO:K02677] [EC:]
100333967  si:ch73-374l24.1; protein kinase C alpha type isoform X1 [KO:K02677] [EC:]
100006675  prkcba; protein kinase C, beta a [KO:K19662] [EC:]
393953  prkcbb; protein kinase C beta type [KO:K19662] [EC:]
100003514  prkcg; protein kinase C alpha type-like [KO:K19663] [EC:]
492364  cbl; E3 ubiquitin-protein ligase CBL [KO:K04707] [EC:]
556277  cblb; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:]
369197  stat5a; signal transducer and activator of transcription 5A [KO:K11224]
445474  stat5b; signal transducer and activator of transcription 5B [KO:K11224]
325084  src; proto-oncogene tyrosine-protein kinase Src [KO:K05704] [EC:]
142986  ptk2ab; focal adhesion kinase 1 [KO:K05725] [EC:]
386705  ptk2aa; protein tyrosine kinase 2aa [KO:K05725] [EC:]
445234  crk; adapter molecule crk [KO:K04438]
556443  crkl; crk-like protein [KO:K04438]
100000720  abl1; tyrosine-protein kinase ABL1 isoform X1 [KO:K06619] [EC:]
570636  abl2; tyrosine-protein kinase ABL2 [KO:K08887] [EC:]
564584  nck1a; cytoplasmic protein NCK1 [KO:K07365]
100334953  nck1b; cytoplasmic protein NCK1 isoform X1 [KO:K07365]
445098  nck2b; cytoplasmic protein NCK2b [KO:K19862]
393972  nck2a; cytoplasmic protein NCK2a [KO:K19862]
373103  pak1; serine/threonine-protein kinase PAK 1 [KO:K04409] [EC:]
266749  pak2a; serine/threonine-protein kinase PAK 2a [KO:K04410] [EC:]
325034  pak2b; serine/threonine-protein kinase PAK 2b [KO:K04410] [EC:]
431769  pak4; serine/threonine-protein kinase PAK 4 [KO:K05734] [EC:]
405898  pak5; serine/threonine-protein kinase PAK 5 [KO:K05736] [EC:]
567874  pak6b; serine/threonine-protein kinase PAK 6b [KO:K05735] [EC:]
100536197  serine/threonine-protein kinase PAK 6 [KO:K05735] [EC:]
403052  map2k4a; dual specificity mitogen-activated protein kinase kinase 4a [KO:K04430] [EC:]
568951  map2k4b; dual specificity mitogen-activated protein kinase kinase 4b [KO:K04430] [EC:]
560913  map2k7; dual specificity mitogen-activated protein kinase kinase 7 [KO:K04431] [EC:]
569698  mapk10; mitogen-activated protein kinase 10 isoform 2 [KO:K04440] [EC:]
562720  mapk8a; mitogen-activated protein kinase 8 [KO:K04440] [EC:]
65236  mapk8b; mitogen-activated protein kinase 8 [KO:K04440] [EC:]
100149273  mapk9; mitogen-activated protein kinase 9 [KO:K04440] [EC:]
335916  jun; transcription factor AP-1 [KO:K04448]
567895  elk1; ETS domain-containing protein Elk-1 [KO:K04375]
503869  btc; probetacellulin precursor [KO:K09783]
797938  hbegfa; heparin-binding EGF-like growth factor a precursor [KO:K08523]
407664  hbegfb; heparin-binding EGF-like growth factor b precursor [KO:K08523]
544664  erbb3b; receptor tyrosine-protein kinase erbB-3b precursor [KO:K05084] [EC:]
100149258  uncharacterized protein LOC100149258 precursor [KO:K05084] [EC:]
386635  erbb3a; receptor tyrosine-protein kinase erbB-3a precursor [KO:K05084] [EC:]
796461  nrg1; pro-neuregulin-1, membrane-bound isoform isoform 1 [KO:K05455]
100006951  nrg2a; neuregulin 2a [KO:K05456]
100270726  nrg2b; neuregulin 2b [KO:K05456]
100007677  erbb4a; receptor tyrosine-protein kinase erbB-4 precursor [KO:K05085] [EC:]
101885162  si:ch73-383l1.1; receptor tyrosine-protein kinase erbB-4 [KO:K05085] [EC:]
569836  erbb4b; receptor tyrosine-protein kinase erbB-4 [KO:K05085] [EC:]
323818  shc1; SHC-transforming protein 1 isoform X3 [KO:K06279]
562011  shc2; SHC-transforming protein 2 [KO:K17447]
100332111  shc3; SHC-transforming protein 3 [KO:K17448]
406308  grb2b; growth factor receptor-bound protein 2b [KO:K04364]
493609  grb2a; growth factor receptor-bound protein 2a [KO:K04364]
561670  sos2; son of sevenless homolog 2 [KO:K03099]
556286  sos1; son of sevenless homolog 1 [KO:K03099]
553656  hrasb; HRas proto-oncogene, GTPase b [KO:K02833]
550286  hrasa; HRas proto-oncogene, GTPase a [KO:K02833]
445289  kras; GTPase KRas isoform 2 [KO:K07827]
393228  zgc:55558 [KO:K07827]
30380  nras; GTPase NRas [KO:K07828]
403063  araf; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:]
403065  braf; serine/threonine-protein kinase B-raf isoform 1 [KO:K04365] [EC:]
30716  raf1a; Raf-1 proto-oncogene, serine/threonine kinase a [KO:K04366] [EC:]
557109  raf1b; RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:]
406728  map2k1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:]
563181  map2k2a; dual specificity mitogen-activated protein kinase kinase 2a [KO:K04369] [EC:]
100002225  map2k2b; dual specificity mitogen-activated protein kinase kinase 2b [KO:K04369] [EC:]
360144  mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:]
399480  mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:]
393141  mycb; transcriptional regulator Myc-B [KO:K04377]
30686  myca; transcriptional regulator Myc-A [KO:K04377]
406666  gab1; GRB2-associated-binding protein 1 [KO:K09593]
100535494  pro-neuregulin-3, membrane-bound isoform isoform X1 [KO:K05457]
101882495  nrg3b; pro-neuregulin-3, membrane-bound isoform isoform X1 [KO:K05457]
394174  pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:]
561737  pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:]
100002263  pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:]
404211  pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
100000252  pik3r3b; phosphoinositide-3-kinase, regulatory subunit 3b (gamma) [KO:K02649]
557176  pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
403146  akt2l; v-akt murine thymoma viral oncogene homolog 2, like [KO:K04456] [EC:]
560549  akt3a; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:]
378972  akt2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:]
100149794  akt3b; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:]
101910198  akt1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:]
324254  mtor; serine/threonine-protein kinase mTOR [KO:K07203] [EC:]
562242  rps6kb1a; ribosomal protein S6 kinase beta-1 [KO:K04688] [EC:]
406349  rps6kb1b; ribosomal protein S6 kinase beta-1 [KO:K04688] [EC:]
799566  eif4ebp1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
58100  badb; BCL2 associated agonist of cell death b isoform 1 [KO:K02158]
564921  bada; bcl2-associated agonist of cell death isoform X1 [KO:K02158]
30654  gsk3ba; glycogen synthase kinase-3 beta [KO:K03083] [EC:]
557882  gsk3bb; glycogen synthase kinase 3 beta, genome duplicate b [KO:K03083] [EC:]
368329  cdkn1bb; cyclin-dependent kinase inhibitor 1Bb [KO:K06624]
402862  cdkn1ba; cyclin-dependent kinase inhibitor 1Ba [KO:K06624]
100151416  cdkn1a; cyclin-dependent kinase inhibitor 1 [KO:K06625]
C00076  Calcium cation
C00165  Diacylglycerol
C01245  D-myo-Inositol 1,4,5-trisphosphate
C05981  Phosphatidylinositol-3,4,5-trisphosphate
Marmor MD, Skaria KB, Yarden Y.
Signal transduction and oncogenesis by ErbB/HER receptors.
Int J Radiat Oncol Biol Phys 58:903-13 (2004)
Yarden Y, Sliwkowski MX.
Untangling the ErbB signalling network.
Nat Rev Mol Cell Biol 2:127-37 (2001)
Citri A, Yarden Y.
EGF-ERBB signalling: towards the systems level.
Nat Rev Mol Cell Biol 7:505-16 (2006)
Scaltriti M, Baselga J.
The epidermal growth factor receptor pathway: a model for targeted therapy.
Clin Cancer Res 12:5268-72 (2006)
Normanno N, De Luca A, Bianco C, Strizzi L, Mancino M, Maiello MR, Carotenuto A, De Feo G, Caponigro F, Salomon DS.
Epidermal growth factor receptor (EGFR) signaling in cancer.
Gene 366:2-16 (2006)
Holbro T, Hynes NE.
ErbB receptors: directing key signaling networks throughout life.
Annu Rev Pharmacol Toxicol 44:195-217 (2004)
Liang J, Slingerland JM.
Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression.
Cell Cycle 2:339-45 (2003)
Hynes NE, Lane HA.
ERBB receptors and cancer: the complexity of targeted inhibitors.
Nat Rev Cancer 5:341-54 (2005)
Oda K, Matsuoka Y, Funahashi A, Kitano H.
A comprehensive pathway map of epidermal growth factor receptor signaling.
Mol Syst Biol 1:2005.0010 (2005)
Schulze WX, Deng L, Mann M.
Phosphotyrosine interactome of the ErbB-receptor kinase family.
Mol Syst Biol 1:2005.0008 (2005)
Olayioye MA, Neve RM, Lane HA, Hynes NE.
The ErbB signaling network: receptor heterodimerization in development and cancer.
EMBO J 19:3159-67 (2000)
McCarty JH.
The Nck SH2/SH3 adaptor protein: a regulator of multiple intracellular signal transduction events.
Clark DE, Williams CC, Duplessis TT, Moring KL, Notwick AR, Long W, Lane WS, Beuvink I, Hynes NE, Jones FE.
ERBB4/HER4 potentiates STAT5A transcriptional activity by regulating novel STAT5A serine phosphorylation events.
J Biol Chem 280:24175-80 (2005)
Muthuswamy SK, Gilman M, Brugge JS.
Controlled dimerization of ErbB receptors provides evidence for differential signaling by homo- and heterodimers.
Mol Cell Biol 19:6845-57 (1999)
Hashimoto Y, Katayama H, Kiyokawa E, Ota S, Kurata T, Gotoh N, Otsuka N, Shibata M, Matsuda M.
Phosphorylation of CrkII adaptor protein at tyrosine 221 by epidermal growth factor receptor.
J Biol Chem 273:17186-91 (1998)
dre04010  MAPK signaling pathway
dre04020  Calcium signaling pathway
dre04110  Cell cycle
dre04150  mTOR signaling pathway
KO pathway

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