ErbB signaling pathway - Homo sapiens (human)

Curator(s): Peter D'Adamo

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.    
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ErbB signaling pathway - Homo sapiens (human) cluster_node53 !1 cluster_NUCLEUS NUCLEUS cluster_node54 CELL MEMBRANE node1 2 node2 EGF TGFA AR node2->node1 EGF~TGFA~AR node4 ErbB-1 ErbB-1 node2->node4 node6 ErbB-1 ErbB-2 node2->node6 node3 9 node5 12 node7 3 node8 BTC HBEGF EREG node8->node7 BTC~HBEGF~EREG node8->node4 node8->node6 node18 ErbB-2 ErbB-4 node8->node18 node16 ErbB-4 ErbB-4 node8->node16 node9 5 node12 NRG1 NRG2 node12->node18 node12->node16 node14 ErbB-2 ErbB-3 node12->node14 node11 ErbB-3 ErbB-3 node12->node11 node13 3 node15 NRG3 NRG4 node15->node18 node15->node16 node17 3 node19 (HER2/Neu) overexpression (cancers) activation by ErbB2 node20 1 Ras Ras->node20 Ras Raf Ras->Raf node21 2 SOS SOS->Ras SOS->node21 SOS node22 4 Raf->node22 Raf MEK Raf->MEK +p node23 2 MEK->node23 MEK node25 ERK1/2 MEK->node25 +p MAPK Signaling Pathway MEK->MAPK Signaling Pathway node24 15 node25->node24 ERK1/2 node27 ELK (2) node25->node27 +p Myc node25->Myc +p node26 5 node30 12 PI3K PI3K->node30 PI3K PIP3 PI3K->PIP3 node31 3 PIP3->node31 PIP3 node33 PKB/Akt PIP3->node33 node32 17 node33->node32 PKB/Akt mechanistic target of rapamycin (serine/threonine kinase) MTOR node33->MTOR +p BCL2-associated agonist of cell death BAD node33->BAD p27 node33->p27 +p p21 node33->p21 +p glycogen synthase kinase 3 beta GSK3B node33->GSK3B node34 20 MTOR->node34 MTOR p70S6K MTOR->p70S6K +p node39 eIF-4EBP MTOR->node39 +p node35 2 BAD->node35 BAD Cell Survival BAD->Cell Survival node36 3 p27->node36 p27 Cell cycle p27->Cell cycle node37 1 p21->node37 p21 p21->Cell cycle node38 5 GSK3B->node38 GSK3B Metabolism GSK3B->Metabolism Protein Synthesis p70S6K->Protein Synthesis node39->Protein Synthesis MTOR Signaling Pathway Protein Synthesis->MTOR Signaling Pathway GRB2-associated binding protein 1 GAB1 GAB1->PI3K No signaling node40 1 STAT5 STAT5->node40 STAT5 node41 DNA (2) STAT5->node41 MAPK Signaling Pathway->node25 JNKK MAPK Signaling Pathway->JNKK node43 1 node44 STAT5 (2) node44->node43 STAT5 (2) node42 DNA (3) node44->node42 node45 2 FAK node46 Adhesion/Migration FAK->node46 Cbl Receptor ubiquitylation Cbl->Receptor ubiquitylation Degradation Receptor ubiquitylation->Degradation IP3 Endoplasmic reticulum IP3->Endoplasmic reticulum DG PKC DG->PKC node47 Ca2+ Endoplasmic reticulum->node47 node47->PKC CAMK node47->CAMK node48 5 PKC->node48 PKC Cellular targets PKC->Cellular targets Proliferation Cellular targets->Proliferation CAMK->Cellular targets Crk Abl Crk->Abl PAK PAK->JNKK JNK JNKK->JNK +p node49 11 JNK->node49 JNK node51 ELK (1) JNK->node51 +p jun proto-oncogene JUN JNK->JUN +p node50 1 node4->node3 ErbB-1~ErbB-1 node4->node44 +p node4->Cbl +p node4->Crk growth factor receptor-bound protein 2 GRB2 node4->GRB2 Nck node4->Nck PLCy node4->PLCy +p v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian) SRC node4->SRC Shc node4->Shc p+ node6->node5 ErbB-1~ErbB-2 node6->node44 node6->Crk node6->GRB2 node6->Nck node6->PLCy node6->SRC node6->Shc p+ node18->node17 ErbB-2~ErbB-4 node18->PI3K node18->STAT5 +p node18->GRB2 node18->Shc p+ node16->PI3K node16->GRB2 node16->Shc p+ node28 DNA (1) node29 Migration/Invasion node28->node29 Differentiation node41->Differentiation Survival node42->Survival node52 DNA (4) Angiogenesis node52->Angiogenesis node51->node52 node27->node28 Myc->node26 Myc Myc->node28 GRB2->SOS GRB2->GAB1 Nck->PAK PLCy->IP3 PLCy->DG SRC->node45 SRC SRC->FAK +p Shc->GRB2 node10 ErbB-2 ErbB-2 node10->node9 ErbB-2~ErbB-2 node10->node19 node10->GRB2 node10->Shc p+ node14->node13 ErbB-2~ErbB-3 node14->PI3K node14->GRB2 node14->Shc p+ node11->No signaling node11->GRB2 node11->Shc p+ JUN->node50 JUN JUN->node52 print "