The mitogen-activated protein kinase (MAPK) cascade

Curator(s): Peter D'Adamo | Joe Strothman

The mitogen-activated protein kinase (MAPK) cascade is a highly conserved module that is involved in various cellular functions, including cell proliferation, differentiation and migration. Mammals express at least four distinctly regulated groups of MAPKs, extracellular signal-related kinases (ERK)-1/2, Jun amino-terminal kinases (JNK1/2/3), p38 proteins (p38alpha/beta/gamma/delta) and ERK5, that are activated by specific MAPKKs: MEK1/2 for ERK1/2, MKK3/6 for the p38, MKK4/7 (JNKK1/2) for the JNKs, and MEK5 for ERK5. Each MAPKK, however, can be activated by more than one MAPKKK, increasing the complexity and diversity of MAPK signalling. Presumably each MAPKKK confers responsiveness to distinct stimuli. For example, activation of ERK1/2 by growth factors depends on the MAPKKK c-Raf, but other MAPKKKs may activate ERK1/2 in response to pro-inflammatory stimuli.    
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The mitogen-activated protein kinase (MAPK) cascade cluster_MEMBRANE MEMBRANE cluster_node72 SCAFFOLD (1) cluster_node73 SCAFFOLD (2) node1 NGF BDNF NTF3 NTF4 neurotrophic tyrosine kinase,receptor,type 1 NTRK1 node1->NTRK1 node2 2 epidermal growth factor EGF EGF->node2 EGF MEK5 EGF->MEK5 epidermal growth factor receptor EGFR EGF->EGFR node3 1 FGF FGF->node3 FGF FGFR FGF->FGFR node4 1 PDGF PDGF->node4 PDGF PDGFR PDGF->PDGFR node5 9 growth factor receptor-bound protein 2 GRB2 SOS GRB2->SOS node6 2 SOS->node6 SOS RAS SUBFAMILY SOS->RAS SUBFAMILY node7 1 RAS SUBFAMILY->node7 RAS SUBFAMILY node12 BRAF CMOS RAF1 RAS SUBFAMILY->node12 Ca2+ G12 Gap1m G12->Gap1m Gap1m->RAS SUBFAMILY node8 NF1 p120GAP node8->RAS SUBFAMILY CACN node66 Ca2+ CACN->node66 node9 RASGRF RASGRP node9->RAS SUBFAMILY DAG PKC DAG->PKC Phosphatidylinositol SS RAP1 RAP1->node12 +p PKA PKA->RAP1 +p Rap guanine nucleotide exchange factor (GEF) 2 RAPGEF2 RAPGEF2->RAS SUBFAMILY node10 1 PKC->RAS SUBFAMILY +p PKC->node10 PKC PKC->node12 +p node11 2 node12->node11 BRAF~CMOS~RAF1 node14 MAP2K1 MAP2K2 node12->node14 +p node13 2 node15 15 node17 PTP (2) P38 node17->P38 -p JNK node17->JNK -p node18 1 node19 MKP (1) node19->node18 MKP (1) node16 MAPK1 MAPK3 node19->node16 -p node20 TAU STMN1 cPLA2 node21 1 node22 MKNK1/2 RSK2 node22->node21 MNK1/2~RSK2 node23 CREB (1) node22->node23 +p node29 DNA (2) node23->node29 node24 5 node25 MYC ELK4 ELK1 node25->node24 Elk-1~Sap1a~c-Myc serum response factor (c-fos serum response element-binding transcription factor) SRF node25->SRF node26 2 SRF->node26 SRF node27 DNA (1) SRF->node27 node28 c-fos node27->node28 node28->node29 Proliferation node29->Proliferation Differentiation node29->Differentiation node30 CDC42 RAC1 node31 PAK1 PAK2 node30->node31 mitogen-activated protein kinase kinase kinase 1 MAP3K1 node30->MAP3K1 node32 MAP3K2 MAP3K3 node31->node32 protein phosphatase 3,catalytic subunit,alpha isozyme PPP3CA node34 NFATC2 NFATC4 JUN JUND PPP3CA->node34 node33 1 node34->node33 NFATC2~NFATC4~JUN~JUND node36 DNA (3) node34->node36 node35 11 node36->Proliferation node36->Differentiation Inflammation node36->Inflammation node37 2 node38 1 node39 5 node40 21 tumor necrosis factor TNF TNF->node40 TNF TNFR TNF->TNFR node41 7 IL1 IL1->node41 IL1 IL1R IL1->IL1R Fas ligand (TNF superfamily,member 6) FASLG Fas (TNF receptor superfamily,member 6) FAS FASLG->FAS node42 12 TGFB TGFB->node42 TGFB TGFBR TGFB->TGFBR node43 1 LPS LPS->node43 LPS CD14 molecule CD14 LPS->CD14 node44 G-Protein IP3 node44->IP3 node45 1 death-domain associated protein DAXX DAXX->node45 DAXX mitogen-activated protein kinase kinase kinase 5 MAP3K5 DAXX->MAP3K5 node46 MAP2K3 MAP2K6 MAP3K5->node46 node46->P38 +p node47 2 P38->node47 P38 node57 PRAK MAPKAPK MSK1/2 CDC25B P38->node57 +p node70 Sap1a GADD153 MAX MEF2C P38->node70 +p TNF receptor-associated factor 2 TRAF2 glucokinase (hexokinase 4) GCK TRAF2->GCK TRAF2->MAP3K1 node48 26 caspase 3,apoptosis-related cysteine peptidase CASP3 CASP3->node31 CASP3->node48 CASP3 node50 MST1/2 CASP3->node50 CASP3->MAP3K1 node49 1 ROS ROS->node30 ROS->node49 ROS ROS->MEK5 Heat Shock Heat Shock->node30 Radiation Radiation->node30 Cytotoxic drugs Cytotoxic drugs->node30 node51 3 TNF receptor-associated factor 6 TRAF6 TRAF6->node51 TRAF6 TGF-beta activated kinase 1/MAP3K7 binding protein 2 TAB2 TRAF6->TAB2 ECSIT homolog (Drosophila) ECSIT TRAF6->ECSIT TAK1 TAB2->TAK1 +p nemo-like kinase NLK TAK1->NLK +p node60 NIK IKK TAK1->node60 +p TGF-beta activated kinase 1/MAP3K7 binding protein 1 TAB1 TAB1->TAK1 +p node52 7 node53 ATF2 ELK1 TP53 node53->node52 ATF2~ELK1~TP53 p53 signaling pathway node53->p53 signaling pathway node54 2 GCK->node54 GCK node55 29 AKT AKT->MAP3K5 +p AKT->node55 AKT mitogen-activated protein kinase kinase 4 MAP2K4 AKT->MAP2K4 +p node56 LZK MUK MLTK mitogen-activated protein kinase kinase 7 MAP2K7 node56->MAP2K7 PP2CA PP2CA->node46 -p PP2CA->MAP2K7 -p PP5 PP5->MAP3K5 -p HSP27 node57->HSP27 +p node65 CREB (2) node57->node65 +p node58 3 HSP27->node58 HSP27 Wnt signaling pathway NLK->Wnt signaling pathway node59 7 node60->node59 NIK~IKK NFkB node60->NFkB node61 32 NFkB->Inflammation NFkB->node61 NFkB node67 Anti-apoptosis NFkB->node67 node62 PTP (1) node62->node16 -p node63 DNA (4) Apoptosis node63->Apoptosis node64 DNA (5) node64->Proliferation node64->Differentiation ERK5 MEK5->ERK5 +p Nur77 ERK5->Nur77 +p Nur77->node64 node66->node9 node66->PPP3CA node68 1 node69 MKP (2) node69->P38 -p node69->node68 MKP (2) node69->JNK -p node70->node63 node71 Tpl2/Cot node71->node60 +p node71->node14 +p Serum Serum->MEK5 Srk tyrosinkinase downstream Srk tyrosinkinase downstream->MEK5 IP3->Phosphatidylinositol SS IP3->node66 cAMP cAMP->PKA cAMP->RAPGEF2 MAP2K4->JNK +p node14->node13 MEK1~MEK2 node14->node16 +p MAP3K1->node60 +p MAP3K1->MAP2K4 CD14->node39 CD14 CD14->TAB1 EGFR->node5 EGFR EGFR->GRB2 FAS->node38 FAS FAS->DAXX FGFR->GRB2 HGK HGK->MAP3K1 +p IL1R->TRAF2 IL1R->CASP3 IL1R->TRAF6 JNK->node34 +p JNK->node35 JNK JNK->node53 +p MAP2K7->JNK +p mitogen-activated protein kinase kinase kinase 11 MAP3K11 MAP3K11->MAP2K7 +p mitogen-activated protein kinase kinase kinase kinase 1 MAP4K1 MAP4K1->MAP3K1 MAP4K1->MAP3K11 +p node16->node15 MAPK3~MAPK1 node16->node20 +p node16->cPLA2 +p node16->node22 node16->node25 +p NTRK1->GRB2 PDGFR->GRB2 TGFBR->DAXX TNFR->node37 TNFR TNFR->CASP3 MP1 print "