Insulin signaling pathway - Homo sapiens (human)

Curator(s): Julie Conway

Insulin binding to its receptor results in the tyrosine phosphorylation of insulin receptor substrates (IRS) by the insulin receptor tyrosine kinase (INSR). This allows association of IRSs with the regulatory subunit of phosphoinositide 3-kinase (PI3K). PI3K activates 3-phosphoinositide-dependent protein kinase 1 (PDK1), which activates Akt, a serine kinase. Akt in turn deactivates glycogen synthase kinase 3 (GSK-3), leading to activation of glycogen synthase (GYS) and thus glycogen synthesis. Activation of Akt also results in the translocation of GLUT4 vesicles from their intracellular pool to the plasma membrane, where they allow uptake of glucose into the cell. Akt also leads to mTOR-mediated activation of protein synthesis by eIF4 and p70S6K. The translocation of GLUT4 protein is also elicited through the CAP/Cbl/TC10 pathway, once Cbl is phosphorylated by INSR.Other signal transduction proteins interact with IRS including GRB2. GRB2 is part of the cascade including SOS, RAS, RAF and MEK that leads to activation of mitogen-activated protein kinase (MAPK) and mitogenic responses in the form of gene transcription. SHC is another substrate of INSR. When tyrosine phosphorylated, SHC associates with GRB2 and can thus activate the RAS/MAPK pathway independently of IRS-1.    
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Insulin signaling pathway - Homo sapiens (human) cluster_node49 !2 cluster_node50 !3 cluster_node51 !1 node1 2 node2 4 node3 4 node5 3 node6 29 node7 5 node9 2 node10 1 node11 4 node12 2 node14 15 node16 1 Proliferation Differentiation node17 20 node18 MTOR RPTOR node18->node17 MTOR~RPTOR node19 4EBP1 node18->node19 +p p70S6K node18->p70S6K +p eIF4E node19->eIF4E S6 p70S6K->S6 +p node20 1 node21 TSC2 TSC1 node21->node20 TSC2~TSC1 Ras homolog enriched in brain RHEB node21->RHEB RHEB->node18 node22 1 eIF4E->node22 eIF4E Protein Synthesis eIF4E->Protein Synthesis S6->Protein Synthesis APS node26 7 node27 17 aPKC node28 SREBP-1C aPKC->node28 GLUT4 Vesicle aPKC->GLUT4 Vesicle node29 1 node28->node29 ACC node29->ACC Fas (TNF receptor superfamily,member 6) FAS node29->FAS PYK node29->PYK glycerol kinase GK node29->GK Lipogenesis ACC->Lipogenesis node30 6 FAS->node30 FAS FAS->Lipogenesis node33 2 PYK->node33 node31 3 GK->node31 GK GK->node33 node32 Glycolysis / Gluconeogenesis node39 3 node32->node39 node33->node32 node34 16 AMPK AMPK->ACC +p AMPK->node34 AMPK PP1 PHK PP1->PHK -p GYS PP1->GYS -p PYG PHK->PYG +p Glycogen PYG->Glycogen PDE3 cAMP PDE3->cAMP PKA cAMP->PKA node35 2 BCL2-associated agonist of cell death BAD BAD->node35 BAD node36 Anti-apoptosis BAD->node36 node40 4 Lipogenesis->node40 node37 1 PKA->node37 PKA HSL PKA->HSL +p node38 1 HSL->node38 HSL Antilipolysis HSL->Antilipolysis Antilipolysis->node40 Glucose Homeostasis node39->Glucose Homeostasis Lipid Homeostasis node40->Lipid Homeostasis insulin INS insulin receptor INSR INS->INSR node41 4 forkhead box O1 FOXO1 FOXO1->node41 FOXO1 node43 PGC-1a FOXO1->node43 node44 DNA(2) FOXO1->node44 node42 4 node43->node42 PGC-1a glucose-6-phosphatase,catalytic subunit G6PC node44->G6PC FBP node44->FBP PEPCK node44->PEPCK node45 5 G6PC->node45 FBP->node45 PEPCK->node45 node45->node32 SOCS SOCS->INSR PTP1B PTP1B->INSR -p IRS PTP1B->IRS -py node46 5 node48 SHIP SKIP PIP3 node48->PIP3 AKT AKT->node6 AKT AKT->node18 +p AKT->node21 +p AKT->PP1 AKT->PDE3 +p AKT->BAD +p AKT->FOXO1 +p AKT->GLUT4 Vesicle node8 GSK-3B AKT->node8 +p GLUT4 GLUT4 Vesicle->GLUT4 translocation to PM node8->node7 GSK-3B node8->GYS +p node23 CAP CBL node23->APS node24 CRKII GRF2 node23->node24 TC10 node24->TC10 node25 CIP4/2 node25->GLUT4 Vesicle TC10->node25 EXO70 TC10->EXO70 DNA DNA->Proliferation DNA->Differentiation ELK1,member of ETS oncogene family ELK1 ELK1->DNA node15 ERK1/2 node15->node14 ERK1/2 node15->ELK1 +p MNK node15->MNK +p MNK->node16 MNK EXO70->GLUT4 Vesicle Flotillin Flotillin->node23 GLUT4->node26 GLUT4 GLUT4->GLUT4 Vesicle Glucose GLUT4->Glucose Glucose->node27 Glucose Glucose Uptake Glucose->Glucose Uptake growth factor receptor-bound protein 2 GRB2 SOS GRB2->SOS SOS->node9 SOS RAS SOS->RAS GYS->Glycogen Glycogenesis Glycogen->Glycogenesis Glucose Uptake->node39 Glycogenesis->node39 INSR->node1 INSR INSR->APS +p INSR->node23 +p INSR->IRS +py SHC INSR->SHC +p IRS->node2 IRS IRS->GRB2 P13K IRS->P13K SHC->GRB2 P13K->node3 P13K P13K->PIP3 node47 JNK IKK node47->node46 JNK~IKK node47->IRS +ps LAR LAR->INSR -p LAR->IRS -py LAR->SHC node13 MEK1/2 node13->node12 MEK1/2 node13->node15 +p PIP3->node5 PIP3 PIP3->node18 PIP3->aPKC node4 PDK1/2 PIP3->node4 node4->p70S6K +p node4->aPKC +p node4->AKT +p RAF RAF->node11 RAF RAF->node13 +p RAS->node10 RAS RAS->RAF print "