ENTRY ko04910 Pathway NAME Insulin signaling pathway DESCRIPTION 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. CLASS Organismal Systems; Endocrine system PATHWAY_MAP ko04910 Insulin signaling pathway ORTHOLOGY K00665 FASN; fatty acid synthase, animal type [EC:2.3.1.85] K00688 PYG, glgP; glycogen phosphorylase [EC:2.4.1.1] K00693 GYS; glycogen synthase [EC:2.4.1.11] K00844 HK; hexokinase [EC:2.7.1.1] K00871 PHKG; phosphorylase kinase gamma subunit [EC:2.7.11.19] K00922 PIK3CA_B_D; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153] K01084 G6PC; glucose-6-phosphatase [EC:3.1.3.9] K01106 INPP5A; inositol polyphosphate 5-phosphatase INPP5A [EC:3.1.3.56] K01596 E4.1.1.32, pckA, PCK; phosphoenolpyruvate carboxykinase (GTP) [EC:4.1.1.32] K01946 ACACB; acetyl-CoA carboxylase / biotin carboxylase 2 [EC:6.4.1.2 6.3.4.14 2.1.3.15] K02158 BAD; Bcl-2-antagonist of cell death K02183 CALM; calmodulin K02649 PIK3R1_2_3; phosphoinositide-3-kinase regulatory subunit alpha/beta/delta K02833 HRAS; GTPase HRas K02991 RP-S6e, RPS6; small subunit ribosomal protein S6e K03083 GSK3B; glycogen synthase kinase 3 beta [EC:2.7.11.26] K03099 SOS; son of sevenless K03259 EIF4E; translation initiation factor 4E K03841 FBP; fructose-1,6-bisphosphatase I [EC:3.1.3.11] K04345 PKA; protein kinase A [EC:2.7.11.11] K04364 GRB2; growth factor receptor-bound protein 2 K04365 BRAF; B-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1] K04366 RAF1; RAF proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1] K04368 MAP2K1, MEK1; mitogen-activated protein kinase kinase 1 [EC:2.7.12.2] K04369 MAP2K2, MEK2; mitogen-activated protein kinase kinase 2 [EC:2.7.12.2] K04371 ERK, MAPK1_3; mitogen-activated protein kinase 1/3 [EC:2.7.11.24] K04372 MKNK, MNK; MAP kinase interacting serine/threonine kinase [EC:2.7.11.1] K04375 ELK1; ETS domain-containing protein Elk-1 K04438 CRK, CRKII; C-crk adapter molecule crk K04440 JNK; mitogen-activated protein kinase 8/9/10 (c-Jun N-terminal kinase) [EC:2.7.11.24] K04456 AKT; RAC serine/threonine-protein kinase [EC:2.7.11.1] K04526 INS; insulin K04527 INSR, CD220; insulin receptor [EC:2.7.10.1] K04688 RPS6KB; ribosomal protein S6 kinase beta [EC:2.7.11.1] K04694 SOCS1, JAB; suppressor of cytokine signaling 1 K04695 SOCS2, CIS2; suppressor of cytokine signaling 2 K04696 SOCS3, CIS3; suppressor of cytokine signaling 3 K04697 SOCS4; suppressor of cytokine signaling 4 K04707 CBL; E3 ubiquitin-protein ligase CBL [EC:2.3.2.27] K04739 PRKAR; cAMP-dependent protein kinase regulator K05695 PTPRF, LAR; receptor-type tyrosine-protein phosphatase F [EC:3.1.3.48] K05696 PTPN1, PTP1B; tyrosine-protein phosphatase non-receptor type 1 [EC:3.1.3.48] K06069 PRKCI; atypical protein kinase C iota type [EC:2.7.11.13] K06086 SORBS1, SH3D5, PONSIN, CAP; sorbin and SH3 domain containing protein 1 K06269 PPP1C; serine/threonine-protein phosphatase PP1 catalytic subunit [EC:3.1.3.16] K06276 PDPK1; 3-phosphoinositide dependent protein kinase-1 [EC:2.7.11.1] K06277 RAPGEF1, GRF2; Rap guanine nucleotide exchange factor 1 K06279 SHC1; SHC-transforming protein 1 K07187 IRS2; insulin receptor substrate 2 K07188 LIPE, HSL; hormone-sensitive lipase [EC:3.1.1.79] K07189 PPP1R3; protein phosphatase 1 regulatory subunit 3A/B/C/D/E K07190 PHKA_B; phosphorylase kinase alpha/beta subunit K07191 SLC2A4, GLUT4; MFS transporter, SP family, solute carrier family 2 (facilitated glucose transporter), member 4 K07192 FLOT; flotillin K07193 SH2B, APS; SH2B adapter protein 2 K07194 RHOQ, TC10; Ras homolog gene family, member Q K07195 EXOC7, EXO70; exocyst complex component 7 K07196 TRIP10, CIP4; thyroid hormone receptor interactor 10 K07197 SREBP1, SREBF1; sterol regulatory element-binding transcription factor 1 K07198 PRKAA, AMPK; 5'-AMP-activated protein kinase, catalytic alpha subunit [EC:2.7.11.31] K07199 PRKAB; 5'-AMP-activated protein kinase, regulatory beta subunit K07200 PRKAG; 5'-AMP-activated protein kinase, regulatory gamma subunit K07201 FOXO1; forkhead box protein O1 K07202 PPARGC1A, PGC1A; alpha peroxisome proliferator-activated receptor gamma coactivator 1-alpha K07203 MTOR, FRAP, TOR; serine/threonine-protein kinase mTOR [EC:2.7.11.1] K07204 RAPTOR; regulatory associated protein of mTOR K07205 EIF4EBP1; eukaryotic translation initiation factor 4E binding protein 1 K07206 TSC1; tuberous sclerosis 1 K07207 TSC2; tuberous sclerosis 2 K07208 RHEB; Ras homolog enriched in brain K07209 IKBKB, IKKB; inhibitor of nuclear factor kappa-B kinase subunit beta [EC:2.7.11.10] K07827 KRAS, KRAS2; GTPase KRas K07828 NRAS; GTPase NRas K08845 ARAF, ARAF1; A-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1] K11262 ACACA; acetyl-CoA carboxylase / biotin carboxylase 1 [EC:6.4.1.2 6.3.4.14 2.1.3.15] K12406 PKLR; pyruvate kinase isozymes R/L [EC:2.7.1.40] K12407 GCK; glucokinase [EC:2.7.1.2] K13296 PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [EC:3.1.4.17] K15909 SHIP2, INPPL1; phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 2 [EC:3.1.3.86] K16172 IRS1; insulin receptor substrate 1 K17445 IRS3; insulin receptor substrate 3 K17446 IRS4; insulin receptor substrate 4 K17447 SHC2; SHC-transforming protein 2 K17448 SHC3; SHC-transforming protein 3 K17449 SHC4; SHC-transforming protein 4 K17453 PPP1R3F, R3F; protein phosphatase 1 regulatory subunit 3F K18952 PRKCZ; atypical protein kinase C zeta type [EC:2.7.11.13] K22517 CBLB; E3 ubiquitin-protein ligase CBL-B [EC:2.3.2.27] COMPOUND C00031 D-Glucose C00369 Starch C00575 3',5'-Cyclic AMP C05981 Phosphatidylinositol-3,4,5-trisphosphate REFERENCE PMID:14635525 AUTHORS Ogawa W, Kasuga M. 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JOURNAL Adv Enzyme Regul 43:15-28 (2003) DOI:10.1016/S0065-2571(02)00043-2 REL_PATHWAY ko00010 Glycolysis / Gluconeogenesis ko00061 Fatty acid biosynthesis ko00500 Starch and sucrose metabolism ko04010 MAPK signaling pathway ko04070 Phosphatidylinositol signaling system ko04210 Apoptosis ///