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 K04526 insulin K04527 insulin receptor [EC:2.7.10.1] K16172 insulin receptor substrate 1 K07187 insulin receptor substrate 2 K17445 insulin receptor substrate 3 K17446 insulin receptor substrate 4 K02649 phosphoinositide-3-kinase regulatory subunit alpha/beta/delta K00922 phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153] K06276 3-phosphoinositide dependent protein kinase-1 [EC:2.7.11.1] K04456 RAC serine/threonine-protein kinase [EC:2.7.11.1] K03083 glycogen synthase kinase 3 beta [EC:2.7.11.26] K00693 glycogen synthase [EC:2.4.1.11] K06269 serine/threonine-protein phosphatase PP1 catalytic subunit [EC:3.1.3.16] K07189 protein phosphatase 1 regulatory subunit 3A/B/C/D/E K17453 protein phosphatase 1 regulatory subunit 3F K00871 phosphorylase kinase gamma subunit [EC:2.7.11.19] K07190 phosphorylase kinase alpha/beta subunit K02183 calmodulin K00688 glycogen phosphorylase [EC:2.4.1.1] K13296 cGMP-inhibited 3',5'-cyclic phosphodiesterase B [EC:3.1.4.17] K04345 protein kinase A [EC:2.7.11.11] K04739 cAMP-dependent protein kinase regulator K07188 hormone-sensitive lipase [EC:3.1.1.79] K18952 atypical protein kinase C zeta type [EC:2.7.11.13] K06069 atypical protein kinase C iota type [EC:2.7.11.13] K07191 MFS transporter, SP family, solute carrier family 2 (facilitated glucose transporter), member 4 K07192 flotillin K07193 SH2B adapter protein 2 K06086 sorbin and SH3 domain containing protein 1 K04707 E3 ubiquitin-protein ligase CBL [EC:2.3.2.27] K22517 E3 ubiquitin-protein ligase CBL-B [EC:2.3.2.27] K04438 C-crk adapter molecule crk K06277 Rap guanine nucleotide exchange factor 1 K07194 Ras homolog gene family, member Q K07195 exocyst complex component 7 K07196 thyroid hormone receptor interactor 10 K07197 sterol regulatory element-binding transcription factor 1 K11262 acetyl-CoA carboxylase / biotin carboxylase 1 [EC:6.4.1.2 6.3.4.14 2.1.3.15] K01946 acetyl-CoA carboxylase / biotin carboxylase 2 [EC:6.4.1.2 6.3.4.14 2.1.3.15] K00665 fatty acid synthase, animal type [EC:2.3.1.85] K12406 pyruvate kinase isozymes R/L [EC:2.7.1.40] K00844 hexokinase [EC:2.7.1.1] K12407 glucokinase [EC:2.7.1.2] K07198 5'-AMP-activated protein kinase, catalytic alpha subunit [EC:2.7.11.31] K07199 5'-AMP-activated protein kinase, regulatory beta subunit K07200 5'-AMP-activated protein kinase, regulatory gamma subunit K07201 forkhead box protein O1 K07202 alpha peroxisome proliferator-activated receptor gamma coactivator 1-alpha K01084 glucose-6-phosphatase [EC:3.1.3.9] K03841 fructose-1,6-bisphosphatase I [EC:3.1.3.11] K01596 phosphoenolpyruvate carboxykinase (GTP) [EC:4.1.1.32] K07203 serine/threonine-protein kinase mTOR [EC:2.7.11.1] K07204 regulatory associated protein of mTOR K04688 ribosomal protein S6 kinase beta [EC:2.7.11.1] K02991 small subunit ribosomal protein S6e K07205 eukaryotic translation initiation factor 4E binding protein 1 K03259 translation initiation factor 4E K07206 tuberous sclerosis 1 K07207 tuberous sclerosis 2 K07208 Ras homolog enriched in brain K02158 Bcl-2-antagonist of cell death K06279 SHC-transforming protein 1 K17447 SHC-transforming protein 2 K17448 SHC-transforming protein 3 K17449 SHC-transforming protein 4 K04364 growth factor receptor-bound protein 2 K03099 son of sevenless K02833 GTPase HRas K07827 GTPase KRas K07828 GTPase NRas K08845 A-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1] K04365 B-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1] K04366 RAF proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1] K04368 mitogen-activated protein kinase kinase 1 [EC:2.7.12.2] K04369 mitogen-activated protein kinase kinase 2 [EC:2.7.12.2] K04371 mitogen-activated protein kinase 1/3 [EC:2.7.11.24] K04372 MAP kinase interacting serine/threonine kinase [EC:2.7.11.1] K04375 ETS domain-containing protein Elk-1 K04694 suppressor of cytokine signaling 1 K04695 suppressor of cytokine signaling 2 K04696 suppressor of cytokine signaling 3 K04697 suppressor of cytokine signaling 4 K05696 tyrosine-protein phosphatase non-receptor type 1 [EC:3.1.3.48] K05695 receptor-type tyrosine-protein phosphatase F [EC:3.1.3.48] K04440 mitogen-activated protein kinase 8/9/10 (c-Jun N-terminal kinase) [EC:2.7.11.24] K07209 inhibitor of nuclear factor kappa-B kinase subunit beta [EC:2.7.11.10] K15909 phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 2 [EC:3.1.3.86] K01106 inositol polyphosphate 5-phosphatase INPP5A [EC:3.1.3.56] 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. TITLE [Mechanism of insulin action and diabetes mellitus] JOURNAL Seikagaku 75:1332-44 (2003) REFERENCE PMID:11282018 AUTHORS Bevan P. TITLE Insulin signalling. JOURNAL J Cell Sci 114:1429-30 (2001) REFERENCE PMID:12867054 AUTHORS Kanzaki M, Pessin JE. TITLE Insulin signaling: GLUT4 vesicles exit via the exocyst. JOURNAL Curr Biol 13:R574-6 (2003) DOI:10.1016/S0960-9822(03)00478-0 REFERENCE PMID:10196204 AUTHORS Moodie SA, Alleman-Sposeto J, Gustafson TA. TITLE Identification of the APS protein as a novel insulin receptor substrate. JOURNAL J Biol Chem 274:11186-93 (1999) DOI:10.1074/jbc.274.16.11186 REFERENCE PMID:15733744 AUTHORS Gual P, Le Marchand-Brustel Y, Tanti JF. TITLE Positive and negative regulation of insulin signaling through IRS-1 phosphorylation. JOURNAL Biochimie 87:99-109 (2005) DOI:10.1016/j.biochi.2004.10.019 REFERENCE PMID:9748166 AUTHORS Le Good JA, Ziegler WH, Parekh DB, Alessi DR, Cohen P, Parker PJ. TITLE Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1. JOURNAL Science 281:2042-5 (1998) DOI:10.1126/science.281.5385.2042 REFERENCE PMID:11742412 AUTHORS Saltiel AR, Kahn CR. TITLE Insulin signalling and the regulation of glucose and lipid metabolism. JOURNAL Nature 414:799-806 (2001) DOI:10.1038/414799a REFERENCE PMID:15624019 AUTHORS Inoki K, Corradetti MN, Guan KL. TITLE Dysregulation of the TSC-mTOR pathway in human disease. JOURNAL Nat Genet 37:19-24 (2005) DOI:10.1038/ng1494 REFERENCE PMID:16288289 AUTHORS Ruggero D, Sonenberg N. TITLE The Akt of translational control. JOURNAL Oncogene 24:7426-34 (2005) DOI:10.1038/sj.onc.1209098 REFERENCE PMID:10567225 AUTHORS Nave BT, Ouwens M, Withers DJ, Alessi DR, Shepherd PR. TITLE Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. JOURNAL Biochem J 344 Pt 2:427-31 (1999) DOI:10.1042/bj3440427 REFERENCE PMID:9445476 AUTHORS Pullen N, Dennis PB, Andjelkovic M, Dufner A, Kozma SC, Hemmings BA, Thomas G. TITLE Phosphorylation and activation of p70s6k by PDK1. JOURNAL Science 279:707-10 (1998) DOI:10.1126/science.279.5351.707 REFERENCE PMID:9609110 AUTHORS Ogawa W, Matozaki T, Kasuga M. TITLE Role of binding proteins to IRS-1 in insulin signalling. JOURNAL Mol Cell Biochem 182:13-22 (1998) REFERENCE PMID:9609111 AUTHORS Ceresa BP, Pessin JE. TITLE Insulin regulation of the Ras activation/inactivation cycle. JOURNAL Mol Cell Biochem 182:23-9 (1998) REFERENCE PMID:15229476 AUTHORS Pollak MN, Schernhammer ES, Hankinson SE. TITLE Insulin-like growth factors and neoplasia. JOURNAL Nat Rev Cancer 4:505-18 (2004) DOI:10.1038/nrc1387 REFERENCE PMID:9346240 AUTHORS Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME. TITLE Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. JOURNAL Cell 91:231-41 (1997) DOI:10.1016/S0092-8674(00)80405-5 REFERENCE PMID:17344645 AUTHORS Ferre P, Foufelle F TITLE SREBP-1c transcription factor and lipid homeostasis: clinical perspective. JOURNAL Horm Res 68:72-82 (2007) DOI:10.1159/000100426 REFERENCE PMID:18291668 AUTHORS Raghow R, Yellaturu C, Deng X, Park EA, Elam MB TITLE SREBPs: the crossroads of physiological and pathological lipid homeostasis. JOURNAL Trends Endocrinol Metab 19:65-73 (2008) DOI:10.1016/j.tem.2007.10.009 REFERENCE PMID:11343120 AUTHORS Clement S, Krause U, Desmedt F, Tanti JF, Behrends J, Pesesse X, Sasaki T, Penninger J, Doherty M, Malaisse W, Dumont JE, Le Marchand-Brustel Y, Erneux C, Hue L, Schurmans S TITLE The lipid phosphatase SHIP2 controls insulin sensitivity. JOURNAL Nature 409:92-7 (2001) DOI:10.1038/35051094 REFERENCE PMID:12791379 AUTHORS Backers K, Blero D, Paternotte N, Zhang J, Erneux C TITLE The termination of PI3K signalling by SHIP1 and SHIP2 inositol 5-phosphatases. 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 ///