KEGG   PATHWAY: opi04910
Entry
opi04910                    Pathway                                
Name
Insulin signaling pathway - Ochotona princeps (American pika)
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
opi04910  Insulin signaling pathway
opi04910

Organism
Ochotona princeps (American pika) [GN:opi]
Gene
101533865  insulin isoform X2 [KO:K04526]
101530887  INSR; insulin receptor [KO:K04527] [EC:2.7.10.1]
101526197  IRS1; insulin receptor substrate 1 [KO:K16172]
101527103  IRS2; insulin receptor substrate 2 [KO:K07187]
101525112  insulin receptor substrate 1-like [KO:K17445]
101528328  IRS4; LOW QUALITY PROTEIN: insulin receptor substrate 4 [KO:K17446]
101532354  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
101517982  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
101528030  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
101519449  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
101533851  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X3 [KO:K00922] [EC:2.7.1.153]
101533024  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
101528473  PDPK1; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
101533296  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
101519021  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
101525801  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
101533693  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
101523220  GYS2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
101527848  GYS1; glycogen [starch] synthase, muscle isoform X1 [KO:K00693] [EC:2.4.1.11]
101525073  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit isoform X1 [KO:K06269] [EC:3.1.3.16]
101522201  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit isoform X1 [KO:K06269] [EC:3.1.3.16]
101533284  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit isoform X1 [KO:K06269] [EC:3.1.3.16]
101520329  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
101520417  PPP1R3E; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
101516130  PPP1R3A; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
101530053  PPP1R3B; protein phosphatase 1 regulatory subunit 3B [KO:K07189]
101526807  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
101520665  PPP1R3F; protein phosphatase 1 regulatory subunit 3F isoform X2 [KO:K17453]
101520150  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform isoform X1 [KO:K00871] [EC:2.7.11.19]
101517824  PHKG2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform [KO:K00871] [EC:2.7.11.19]
101536490  PHKB; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
101519796  PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform [KO:K07190]
101524440  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform [KO:K07190]
101522293  CALM2; calmodulin-2 isoform X1 [KO:K02183]
101516106  CALM1; calmodulin-1 isoform X1 [KO:K02183]
101519171  CALML4; calmodulin-like protein 4 [KO:K02183]
101529054  CALML5; calmodulin-like protein 5 [KO:K02183]
101529298  CALML3; calmodulin-like protein 3 [KO:K02183]
101516467  CALM3; calmodulin-3 [KO:K02183]
101526965  PYGL; glycogen phosphorylase, liver form isoform X1 [KO:K00688] [EC:2.4.1.1]
101517184  PYGB; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
101517519  PYGM; glycogen phosphorylase, muscle form isoform X1 [KO:K00688] [EC:2.4.1.1]
101521260  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B isoform X1 [KO:K13296] [EC:3.1.4.17]
101534210  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
101525119  cAMP-dependent protein kinase catalytic subunit alpha-like [KO:K04345] [EC:2.7.11.11]
101516221  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
101528191  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit [KO:K04739]
101520853  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit isoform X2 [KO:K04739]
101536550  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit [KO:K04739]
101535097  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
101528437  LIPE; hormone-sensitive lipase [KO:K07188] [EC:3.1.1.79]
101536130  PRKCZ; protein kinase C zeta type [KO:K18952] [EC:2.7.11.13]
101534150  PRKCI; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
101535491  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 isoform X2 [KO:K07191]
101529653  FLOT1; flotillin-1 isoform X1 [KO:K07192]
101520453  FLOT2; flotillin-2 isoform X1 [KO:K07192]
101536336  SH2B2; SH2B adapter protein 2 [KO:K07193]
101523827  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X1 [KO:K06086]
101522794  CBL; E3 ubiquitin-protein ligase CBL [KO:K04707] [EC:2.3.2.27]
101527411  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
101527001  CRK; adapter molecule crk isoform X1 [KO:K04438]
101519209  CRKL; crk-like protein [KO:K04438]
101522659  RAPGEF1; rap guanine nucleotide exchange factor 1 [KO:K06277]
101521302  RHOQ; rho-related GTP-binding protein RhoQ [KO:K07194]
101526500  EXOC7; exocyst complex component 7 isoform X1 [KO:K07195]
101520210  TRIP10; cdc42-interacting protein 4 isoform X1 [KO:K07196]
101536639  SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
101535787  ACACA; acetyl-CoA carboxylase 1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
101529798  ACACB; acetyl-CoA carboxylase 2 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
101535716  fatty acid synthase [KO:K00665] [EC:2.3.1.85]
101534803  PKLR; pyruvate kinase PKLR [KO:K12406] [EC:2.7.1.40]
101518316  HK2; hexokinase-2 [KO:K00844] [EC:2.7.1.1]
101517233  HKDC1; hexokinase HKDC1 [KO:K00844] [EC:2.7.1.1]
101516172  HK1; hexokinase-1 [KO:K00844] [EC:2.7.1.1]
101524409  HK3; LOW QUALITY PROTEIN: hexokinase-3 [KO:K00844] [EC:2.7.1.1]
101521696  GCK; hexokinase-4 [KO:K12407] [EC:2.7.1.2]
101536083  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
101525509  serine/threonine protein kinase OSK1-like [KO:K07198] [EC:2.7.11.31]
101529543  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
101520164  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199]
101524207  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
101526129  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
101530247  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
101535143  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
101528756  FOXO1; forkhead box protein O1 [KO:K07201]
101527618  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
101516625  G6PC2; glucose-6-phosphatase 2 [KO:K01084] [EC:3.1.3.9]
101525551  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
101531051  G6PC; glucose-6-phosphatase [KO:K01084] [EC:3.1.3.9]
101521820  fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
101522070  LOW QUALITY PROTEIN: fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
101523761  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
101528794  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] isoform X1 [KO:K01596] [EC:4.1.1.32]
101525384  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
101536034  RPTOR; regulatory-associated protein of mTOR [KO:K07204]
101526118  RPS6KB2; ribosomal protein S6 kinase beta-2 [KO:K04688] [EC:2.7.11.1]
101528246  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
101529521  RPS6; 40S ribosomal protein S6 [KO:K02991]
101532982  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
101520923  EIF4E; eukaryotic translation initiation factor 4E isoform X1 [KO:K03259]
101518184  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
101528599  LOW QUALITY PROTEIN: eukaryotic translation initiation factor 4E type 1B-like [KO:K03259]
101524098  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
101520687  TSC1; hamartin [KO:K07206]
101519464  TSC2; tuberin isoform X2 [KO:K07207]
101535564  RHEB; GTP-binding protein Rheb [KO:K07208]
101534340  BAD; bcl2-associated agonist of cell death [KO:K02158]
101529134  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
101522080  SHC2; SHC-transforming protein 2 [KO:K17447]
101522287  SHC3; SHC-transforming protein 3 [KO:K17448]
101535980  SHC4; SHC-transforming protein 4 [KO:K17449]
101531037  GRB2; growth factor receptor-bound protein 2 isoform X1 [KO:K04364]
101534610  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
101525349  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
101531636  HRAS; GTPase HRas [KO:K02833]
101534080  KRAS; GTPase KRas isoform X1 [KO:K07827]
101524465  NRAS; GTPase NRas [KO:K07828]
101529871  ARAF; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
101526188  BRAF; serine/threonine-protein kinase B-raf isoform X2 [KO:K04365] [EC:2.7.11.1]
101534290  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X2 [KO:K04366] [EC:2.7.11.1]
101533612  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
105942099  LOW QUALITY PROTEIN: dual specificity mitogen-activated protein kinase kinase 2-like [KO:K04369] [EC:2.7.12.2]
101529486  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
101530701  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
101525427  mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
101535070  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 [KO:K04372] [EC:2.7.11.1]
101529510  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 [KO:K04372] [EC:2.7.11.1]
101530378  ELK1; ETS domain-containing protein Elk-1 [KO:K04375]
101529126  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
101517558  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
101522074  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
101534372  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
101518547  PTPN1; tyrosine-protein phosphatase non-receptor type 1 [KO:K05696] [EC:3.1.3.48]
101529383  PTPRF; receptor-type tyrosine-protein phosphatase F isoform X2 [KO:K05695] [EC:3.1.3.48]
101531453  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
101524844  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
101518695  MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
101517015  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
101520594  INPPL1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 [KO:K15909] [EC:3.1.3.86]
101535675  INPP5A; inositol polyphosphate-5-phosphatase A [KO:K01106] [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
Related
pathway
opi00010  Glycolysis / Gluconeogenesis
opi00061  Fatty acid biosynthesis
opi00500  Starch and sucrose metabolism
opi04010  MAPK signaling pathway
opi04070  Phosphatidylinositol signaling system
opi04210  Apoptosis
KO pathway
ko04910   
LinkDB

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