KEGG   PATHWAY: aml04910
Entry
aml04910                    Pathway                                
Name
Insulin signaling pathway - Ailuropoda melanoleuca (giant panda)
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
aml04910  Insulin signaling pathway
aml04910

Organism
Ailuropoda melanoleuca (giant panda) [GN:aml]
Gene
100483432  INS; insulin isoform X2 [KO:K04526]
100473956  INSR; insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
100477645  IRS1; insulin receptor substrate 1 [KO:K16172]
100477685  IRS2; LOW QUALITY PROTEIN: insulin receptor substrate 2 [KO:K07187]
100467269  uncharacterized protein LOC100467269 [KO:K17445]
105240373  IRS4; LOW QUALITY PROTEIN: insulin receptor substrate 4 [KO:K17446]
100475291  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
100483828  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
100467916  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
100463775  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
100479294  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
100479580  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
100473305  PDPK1; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
100468763  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100480414  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
100465793  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
100479224  GSK3B; glycogen synthase kinase-3 beta isoform X2 [KO:K03083] [EC:2.7.11.26]
100476206  GYS1; glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
100470220  GYS2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
100464499  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
100471456  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
100476029  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
100472164  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
100482992  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
100481384  PPP1R3B; protein phosphatase 1 regulatory subunit 3B isoform X2 [KO:K07189]
100481006  PPP1R3A; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
105240599  PPP1R3E; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
100477460  PPP1R3F; protein phosphatase 1 regulatory subunit 3F isoform X3 [KO:K17453]
100477667  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform isoform X2 [KO:K00871] [EC:2.7.11.19]
100478501  PHKG2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform [KO:K00871] [EC:2.7.11.19]
100468646  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
100479757  PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X5 [KO:K07190]
100482884  PHKB; phosphorylase b kinase regulatory subunit beta [KO:K07190]
100478600  CALML6; calmodulin-like protein 6 [KO:K02183]
100470909  CALM2; calmodulin-2 [KO:K02183]
100484519  calmodulin [KO:K02183]
100484770  calmodulin-like protein 3 [KO:K02183]
100481177  CALM1; calmodulin-1 [KO:K02183]
100472122  CALM3; calmodulin-3 [KO:K02183]
100478732  CALML4; LOW QUALITY PROTEIN: calmodulin-like protein 4 [KO:K02183]
117799706  calmodulin-alpha-like [KO:K02183]
100475413  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
100466701  PYGB; glycogen phosphorylase, brain form isoform X1 [KO:K00688] [EC:2.4.1.1]
100472664  PYGM; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
100482771  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B isoform X2 [KO:K13296] [EC:3.1.4.17]
100468252  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X2 [KO:K04345] [EC:2.7.11.11]
100469628  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
100470571  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit isoform X1 [KO:K04739]
100472973  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit isoform X2 [KO:K04739]
100473970  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
105240601  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
100479605  LIPE; hormone-sensitive lipase isoform X1 [KO:K07188] [EC:3.1.1.79]
100477838  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
100476899  PRKCI; protein kinase C iota type isoform X1 [KO:K06069] [EC:2.7.11.13]
100473294  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 isoform X1 [KO:K07191]
100479641  FLOT2; flotillin-2 isoform X1 [KO:K07192]
100472305  FLOT1; flotillin-1 isoform X1 [KO:K07192]
105240494  SH2B2; SH2B adapter protein 2 [KO:K07193]
100470895  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X39 [KO:K06086]
100470573  CBL; E3 ubiquitin-protein ligase CBL isoform X1 [KO:K04707] [EC:2.3.2.27]
100473515  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
100466609  CRKL; crk-like protein [KO:K04438]
100467322  CRK; adapter molecule crk isoform X1 [KO:K04438]
100478465  RAPGEF1; rap guanine nucleotide exchange factor 1 [KO:K06277]
100477018  RHOQ; rho-related GTP-binding protein RhoQ [KO:K07194]
100472763  EXOC7; exocyst complex component 7 isoform X2 [KO:K07195]
100475595  TRIP10; cdc42-interacting protein 4 isoform X1 [KO:K07196]
100476071  SREBF1; sterol regulatory element-binding protein 1 [KO:K07197]
100474573  ACACA; acetyl-CoA carboxylase 1 isoform X1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
100474644  ACACB; acetyl-CoA carboxylase 2 isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
100468470  FASN; LOW QUALITY PROTEIN: fatty acid synthase [KO:K00665] [EC:2.3.1.85]
100474752  PKLR; pyruvate kinase PKLR isoform X1 [KO:K12406] [EC:2.7.1.40]
100483014  HK3; hexokinase-3 isoform X2 [KO:K00844] [EC:2.7.1.1]
100483319  HK1; hexokinase-1 [KO:K00844] [EC:2.7.1.1]
100470774  HK2; hexokinase-2 isoform X1 [KO:K00844] [EC:2.7.1.1]
100475939  HKDC1; hexokinase HKDC1 [KO:K00844] [EC:2.7.1.1]
100475738  GCK; hexokinase-4 isoform X2 [KO:K12407] [EC:2.7.1.2]
100481376  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X1 [KO:K07198] [EC:2.7.11.31]
100470115  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
100475764  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X2 [KO:K07199]
100463656  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
100480315  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
100468143  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 isoform X1 [KO:K07200]
100474747  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
100471182  FOXO1; LOW QUALITY PROTEIN: forkhead box protein O1 [KO:K07201]
100471439  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha [KO:K07202]
100480642  G6PC; glucose-6-phosphatase [KO:K01084] [EC:3.1.3.9]
100475867  G6PC2; glucose-6-phosphatase 2 isoform X1 [KO:K01084] [EC:3.1.3.9]
100482095  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
100475474  FBP2; fructose-1,6-bisphosphatase isozyme 2 isoform X1 [KO:K03841] [EC:3.1.3.11]
100475720  FBP1; fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
100470754  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
100467669  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
100471122  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
100478081  RPTOR; regulatory-associated protein of mTOR isoform X1 [KO:K07204]
100484786  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
100464998  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
100475057  RPS6; 40S ribosomal protein S6 [KO:K02991]
100469745  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
100465592  EIF4E; eukaryotic translation initiation factor 4E isoform X1 [KO:K03259]
100483338  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
100463829  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
100471530  TSC1; hamartin isoform X1 [KO:K07206]
100465690  TSC2; tuberin isoform X1 [KO:K07207]
100465977  RHEB; GTP-binding protein Rheb [KO:K07208]
100473937  BAD; bcl2-associated agonist of cell death [KO:K02158]
100480856  SHC1; SHC-transforming protein 1 isoform X2 [KO:K06279]
100480694  SHC2; LOW QUALITY PROTEIN: SHC-transforming protein 2 [KO:K17447]
100468080  SHC3; SHC-transforming protein 3 [KO:K17448]
100475137  SHC4; SHC-transforming protein 4 isoform X2 [KO:K17449]
100468916  GRB2; growth factor receptor-bound protein 2 isoform X1 [KO:K04364]
100474396  SOS2; son of sevenless homolog 2 isoform X9 [KO:K03099]
100482526  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
100473836  HRAS; GTPase HRas isoform X1 [KO:K02833]
100483919  KRAS; GTPase KRas isoform X1 [KO:K07827]
100464196  NRAS; GTPase NRas [KO:K07828]
100475955  ARAF; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
100469346  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
100482255  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
100478039  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
100465700  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
100470035  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
100472388  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
100463933  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 [KO:K04372] [EC:2.7.11.1]
100481494  ELK1; ETS domain-containing protein Elk-1 isoform X2 [KO:K04375]
100480183  SOCS1; LOW QUALITY PROTEIN: suppressor of cytokine signaling 1 [KO:K04694]
100474808  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
100475555  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
100464791  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
100481720  PTPN1; tyrosine-protein phosphatase non-receptor type 1 [KO:K05696] [EC:3.1.3.48]
100473464  PTPRF; LOW QUALITY PROTEIN: receptor-type tyrosine-protein phosphatase F [KO:K05695] [EC:3.1.3.48]
100477951  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
100482196  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
100477600  MAPK9; mitogen-activated protein kinase 9 isoform X2 [KO:K04440] [EC:2.7.11.24]
100471679  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
100482460  INPPL1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 isoform X1 [KO:K15909] [EC:3.1.3.86]
100465896  INPP5A; inositol polyphosphate-5-phosphatase A isoform X1 [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
aml00010  Glycolysis / Gluconeogenesis
aml00061  Fatty acid biosynthesis
aml00500  Starch and sucrose metabolism
aml04010  MAPK signaling pathway
aml04070  Phosphatidylinositol signaling system
aml04210  Apoptosis
KO pathway
ko04910   
LinkDB

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