KEGG   PATHWAY: ppad04910
Entry
ppad04910                   Pathway                                
Name
Insulin signaling pathway - Panthera pardus (leopard)
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
ppad04910  Insulin signaling pathway
ppad04910

Organism
Panthera pardus (leopard) [GN:ppad]
Gene
109259395  INS; insulin [KO:K04526]
109254164  INSR; insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
109264970  IRS1; insulin receptor substrate 1 [KO:K16172]
109264073  IRS2; LOW QUALITY PROTEIN: insulin receptor substrate 2 [KO:K07187]
109251297  insulin receptor substrate 1-like isoform X1 [KO:K17445]
109253661  IRS4; insulin receptor substrate 4 [KO:K17446]
109266953  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
109275060  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
109247606  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
109274075  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
109275159  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
109259912  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
109278175  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
109256570  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
109251379  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
109257810  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
109266441  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
109268721  GYS2; glycogen [starch] synthase, liver isoform X1 [KO:K00693] [EC:2.4.1.11]
109253089  GYS1; glycogen [starch] synthase, muscle isoform X1 [KO:K00693] [EC:2.4.1.11]
109266491  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
109246846  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
109277658  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit isoform X1 [KO:K06269] [EC:3.1.3.16]
109248399  PPP1R3A; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
109264647  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
109277245  PPP1R3B; protein phosphatase 1 regulatory subunit 3B isoform X1 [KO:K07189]
109253452  PPP1R3D; protein phosphatase 1 regulatory subunit 3D isoform X1 [KO:K07189]
109255031  PPP1R3E; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
109248098  PPP1R3F; protein phosphatase 1 regulatory subunit 3F isoform X1 [KO:K17453]
109258973  PHKG2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform [KO:K00871] [EC:2.7.11.19]
109250661  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform [KO:K00871] [EC:2.7.11.19]
109256391  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
109260682  PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
109270977  PHKB; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
109273951  calmodulin-like protein 6 isoform X1 [KO:K02183]
109246761  CALM2; calmodulin [KO:K02183]
109253192  CALM3; calmodulin isoform X1 [KO:K02183]
109273783  calmodulin-like protein 3 [KO:K02183]
109273784  calmodulin-like [KO:K02183]
109273854  calmodulin-like protein 6 [KO:K02183]
109274449  CALM1; calmodulin [KO:K02183]
109262791  CALML4; calmodulin-like protein 4 isoform X1 [KO:K02183]
109257442  calmodulin-alpha-like [KO:K02183]
109262226  calmodulin-like [KO:K02183]
109268488  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
109259567  PYGB; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
109246681  PYGM; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
109271173  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
109246175  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
109253991  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
109277038  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
109247777  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
109268067  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit [KO:K04739]
109251098  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit [KO:K04739]
109257948  LIPE; hormone-sensitive lipase isoform X1 [KO:K07188] [EC:3.1.1.79]
109273956  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
109262118  PRKCI; protein kinase C iota type isoform X1 [KO:K06069] [EC:2.7.11.13]
109245971  SLC2A4; LOW QUALITY PROTEIN: solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
109249515  FLOT1; flotillin-1 isoform X1 [KO:K07192]
109251828  FLOT2; flotillin-2 isoform X1 [KO:K07192]
109250551  SH2B2; SH2B adapter protein 2 isoform X1 [KO:K07193]
109264686  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X1 [KO:K06086]
109278523  CBL; E3 ubiquitin-protein ligase CBL [KO:K04707] [EC:2.3.2.27]
109266341  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
109259695  CRKL; crk-like protein [KO:K04438]
109255155  CRK; adapter molecule crk isoform X1 [KO:K04438]
109249998  RAPGEF1; rap guanine nucleotide exchange factor 1 [KO:K06277]
109245819  RHOQ; rho-related GTP-binding protein RhoQ isoform X1 [KO:K07194]
109276904  EXOC7; exocyst complex component 7 isoform X1 [KO:K07195]
109261026  TRIP10; cdc42-interacting protein 4 isoform X1 [KO:K07196]
109245768  SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
109251979  ACACA; acetyl-CoA carboxylase 1 isoform X1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
109277478  ACACB; acetyl-CoA carboxylase 2 isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
109276748  FASN; fatty acid synthase isoform X1 [KO:K00665] [EC:2.3.1.85]
109256357  PKLR; LOW QUALITY PROTEIN: pyruvate kinase PKLR [KO:K12406] [EC:2.7.1.40]
109263394  HK2; hexokinase-2 isoform X1 [KO:K00844] [EC:2.7.1.1]
109264349  HK1; hexokinase-1 isoform X1 [KO:K00844] [EC:2.7.1.1]
109264350  HKDC1; putative hexokinase HKDC1 [KO:K00844] [EC:2.7.1.1]
109267563  HK3; hexokinase-3 isoform X1 [KO:K00844] [EC:2.7.1.1]
109267871  GCK; glucokinase [KO:K12407] [EC:2.7.1.2]
109275841  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
109266797  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X1 [KO:K07198] [EC:2.7.11.31]
109277549  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
109259142  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199]
109265053  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 isoform X1 [KO:K07200]
109252396  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
109249057  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
109266009  FOXO1; forkhead box protein O1 [KO:K07201]
109269600  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
109258593  G6PC; glucose-6-phosphatase isoform X1 [KO:K01084] [EC:3.1.3.9]
109269808  G6PC2; glucose-6-phosphatase 2 [KO:K01084] [EC:3.1.3.9]
109258179  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
109251666  FBP1; fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
109251668  FBP2; fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
109253481  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
109254991  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial isoform X1 [KO:K01596] [EC:4.1.1.32]
109274103  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
109276800  RPTOR; regulatory-associated protein of mTOR isoform X1 [KO:K07204]
109246850  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
109256121  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
109247060  RPS6; 40S ribosomal protein S6 isoform X1 [KO:K02991]
109262313  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 isoform X1 [KO:K07205]
109247116  EIF4E; eukaryotic translation initiation factor 4E isoform X1 [KO:K03259]
109267401  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
109264897  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
109249982  TSC1; hamartin isoform X1 [KO:K07206]
109278145  TSC2; tuberin isoform X1 [KO:K07207]
109252395  RHEB; GTP-binding protein Rheb isoform X1 [KO:K07208]
109246663  BAD; bcl2-associated agonist of cell death [KO:K02158]
109256269  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
109257730  SHC2; SHC-transforming protein 2 isoform X1 [KO:K17447]
109275536  SHC3; SHC-transforming protein 3 isoform X1 [KO:K17448]
109263016  SHC4; SHC-transforming protein 4 [KO:K17449]
109276940  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
109268505  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
109265500  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
109259759  GTPase HRas [KO:K02833]
109268745  KRAS; GTPase KRas isoform X1 [KO:K07827]
109272105  NRAS; GTPase NRas [KO:K07828]
109248156  ARAF; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
109269114  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
109257492  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
109262816  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
109255967  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:2.7.12.2]
109259699  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
109261343  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
109257687  MKNK2; LOW QUALITY PROTEIN: MAP kinase-interacting serine/threonine-protein kinase 2 [KO:K04372] [EC:2.7.11.1]
109266939  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X1 [KO:K04372] [EC:2.7.11.1]
109248161  ELK1; ETS domain-containing protein Elk-1 [KO:K04375]
109278321  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
109265338  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
109276855  SOCS3; suppressor of cytokine signaling 3 isoform X1 [KO:K04696]
109268440  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
109272277  PTPN1; tyrosine-protein phosphatase non-receptor type 1 isoform X1 [KO:K05696] [EC:3.1.3.48]
109254790  PTPRF; receptor-type tyrosine-protein phosphatase F [KO:K05695] [EC:3.1.3.48]
109278973  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
109276314  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
109264550  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
109262264  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
109267136  INPPL1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 isoform X1 [KO:K15909] [EC:3.1.3.86]
109256690  INPP5A; type I inositol 1,4,5-trisphosphate 5-phosphatase 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
ppad00010  Glycolysis / Gluconeogenesis
ppad00061  Fatty acid biosynthesis
ppad00500  Starch and sucrose metabolism
ppad04010  MAPK signaling pathway
ppad04070  Phosphatidylinositol signaling system
ppad04210  Apoptosis
KO pathway
ko04910   
LinkDB

DBGET integrated database retrieval system