KEGG   PATHWAY: oaa04910Help
Entry
oaa04910                    Pathway                                

Name
Insulin signaling pathway - Ornithorhynchus anatinus (platypus)
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
BRITE hierarchy
Pathway map
Insulin signaling pathway
oaa04910

All organismsOrtholog table
Organism
Ornithorhynchus anatinus (platypus) [GN:oaa]
Gene
INSR; insulin receptor [KO:K04527] [EC:2.7.10.1]
phosphoinositide 3-kinase regulatory subunit 5-like; K02649 phosphoinositide-3-kinase, regulatory subunit [KO:K02649]
PIK3R2; phosphoinositide-3-kinase, regulatory subunit 2 (beta) [KO:K02649]
phosphatidylinositol 3-kinase regulatory subunit alpha-like; K02649 phosphoinositide-3-kinase, regulatory subunit [KO:K02649]
PIK3R3; phosphoinositide-3-kinase, regulatory subunit 3 (gamma) [KO:K02649]
PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
PIK3CG; phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit gamma [KO:K00922] [EC:2.7.1.153]
PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
PDPK1; 3-phosphoinositide dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
AKT3; v-akt murine thymoma viral oncogene homolog 3 [KO:K04456] [EC:2.7.11.1]
RAC-alpha serine/threonine-protein kinase; K04456 RAC serine/threonine-protein kinase [EC:2.7.11.1] [KO:K04456] [EC:2.7.11.1]
glycogen synthase kinase-3 beta-like; K03083 glycogen synthase kinase 3 beta [EC:2.7.11.26] [KO:K03083] [EC:2.7.11.26]
GYS1; glycogen synthase 1 (muscle) [KO:K00693] [EC:2.4.1.11]
PPP1CC; protein phosphatase 1, catalytic subunit, gamma isozyme [KO:K06269] [EC:3.1.3.16]
PPP1CB; protein phosphatase 1, catalytic subunit, beta isozyme [KO:K06269] [EC:3.1.3.16]
PPP1R3B; protein phosphatase 1, regulatory subunit 3B [KO:K07189]
PPP1R3A; protein phosphatase 1, regulatory subunit 3A [KO:K07189]
PPP1R3C; protein phosphatase 1, regulatory subunit 3C [KO:K07189]
protein phosphatase 1 regulatory subunit 3C-like; K07189 protein phosphatase 1 regulatory subunit 3A/B/C/D/E [KO:K07189]
PPP1R3D; protein phosphatase 1, regulatory subunit 3D [KO:K07189]
PPP1R3F; protein phosphatase 1, regulatory subunit 3F [KO:K17453]
PHKG1; phosphorylase kinase, gamma 1 (muscle) [KO:K00871] [EC:2.7.11.19]
PHKG2; phosphorylase kinase, gamma 2 (testis) [KO:K00871] [EC:2.7.11.19]
PHKB; phosphorylase kinase, beta [KO:K07190]
PHKA2; phosphorylase kinase, alpha 2 (liver) [KO:K07190]
PHKA1; phosphorylase kinase, alpha 1 (muscle) [KO:K07190]
CALM1; calmodulin 1 (phosphorylase kinase, delta) [KO:K02183]
uncharacterized LOC100085924; K02183 calmodulin [KO:K02183]
neo-calmodulin; K02183 calmodulin [KO:K02183]
PYGL; phosphorylase, glycogen, liver [KO:K00688] [EC:2.4.1.1]
cGMP-inhibited 3'; K13296 cGMP-inhibited 3',5'-cyclic phosphodiesterase [EC:3.1.4.17] [KO:K13296] [EC:3.1.4.17]
PRKACB; protein kinase, cAMP-dependent, catalytic, beta [KO:K04345] [EC:2.7.11.11]
cAMP-dependent protein kinase catalytic subunit alpha-like; K04345 protein kinase A [EC:2.7.11.11] [KO:K04345] [EC:2.7.11.11]
PRKX; protein kinase, X-linked [KO:K04345] [EC:2.7.11.11]
PRKAR2B; protein kinase, cAMP-dependent, regulatory, type II, beta [KO:K04739]
PRKAR1A; protein kinase, cAMP-dependent, regulatory, type I, alpha [KO:K04739]
PRKCI; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
protein kinase C zeta type-like; K06069 atypical protein kinase C [EC:2.7.11.13] [KO:K06069] [EC:2.7.11.13]
protein kinase C iota type-like; K06069 atypical protein kinase C [EC:2.7.11.13] [KO:K06069] [EC:2.7.11.13]
flotillin-2-like; K07192 flotillin [KO:K07192]
SH2B2; SH2B adaptor protein 2 [KO:K07193]
SORBS1; sorbin and SH3 domain containing 1 [KO:K06086]
E3 ubiquitin-protein ligase CBL-like; K04707 E3 ubiquitin-protein ligase CBL [EC:6.3.2.19] [KO:K04707] [EC:6.3.2.19]
CBLB; Cbl proto-oncogene B, E3 ubiquitin protein ligase [KO:K04707] [EC:6.3.2.19]
CRK; v-crk avian sarcoma virus CT10 oncogene homolog [KO:K04438]
CRKL; v-crk avian sarcoma virus CT10 oncogene homolog-like [KO:K04438]
RAPGEF1; Rap guanine nucleotide exchange factor (GEF) 1 [KO:K06277]
exocyst complex component 7-like; K07195 exocyst complex component 7 [KO:K07195]
TRIP10; thyroid hormone receptor interactor 10 [KO:K07196]
SREBF1; sterol regulatory element binding transcription factor 1 [KO:K07197]
ACACB; acetyl-CoA carboxylase beta [KO:K11262] [EC:6.3.4.14 6.4.1.2]
ACACA; acetyl-CoA carboxylase alpha [KO:K11262] [EC:6.3.4.14 6.4.1.2]
HKDC1; putative hexokinase HKDC1 [KO:K00844] [EC:2.7.1.1]
HK1; hexokinase 1 [KO:K00844] [EC:2.7.1.1]
GCK; glucokinase (hexokinase 4) [KO:K12407] [EC:2.7.1.2]
PRKAA1; protein kinase, AMP-activated, alpha 1 catalytic subunit [KO:K07198] [EC:2.7.11.11]
5'-AMP-activated protein kinase subunit beta-2-like; K07199 5'-AMP-activated protein kinase, regulatory beta subunit [KO:K07199]
PRKAG2; protein kinase, AMP-activated, gamma 2 non-catalytic subunit [KO:K07200]
FOXO1; forkhead box O1 [KO:K07201]
PPARGC1A; peroxisome proliferator-activated receptor gamma, coactivator 1 alpha [KO:K07202]
G6PC2; glucose-6-phosphatase, catalytic, 2 [KO:K01084] [EC:3.1.3.9]
fructose-1; K03841 fructose-1,6-bisphosphatase I [EC:3.1.3.11] [KO:K03841] [EC:3.1.3.11]
fructose-1; K03841 fructose-1,6-bisphosphatase I [EC:3.1.3.11] [KO:K03841] [EC:3.1.3.11]
PCK1; phosphoenolpyruvate carboxykinase 1 (soluble) [KO:K01596] [EC:4.1.1.32]
PCK2; phosphoenolpyruvate carboxykinase 2 (mitochondrial) [KO:K01596] [EC:4.1.1.32]
MTOR; mechanistic target of rapamycin (serine/threonine kinase) [KO:K07203]
RPTOR; regulatory-associated protein of mTOR [KO:K07204]
ribosomal protein S6 kinase beta-2-like; K04688 p70 ribosomal S6 kinase [EC:2.7.11.1] [KO:K04688] [EC:2.7.11.1]
RPS6KB1; ribosomal protein S6 kinase, 70kDa, polypeptide 1 [KO:K04688] [EC:2.7.11.1]
RPS6; ribosomal protein S6 [KO:K02991]
EIF4EBP1; eukaryotic translation initiation factor 4E binding protein 1 [KO:K07205]
eukaryotic translation initiation factor 4E type 2-like; K03259 translation initiation factor 4E [KO:K03259]
eukaryotic translation initiation factor 4E-like; K03259 translation initiation factor 4E [KO:K03259]
eukaryotic translation initiation factor 4E-like; K03259 translation initiation factor 4E [KO:K03259]
TSC1; tuberous sclerosis 1 [KO:K07206]
TSC2; tuberous sclerosis 2 [KO:K07207]
RHEB; Ras homolog enriched in brain [KO:K07208]
SHC2; SHC (Src homology 2 domain containing) transforming protein 2 [KO:K17447]
GRB2; growth factor receptor-bound protein 2 [KO:K04364]
SOS2; son of sevenless homolog 2 (Drosophila) [KO:K03099]
SOS1; son of sevenless homolog 1 (Drosophila) [KO:K03099]
KRAS; Kirsten rat sarcoma viral oncogene homolog [KO:K07827]
ARAF; v-raf murine sarcoma 3611 viral oncogene homolog [KO:K08845] [EC:2.7.11.1]
BRAF; v-raf murine sarcoma viral oncogene homolog B [KO:K04365] [EC:2.7.11.1]
RAF proto-oncogene serine/threonine-protein kinase-like; K04366 RAF proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1] [KO:K04366] [EC:2.7.11.1]
MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
dual specificity mitogen-activated protein kinase kinase 2; K04369 mitogen-activated protein kinase kinase 2 [EC:2.7.12.2] [KO:K04369] [EC:2.7.12.2]
mitogen-activated protein kinase 1-like; K04371 mitogen-activated protein kinase 1/3 [EC:2.7.11.24] [KO:K04371] [EC:2.7.11.24]
mitogen-activated protein kinase 3-like; K04371 mitogen-activated protein kinase 1/3 [EC:2.7.11.24] [KO:K04371] [EC:2.7.11.24]
MAP kinase-interacting serine/threonine-protein kinase 2-like; K04372 MAP kinase interacting serine/threonine kinase [EC:2.7.11.1] [KO:K04372] [EC:2.7.11.1]
suppressor of cytokine signaling 2-like; K04694 suppressor of cytokine signaling 1 [KO:K04694]
SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
suppressor of cytokine signaling 4-like; K04697 suppressor of cytokine signaling 4 [KO:K04697]
PTPN1; protein tyrosine phosphatase, non-receptor type 1 [KO:K05696] [EC:3.1.3.48]
PTPRF; protein tyrosine phosphatase, receptor type, F [KO:K05695] [EC:3.1.3.48]
MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
IKBKB; inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta [KO:K07209] [EC:2.7.11.10]
phosphatidylinositol 3; K15909 phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 2 [EC:3.1.3.86] [KO:K15909] [EC:3.1.3.86]
Compound
C00031  
D-Glucose
C00369  
Starch
C00575  
3',5'-Cyclic AMP
C05981  
Phosphatidylinositol-3,4,5-trisphosphate
Reference
  Authors
Ogawa W, Kasuga M.
  Title
[Mechanism of insulin action and diabetes mellitus]
  Journal
Seikagaku 75:1332-44 (2003)
Reference
  Authors
Bevan P.
  Title
Insulin signalling.
  Journal
J Cell Sci 114:1429-30 (2001)
Reference
  Authors
Kanzaki M, Pessin JE.
  Title
Insulin signaling: GLUT4 vesicles exit via the exocyst.
  Journal
Curr Biol 13:R574-6 (2003)
Reference
  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)
Reference
  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)
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)
Reference
  Authors
Saltiel AR, Kahn CR.
  Title
Insulin signalling and the regulation of glucose and lipid metabolism.
  Journal
Nature 414:799-806 (2001)
Reference
  Authors
Inoki K, Corradetti MN, Guan KL.
  Title
Dysregulation of the TSC-mTOR pathway in human disease.
  Journal
Nat Genet 37:19-24 (2005)
Reference
  Authors
Ruggero D, Sonenberg N.
  Title
The Akt of translational control.
  Journal
Oncogene 24:7426-34 (2005)
Reference
  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)
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)
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
  Authors
Pollak MN, Schernhammer ES, Hankinson SE.
  Title
Insulin-like growth factors and neoplasia.
  Journal
Nat Rev Cancer 4:505-18 (2004)
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)
Reference
  Authors
Ferre P, Foufelle F
  Title
SREBP-1c transcription factor and lipid homeostasis: clinical perspective.
  Journal
Horm Res 68:72-82 (2007)
Reference
  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)
Reference
  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)
Reference
  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)
KO pathway
 

DBGET integrated database retrieval system