KEGG   PATHWAY: mjv04910
Entry
mjv04910                    Pathway                                
Name
Insulin signaling pathway - Manis javanica (Malayan pangolin)
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
mjv04910  Insulin signaling pathway
mjv04910

Organism
Manis javanica (Malayan pangolin) [GN:mjv]
Gene
108383453  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
108383561  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
108383725  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X3 [KO:K03259]
108383930  FLOT2; flotillin-2 isoform X1 [KO:K07192]
108384622  ACACA; acetyl-CoA carboxylase 1 isoform X6 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
108384728  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit isoform X1 [KO:K04739]
108384751  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
108384893  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
108384981  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X1 [KO:K07198] [EC:2.7.11.31]
108385046  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 isoform X3 [KO:K04369] [EC:2.7.12.2]
108385379  PHKG2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform [KO:K00871] [EC:2.7.11.19]
108385635  MAPK10; mitogen-activated protein kinase 10 isoform X4 [KO:K04440] [EC:2.7.11.24]
108385648  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
108386004  TSC1; hamartin isoform X1 [KO:K07206]
108386155  PRKCZ; protein kinase C zeta type isoform X2 [KO:K18952] [EC:2.7.11.13]
108386275  PPP1R3B; protein phosphatase 1 regulatory subunit 3B isoform X2 [KO:K07189]
108386792  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X6 [KO:K06086]
108387187  FASN; fatty acid synthase isoform X2 [KO:K00665] [EC:2.3.1.85]
108387268  RHEB; GTP-binding protein Rheb isoform X1 [KO:K07208]
108387410  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit isoform X2 [KO:K04739]
108388478  [KO:K03259]
108388657  SREBF1; sterol regulatory element-binding protein 1 isoform X3 [KO:K07197]
108389845  SH2B2; SH2B adapter protein 2 isoform X5 [KO:K07193]
108389977  HK2; hexokinase-2 isoform X2 [KO:K00844] [EC:2.7.1.1]
108390365  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
108390378  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial isoform X1 [KO:K01596] [EC:4.1.1.32]
108390475  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X2 [KO:K02649]
108390484  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
108390518  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 isoform X1 [KO:K07200]
108390746  MTOR; serine/threonine-protein kinase mTOR isoform X1 [KO:K07203] [EC:2.7.11.1]
108390936  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
108391745  SHC2; SHC-transforming protein 2 isoform X2 [KO:K17447]
108391894  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
108391994  PTPN1; tyrosine-protein phosphatase non-receptor type 1 isoform X1 [KO:K05696] [EC:3.1.3.48]
108392879  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
108393155  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
108393161  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X2 [KO:K04688] [EC:2.7.11.1]
108393248  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 [KO:K04372] [EC:2.7.11.1]
108393430  LIPE; hormone-sensitive lipase isoform X1 [KO:K07188] [EC:3.1.1.79]
108393437  [KO:K03841] [EC:3.1.3.11]
108393438  FBP1; fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
108393654  PRKCI; protein kinase C iota type isoform X1 [KO:K06069] [EC:2.7.11.13]
108393746  AKT3; RAC-gamma serine/threonine-protein kinase isoform X2 [KO:K04456] [EC:2.7.11.1]
108394025  GCK; hexokinase-4 [KO:K12407] [EC:2.7.1.2]
108394341  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
108394387  SHC3; SHC-transforming protein 3 isoform X1 [KO:K17448]
108394533  CRK; adapter molecule crk isoform X1 [KO:K04438]
108394606  G6PC1; glucose-6-phosphatase catalytic subunit 1 isoform X1 [KO:K01084] [EC:3.1.3.9]
108395842  KRAS; GTPase KRas isoform X1 [KO:K07827]
108395975  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X2 [KO:K02649]
108396005  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
108396139  PHKB; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
108396372  PYGM; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
108396608  PYGB; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
108396704  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
108396796  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B [KO:K13296] [EC:3.1.4.17]
108396822  INPP5A; inositol polyphosphate-5-phosphatase A isoform X2 [KO:K01106] [EC:3.1.3.56]
108396943  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
108397189  IRS1; insulin receptor substrate 1 [KO:K16172]
108397433  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
108397568  G6PC2; glucose-6-phosphatase 2 [KO:K01084] [EC:3.1.3.9]
108398047  NRAS; GTPase NRas [KO:K07828]
108398121  RPTOR; regulatory-associated protein of mTOR isoform X1 [KO:K07204]
108398366  GYS2; glycogen [starch] synthase, liver isoform X1 [KO:K00693] [EC:2.4.1.11]
108398454  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
108398550  ARAF; serine/threonine-protein kinase A-Raf isoform X2 [KO:K08845] [EC:2.7.11.1]
108398608  PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
108399795  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
108399811  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X4 [KO:K06276] [EC:2.7.11.1]
108399878  ACACB; acetyl-CoA carboxylase 2 isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
108400004  PPP1R3E; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
108400412  RPS6; small ribosomal subunit protein eS6 [KO:K02991]
108400461  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
108400557  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit isoform X1 [KO:K06269] [EC:3.1.3.16]
108400653  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
108400663  MAPK1; mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:2.7.11.24]
108401721  PTPRF; receptor-type tyrosine-protein phosphatase F isoform X1 [KO:K05695] [EC:3.1.3.48]
108401782  TRIP10; cdc42-interacting protein 4 isoform X1 [KO:K07196]
108401876  ELK1; ETS domain-containing protein Elk-1 isoform X2 [KO:K04375]
108402196  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
108402203  HK3; hexokinase-3 isoform X4 [KO:K00844] [EC:2.7.1.1]
108402352  SHC4; SHC-transforming protein 4 [KO:K17449]
108402376  PYGL; glycogen phosphorylase, liver form isoform X2 [KO:K00688] [EC:2.4.1.1]
108402614  INS; insulin [KO:K04526]
108403230  IRS2; insulin receptor substrate 2 isoform X1 [KO:K07187]
108403327  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
108403628  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
108404215  PPP1R3F; protein phosphatase 1 regulatory subunit 3F isoform X1 [KO:K17453]
108404448  PPP1R3A; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
108404652  INSR; insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
108404949  [KO:K04372] [EC:2.7.11.1]
108405095  INPPL1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 isoform X2 [KO:K15909] [EC:3.1.3.86]
108405554  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
108405955  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform [KO:K00871] [EC:2.7.11.19]
108405981  EXOC7; exocyst complex component 7 isoform X1 [KO:K07195]
108406099  IRS4; insulin receptor substrate 4 [KO:K17446]
108406495  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
108406654  CALML4; calmodulin-like protein 4 isoform X1 [KO:K02183]
108406801  RAPGEF1; rap guanine nucleotide exchange factor 1 isoform X18 [KO:K06277]
108407272  PKLR; pyruvate kinase PKLR isoform X1 [KO:K12406] [EC:2.7.1.40]
108407280  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
108407537  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
108407571  BAD; bcl2-associated agonist of cell death isoform X1 [KO:K02158]
108407802  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
108408200  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 isoform X2 [KO:K07199]
108408223  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X3 [KO:K07198] [EC:2.7.11.31]
108408343  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
108408568  EIF4E; eukaryotic translation initiation factor 4E isoform X1 [KO:K03259]
108408627  HRAS; GTPase HRas isoform X1 [KO:K02833]
108408988  CRKL; crk-like protein [KO:K04438]
108409075  FLOT1; flotillin-1 isoform X3 [KO:K07192]
108409141  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
108409254  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit isoform X1 [KO:K04739]
108409307  CBL; E3 ubiquitin-protein ligase CBL isoform X1 [KO:K04707] [EC:2.3.2.27]
108409367  [KO:K17445]
108409638  FOXO1; forkhead box protein O1 [KO:K07201]
108410004  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
108410254  TSC2; tuberin isoform X9 [KO:K07207]
118967667  [KO:K02833]
140842982  [KO:K02833]
140842991  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
140843067  [KO:K02833]
140847875  [KO:K02183]
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
mjv00010  Glycolysis / Gluconeogenesis
mjv00061  Fatty acid biosynthesis
mjv00500  Starch and sucrose metabolism
mjv04010  MAPK signaling pathway
mjv04070  Phosphatidylinositol signaling system
mjv04210  Apoptosis
KO pathway
ko04910   

DBGET integrated database retrieval system