KEGG   PATHWAY: pps04910
Entry
pps04910                    Pathway                                
Name
Insulin signaling pathway - Pan paniscus (bonobo)
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
pps04910  Insulin signaling pathway
pps04910

Organism
Pan paniscus (bonobo) [GN:pps]
Gene
100967511  FBP2; fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
100967756  EIF4E; eukaryotic translation initiation factor 4E isoform X8 [KO:K03259]
100968237  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
100968316  [KO:K03259]
100968473  CALM1; calmodulin-1 isoform X2 [KO:K02183]
100969007  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
100969217  AKT3; RAC-gamma serine/threonine-protein kinase isoform X3 [KO:K04456] [EC:2.7.11.1]
100969228  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X1 [KO:K06086]
100969387  INS; insulin [KO:K04526]
100969444  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100969639  HKDC1; hexokinase HKDC1 [KO:K00844] [EC:2.7.1.1]
100969690  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit isoform X1 [KO:K04739]
100969975  HK1; hexokinase-1 isoform X2 [KO:K00844] [EC:2.7.1.1]
100969981  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
100970123  PPP1R3B; protein phosphatase 1 regulatory subunit 3B [KO:K07189]
100970465  NRAS; GTPase NRas isoform X2 [KO:K07828]
100970488  PPP1R3E; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
100970836  FLOT1; flotillin-1 isoform X1 [KO:K07192]
100970917  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
100971050  TSC2; tuberin isoform X16 [KO:K07207]
100971139  [KO:K06276] [EC:2.7.11.1]
100971596  IRS1; insulin receptor substrate 1 [KO:K16172]
100971666  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
100972192  RAPGEF1; rap guanine nucleotide exchange factor 1 isoform X11 [KO:K06277]
100972194  RPS6; small ribosomal subunit protein eS6 [KO:K02991]
100972246  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
100972306  GSK3B; glycogen synthase kinase-3 beta isoform X2 [KO:K03083] [EC:2.7.11.26]
100972311  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
100972602  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B isoform X1 [KO:K13296] [EC:3.1.4.17]
100972624  SHC3; SHC-transforming protein 3 isoform X2 [KO:K17448]
100972797  GYS2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
100972902  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
100972953  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
100973241  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial isoform X1 [KO:K01596] [EC:4.1.1.32]
100973798  CRKL; crk-like protein [KO:K04438]
100974159  SREBF1; sterol regulatory element-binding protein 1 isoform X4 [KO:K07197]
100974757  G6PC1; glucose-6-phosphatase catalytic subunit 1 isoform X1 [KO:K01084] [EC:3.1.3.9]
100974798  SHC2; SHC-transforming protein 2 isoform X1 [KO:K17447]
100974882  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
100974889  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
100975071  LIPE; hormone-sensitive lipase isoform X1 [KO:K07188] [EC:3.1.1.79]
100975196  PTPN1; tyrosine-protein phosphatase non-receptor type 1 [KO:K05696] [EC:3.1.3.48]
100975205  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 isoform X1 [KO:K07199]
100975575  TSC1; hamartin isoform X2 [KO:K07206]
100975618  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X2 [KO:K07198] [EC:2.7.11.31]
100975668  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit isoform X1 [KO:K04739]
100976010  PHKB; phosphorylase b kinase regulatory subunit beta isoform X2 [KO:K07190]
100976055  [KO:K02183]
100976440  RPTOR; regulatory-associated protein of mTOR isoform X1 [KO:K07204]
100976587  CRK; adapter molecule crk isoform X1 [KO:K04438]
100976648  PPP1R3A; protein phosphatase 1 regulatory subunit 3A isoform X1 [KO:K07189]
100977014  CALM3; calmodulin-3 [KO:K02183]
100977025  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 isoform X3 [KO:K04369] [EC:2.7.12.2]
100978326  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
100978589  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
100978591  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 isoform X2 [KO:K04372] [EC:2.7.11.1]
100979074  CALML6; calmodulin-like protein 6 [KO:K02183]
100979245  PRKCI; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
100979542  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
100979621  GCK; hexokinase-4 isoform X1 [KO:K12407] [EC:2.7.1.2]
100980038  SOS2; LOW QUALITY PROTEIN: son of sevenless homolog 2 [KO:K03099]
100980055  PKLR; pyruvate kinase PKLR isoform X2 [KO:K12406] [EC:2.7.1.40]
100980204  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
100980382  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X8 [KO:K04372] [EC:2.7.11.1]
100980454  CALM2; calmodulin-2 isoform X1 [KO:K02183]
100981220  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
100981514  EXOC7; exocyst complex component 7 isoform X6 [KO:K07195]
100981775  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
100982406  IRS2; insulin receptor substrate 2 [KO:K07187]
100982462  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
100982480  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
100982589  PRKACG; cAMP-dependent protein kinase catalytic subunit gamma [KO:K04345] [EC:2.7.11.11]
100982968  RHEB; GTP-binding protein Rheb isoform X2 [KO:K07208]
100983149  HK2; hexokinase-2 isoform X1 [KO:K00844] [EC:2.7.1.1]
100983464  PHKG2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform [KO:K00871] [EC:2.7.11.19]
100983930  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
100983951  PTPRF; receptor-type tyrosine-protein phosphatase F isoform X1 [KO:K05695] [EC:3.1.3.48]
100984173  MAPK10; mitogen-activated protein kinase 10 isoform X5 [KO:K04440] [EC:2.7.11.24]
100984489  G6PC2; glucose-6-phosphatase 2 isoform X1 [KO:K01084] [EC:3.1.3.9]
100984607  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
100985436  ACACA; acetyl-CoA carboxylase 1 isoform X3 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
100985502  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
100985873  FASN; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
100985999  ACACB; acetyl-CoA carboxylase 2 isoform X4 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
100986080  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
100986631  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform isoform X1 [KO:K00871] [EC:2.7.11.19]
100986739  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X2 [KO:K04688] [EC:2.7.11.1]
100987241  PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X2 [KO:K07190]
100987544  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
100987698  PYGB; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
100987712  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
100987713  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
100987922  [KO:K07193]
100988422  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
100988437  [KO:K04369] [EC:2.7.12.2]
100988665  BAD; bcl2-associated agonist of cell death [KO:K02158]
100988815  CBL; E3 ubiquitin-protein ligase CBL [KO:K04707] [EC:2.3.2.27]
100989242  SOCS2; suppressor of cytokine signaling 2 isoform X2 [KO:K04695]
100989390  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
100989690  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
100989732  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
100989775  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit [KO:K04739]
100989947  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 isoform X1 [KO:K07200]
100990031  GYS1; glycogen [starch] synthase, muscle isoform X1 [KO:K00693] [EC:2.4.1.11]
100990080  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
100990081  HK3; hexokinase-3 [KO:K00844] [EC:2.7.1.1]
100990108  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
100990453  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X3 [KO:K07202]
100990459  CALML5; calmodulin-like protein 5 [KO:K02183]
100990590  ARAF; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:2.7.11.1]
100990662  PPP1R3F; protein phosphatase 1 regulatory subunit 3F isoform X2 [KO:K17453]
100990795  CALML3; calmodulin-like protein 3 [KO:K02183]
100990801  KRAS; GTPase KRas isoform X1 [KO:K07827]
100990828  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
100991042  SHC4; SHC-transforming protein 4 isoform X1 [KO:K17449]
100991292  IRS4; insulin receptor substrate 4 [KO:K17446]
100991417  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
100991447  ELK1; ETS domain-containing protein Elk-1 [KO:K04375]
100991455  FLOT2; flotillin-2 isoform X1 [KO:K07192]
100991804  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
100991905  INSR; insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
100992392  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
100992486  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
100992766  INPPL1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 isoform X1 [KO:K15909] [EC:3.1.3.86]
100993144  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
100993163  [KO:K00844] [EC:2.7.1.1]
100993361  SHC1; SHC-transforming protein 1 isoform X9 [KO:K06279]
100993386  HRAS; GTPase HRas isoform X1 [KO:K02833]
100993451  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
100993483  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit [KO:K04739]
100993679  PYGM; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
100994280  TRIP10; cdc42-interacting protein 4 isoform X2 [KO:K07196]
100994315  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
100995177  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
100995567  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
100995871  INPP5A; inositol polyphosphate-5-phosphatase A isoform X2 [KO:K01106] [EC:3.1.3.56]
100995941  FBP1; fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
100996020  FOXO1; forkhead box protein O1 [KO:K07201]
100996156  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X2 [KO:K07200]
100996176  CALML4; calmodulin-like protein 4 isoform X1 [KO:K02183]
103783852  [KO:K07194]
117976196  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
117976254  [KO:K03259]
117981055  SH2B2; SH2B adapter protein 2 isoform X1 [KO:K07193]
129393206  [KO:K07208]
134730135  [KO:K06269] [EC:3.1.3.16]
134730136  [KO:K06269] [EC:3.1.3.16]
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
pps00010  Glycolysis / Gluconeogenesis
pps00061  Fatty acid biosynthesis
pps00500  Starch and sucrose metabolism
pps04010  MAPK signaling pathway
pps04070  Phosphatidylinositol signaling system
pps04210  Apoptosis
KO pathway
ko04910   

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