KEGG   PATHWAY: chx04910
Entry
chx04910                    Pathway                                
Name
Insulin signaling pathway - Capra hircus (goat)
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
chx04910  Insulin signaling pathway
chx04910

Organism
Capra hircus (goat) [GN:chx]
Gene
100860801  LIPE; hormone-sensitive lipase isoform X1 [KO:K07188] [EC:3.1.1.79]
100860902  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
100860904  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100860908  SREBF1; sterol regulatory element-binding protein 1 [KO:K07197]
100860943  TSC2; tuberin [KO:K07207]
100861087  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
100861224  ACACA; acetyl-CoA carboxylase 1 isoform X1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
100861234  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
100861286  FASN; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
100861288  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha [KO:K07202]
100861297  RPS6KB1; ribosomal protein S6 kinase beta-1 [KO:K04688] [EC:2.7.11.1]
100861301  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
100861308  RHEB; GTP-binding protein Rheb [KO:K07208]
100861337  PHKG2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform [KO:K00871] [EC:2.7.11.19]
102168356  HK2; hexokinase-2 [KO:K00844] [EC:2.7.1.1]
102168391  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
102168742  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
102168790  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
102168996  INSR; insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
102169319  [KO:K04688] [EC:2.7.11.1]
102169370  ARAF; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:2.7.11.1]
102169434  FLOT1; flotillin-1 isoform X1 [KO:K07192]
102169697  CALM3; calmodulin [KO:K02183]
102169928  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
102169956  SHC2; LOW QUALITY PROTEIN: SHC-transforming protein 2 [KO:K17447]
102170129  ELK1; ETS domain-containing protein Elk-1 [KO:K04375]
102170135  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta isoform X1 [KO:K02649]
102170356  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
102170408  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
102170609  RHOQ; rho-related GTP-binding protein RhoQ [KO:K07194]
102170730  G6PC; glucose-6-phosphatase isoform X1 [KO:K01084] [EC:3.1.3.9]
102170926  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
102170985  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
102171295  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
102171428  CALML4; calmodulin-like protein 4 isoform X1 [KO:K02183]
102172049  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform [KO:K07190]
102172164  CALM2; calmodulin isoform X1 [KO:K02183]
102172519  KRAS; GTPase KRas isoform X1 [KO:K07827]
102172686  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
102173122  RPTOR; regulatory-associated protein of mTOR isoform X1 [KO:K07204]
102173379  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
102174051  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
102174315  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
102174330  CRK; adapter molecule crk isoform X1 [KO:K04438]
102174359  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit [KO:K04739]
102174360  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
102174453  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X1 [KO:K04372] [EC:2.7.11.1]
102174704  G6PC2; glucose-6-phosphatase 2 isoform X1 [KO:K01084] [EC:3.1.3.9]
102175206  CRKL; crk-like protein [KO:K04438]
102175235  PHKB; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
102175285  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
102175311  [KO:K02183]
102176299  PPP1R3B; protein phosphatase 1 regulatory subunit 3B isoform X1 [KO:K07189]
102176334  RAPGEF1; rap guanine nucleotide exchange factor 1 isoform X1 [KO:K06277]
102176363  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
102177054  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
102177406  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
102177551  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
102178200  ACACB; LOW QUALITY PROTEIN: acetyl-CoA carboxylase 2 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
102178739  TSC1; hamartin [KO:K07206]
102178924  INPPL1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 [KO:K15909] [EC:3.1.3.86]
102178945  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
102178979  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
102179047  PRKCI; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
102179343  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
102179643  IRS4; insulin receptor substrate 4 [KO:K17446]
102179737  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 [KO:K07200]
102179773  SHC4; SHC-transforming protein 4 isoform X1 [KO:K17449]
102179952  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
102179979  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
102180355  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
102180441  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
102180719  PTPRF; receptor-type tyrosine-protein phosphatase F isoform X1 [KO:K05695] [EC:3.1.3.48]
102180727  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
102180932  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 [KO:K04372] [EC:2.7.11.1]
102181064  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
102181338  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
102181571  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
102181705  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
102181924  INPP5A; type I inositol 1,4,5-trisphosphate 5-phosphatase isoform X1 [KO:K01106] [EC:3.1.3.56]
102182403  HK3; hexokinase-3 isoform X1 [KO:K00844] [EC:2.7.1.1]
102182675  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
102182774  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
102183003  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
102183305  PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
102183659  PPP1R3A; protein phosphatase 1 regulatory subunit 3A isoform X1 [KO:K07189]
102183771  PYGM; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
102184058  RPS6; 40S ribosomal protein S6 [KO:K02991]
102184154  SOS2; son of sevenless homolog 2 [KO:K03099]
102184413  EIF4E; eukaryotic translation initiation factor 4E [KO:K03259]
102184858  IRS1; insulin receptor substrate 1 [KO:K16172]
102184915  FOXO1; forkhead box protein O1 [KO:K07201]
102184966  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
102185007  CALM1; calmodulin [KO:K02183]
102185042  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
102185139  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform [KO:K00871] [EC:2.7.11.19]
102185385  CBL; E3 ubiquitin-protein ligase CBL isoform X1 [KO:K04707] [EC:2.3.2.27]
102185424  SH2B2; SH2B adapter protein 2 [KO:K07193]
102185429  GCK; glucokinase [KO:K12407] [EC:2.7.1.2]
102185660  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
102185666  PYGB; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
102185744  FBP2; fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
102185842  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
102186015  FBP1; fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
102186040  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
102186420  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
102186668  HRAS; GTPase HRas isoform X1 [KO:K02833]
102186998  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
102187180  NRAS; GTPase NRas [KO:K07828]
102187248  CALML6; LOW QUALITY PROTEIN: calmodulin-like protein 6 [KO:K02183]
102187289  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X2 [KO:K06086]
102187349  EXOC7; exocyst complex component 7 isoform X1 [KO:K07195]
102187475  TRIP10; cdc42-interacting protein 4 isoform X1 [KO:K07196]
102187521  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
102187548  PKLR; pyruvate kinase PKLR isoform X2 [KO:K12406] [EC:2.7.1.40]
102187711  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
102188204  PPP1R3F; protein phosphatase 1 regulatory subunit 3F isoform X1 [KO:K17453]
102188710  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
102188824  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
102188970  GYS1; glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
102189015  GYS2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
102189022  [KO:K17453]
102189677  SHC3; SHC-transforming protein 3 isoform X1 [KO:K17448]
102189736  HKDC1; putative hexokinase HKDC1 isoform X1 [KO:K00844] [EC:2.7.1.1]
102189930  BAD; bcl2-associated agonist of cell death [KO:K02158]
102190520  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X4 [KO:K04368] [EC:2.7.12.2]
102190697  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
102190759  HK1; hexokinase-1 [KO:K00844] [EC:2.7.1.1]
102190893  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B isoform X2 [KO:K13296] [EC:3.1.4.17]
102191814  PTPN1; tyrosine-protein phosphatase non-receptor type 1 isoform X1 [KO:K05696] [EC:3.1.3.48]
102191828  FLOT2; flotillin-2 isoform X1 [KO:K07192]
106502751  [KO:K02183]
106503587  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
108633219  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit [KO:K04739]
108634241  INS; insulin [KO:K04526]
108635517  [KO:K07197]
108637008  PPP1R3E; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
108637286  IRS2; insulin receptor substrate 2 [KO:K07187]
108638619  RAF1; RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:2.7.11.1]
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
chx00010  Glycolysis / Gluconeogenesis
chx00061  Fatty acid biosynthesis
chx00500  Starch and sucrose metabolism
chx04010  MAPK signaling pathway
chx04070  Phosphatidylinositol signaling system
chx04210  Apoptosis
KO pathway
ko04910   

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