KEGG   PATHWAY: nni04910
Entry
nni04910                    Pathway                                
Name
Insulin signaling pathway - Nipponia nippon (crested ibis)
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
nni04910  Insulin signaling pathway
nni04910

Organism
Nipponia nippon (crested ibis) [GN:nni]
Gene
104010412  insulin [KO:K04526]
104018719  INSR; insulin receptor [KO:K04527] [EC:2.7.10.1]
104016496  IRS1; insulin receptor substrate 1 [KO:K16172]
104023330  IRS4; insulin receptor substrate 4 [KO:K07187]
104012562  IRS2; insulin receptor substrate 2 [KO:K07187]
104015409  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
104018715  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta isoform X1 [KO:K02649]
104008980  PIK3CD; LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
104023668  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
104019595  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
104015160  PDPK1; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
104020263  AKT2; LOW QUALITY PROTEIN: RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
104014534  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
104011272  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
104008666  GSK3B; glycogen synthase kinase-3 beta [KO:K03083] [EC:2.7.11.26]
104012701  GYS2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
104011867  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
104021492  PPP1CB; LOW QUALITY PROTEIN: serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
104020653  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
104009570  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
104021213  PPP1R3B; protein phosphatase 1 regulatory subunit 3B [KO:K07189]
104013591  PPP1R3A; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
104013045  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
104016023  protein phosphatase 1 regulatory subunit 3C-B-like [KO:K07189]
104016101  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform isoform X1 [KO:K00871] [EC:2.7.11.19]
104011276  PHKB; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
104012629  PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform [KO:K07190]
104022518  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform [KO:K07190]
104010482  CALML3; calmodulin-like protein 3 [KO:K02183]
104017200  CALML4; calmodulin-like protein 4 [KO:K02183]
104011816  calmodulin-like [KO:K02183]
104021521  CALM2; calmodulin [KO:K02183]
104022221  CALM1; LOW QUALITY PROTEIN: calmodulin [KO:K02183]
104015802  PYGB; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
104019449  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
104010948  PDE3B; LOW QUALITY PROTEIN: cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
104015461  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
104010804  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit [KO:K04739]
104014291  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
104016987  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
104015070  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit [KO:K04739]
104008940  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
104022050  PRKCI; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
104014482  flotillin-1-like [KO:K07192]
104012753  FLOT2; flotillin-2 isoform X1 [KO:K07192]
104016105  SH2B2; SH2B adapter protein 2 [KO:K07193]
104020417  SORBS1; sorbin and SH3 domain-containing protein 1 [KO:K06086]
104019053  LOW QUALITY PROTEIN: E3 ubiquitin-protein ligase CBL-like [KO:K04707] [EC:2.3.2.27]
104008757  E3 ubiquitin-protein ligase CBL [KO:K04707] [EC:2.3.2.27]
104014116  CBLB; E3 ubiquitin-protein ligase CBL-B [KO:K22517] [EC:2.3.2.27]
104011434  CRKL; crk-like protein [KO:K04438]
104016008  CRK; adapter molecule crk [KO:K04438]
104023176  RAPGEF1; rap guanine nucleotide exchange factor 1 [KO:K06277]
104019732  RHOQ; rho-related GTP-binding protein RhoQ [KO:K07194]
104022874  EXOC7; LOW QUALITY PROTEIN: exocyst complex component 7 [KO:K07195]
104015237  SREBF1; sterol regulatory element-binding protein 1 [KO:K07197]
104016389  ACACA; acetyl-CoA carboxylase 1 isoform X1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
104019168  ACACB; acetyl-CoA carboxylase 2 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
104014322  FASN; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
104013489  HKDC1; putative hexokinase HKDC1 [KO:K00844] [EC:2.7.1.1]
104013490  HK1; hexokinase-1 [KO:K00844] [EC:2.7.1.1]
104018992  HK3; hexokinase-3 [KO:K00844] [EC:2.7.1.1]
104017587  HK2; hexokinase-2 [KO:K00844] [EC:2.7.1.1]
104022603  GCK; glucokinase [KO:K12407] [EC:2.7.1.2]
104019864  5'-AMP-activated protein kinase catalytic subunit alpha-1-like [KO:K07198] [EC:2.7.11.31]
104016188  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 [KO:K07198] [EC:2.7.11.31]
104013818  5'-AMP-activated protein kinase catalytic subunit alpha-1-like [KO:K07198] [EC:2.7.11.31]
104009342  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
104011465  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 isoform X1 [KO:K07199]
104010405  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199]
104010068  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
104014891  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
104017939  5'-AMP-activated protein kinase subunit gamma-1 [KO:K07200]
104010936  FOXO1; forkhead box protein O1 [KO:K07201]
104021058  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha [KO:K07202]
104009880  G6PC; glucose-6-phosphatase [KO:K01084] [EC:3.1.3.9]
104009980  G6PC2; glucose-6-phosphatase 2 [KO:K01084] [EC:3.1.3.9]
104012311  G6PC3; glucose-6-phosphatase 3 [KO:K01084] [EC:3.1.3.9]
104011764  fructose-1,6-bisphosphatase 1-like [KO:K03841] [EC:3.1.3.11]
104011756  fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
104013047  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] isoform X1 [KO:K01596] [EC:4.1.1.32]
104008993  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
104014273  RPTOR; LOW QUALITY PROTEIN: regulatory-associated protein of mTOR [KO:K07204]
104016535  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
104017932  RPS6; 40S ribosomal protein S6 [KO:K02991]
104016060  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
104021192  EIF4E; eukaryotic translation initiation factor 4E [KO:K03259]
104018990  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
104015640  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
104023182  TSC1; hamartin isoform X1 [KO:K07206]
104015144  TSC2; LOW QUALITY PROTEIN: tuberin [KO:K07207]
104014902  RHEB; GTP-binding protein Rheb [KO:K07208]
104012052  SHC1; SHC-transforming protein 1 [KO:K06279]
104016320  SHC2; SHC-transforming protein 2 [KO:K17447]
104009737  SHC3; SHC-transforming protein 3 [KO:K17448]
104017130  SHC4; LOW QUALITY PROTEIN: SHC-transforming protein 4 [KO:K17449]
104020665  GRB2; growth factor receptor-bound protein 2 isoform X1 [KO:K04364]
104022133  SOS1; son of sevenless homolog 1 [KO:K03099]
104019491  SOS2; son of sevenless homolog 2 [KO:K03099]
104017304  HRAS; GTPase HRas [KO:K02833]
104012697  KRAS; GTPase KRas isoform X1 [KO:K07827]
104010364  NRAS; GTPase NRas [KO:K07828]
104012385  BRAF; serine/threonine-protein kinase B-raf [KO:K04365] [EC:2.7.11.1]
104022929  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
104017047  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
104018809  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
104020099  MAPK1; LOW QUALITY PROTEIN: mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
104009659  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 [KO:K04372] [EC:2.7.11.1]
104015402  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 [KO:K04372] [EC:2.7.11.1]
104023449  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
104011649  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
104018614  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
104019434  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
104013067  PTPN1; tyrosine-protein phosphatase non-receptor type 1 [KO:K05696] [EC:3.1.3.48]
104015434  PTPRF; receptor-type tyrosine-protein phosphatase F [KO:K05695] [EC:3.1.3.48]
104018444  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
104013238  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
104019815  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
104016028  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
104011872  INPPL1; LOW QUALITY PROTEIN: phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 [KO:K15909] [EC:3.1.3.86]
104012926  phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2-like [KO:K15909] [EC:3.1.3.86]
104013867  INPP5A; type I inositol 1,4,5-trisphosphate 5-phosphatase [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
nni00010  Glycolysis / Gluconeogenesis
nni00061  Fatty acid biosynthesis
nni00500  Starch and sucrose metabolism
nni04010  MAPK signaling pathway
nni04070  Phosphatidylinositol signaling system
nni04210  Apoptosis
KO pathway
ko04910   
LinkDB

DBGET integrated database retrieval system