KEGG   PATHWAY: nasi04910
Entry
nasi04910                   Pathway                                
Name
Insulin signaling pathway - Neophocaena asiaeorientalis asiaeorientalis (Yangtze finless porpoise)
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
nasi04910  Insulin signaling pathway
nasi04910

Organism
Neophocaena asiaeorientalis asiaeorientalis (Yangtze finless porpoise) [GN:nasi]
Gene
112402369  INS; insulin [KO:K04526]
112400209  INSR; insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
112396733  IRS1; insulin receptor substrate 1 [KO:K16172]
112405567  IRS2; insulin receptor substrate 2 [KO:K07187]
112399963  LOW QUALITY PROTEIN: insulin receptor substrate 1-like [KO:K17445]
112401927  IRS4; LOW QUALITY PROTEIN: insulin receptor substrate 4 [KO:K17446]
112404930  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
112400438  phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
112414874  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
112402798  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
112403325  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
112406349  PIK3CA; LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
112409350  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
112405757  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
112408453  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
112415459  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
112415982  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
112415516  GYS1; glycogen [starch] synthase, muscle isoform X1 [KO:K00693] [EC:2.4.1.11]
112391784  GYS2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
112402102  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
112408799  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit isoform X1 [KO:K06269] [EC:3.1.3.16]
112390556  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
112396041  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
112402954  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
112405014  PPP1R3E; LOW QUALITY PROTEIN: protein phosphatase 1 regulatory subunit 3E [KO:K07189]
112413216  PPP1R3B; protein phosphatase 1 regulatory subunit 3B isoform X1 [KO:K07189]
112408251  PPP1R3A; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
112399843  PPP1R3F; protein phosphatase 1 regulatory subunit 3F isoform X1 [KO:K17453]
112399190  PHKG2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform [KO:K00871] [EC:2.7.11.19]
112399241  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform [KO:K00871] [EC:2.7.11.19]
112395916  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
112396983  PHKB; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
112391609  PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform [KO:K07190]
112409928  CALML6; calmodulin-like protein 6 isoform X1 [KO:K02183]
112410874  CALML4; calmodulin-like protein 4 isoform X1 [KO:K02183]
112405194  CALM2; calmodulin-2 [KO:K02183]
112393864  CALM1; calmodulin-1 [KO:K02183]
112407558  calmodulin-like [KO:K02183]
112407559  calmodulin-like protein 3 [KO:K02183]
112400993  calmodulin-like [KO:K02183]
112415452  CALM3; calmodulin-3 [KO:K02183]
112402391  PYGM; glycogen phosphorylase, muscle form isoform X1 [KO:K00688] [EC:2.4.1.1]
112404645  PYGB; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
112392859  PYGL; glycogen phosphorylase, liver form isoform X1 [KO:K00688] [EC:2.4.1.1]
112407641  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B isoform X1 [KO:K13296] [EC:3.1.4.17]
112414741  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
112415075  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
112410250  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
112410475  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit isoform X1 [KO:K04739]
112403808  cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
112412057  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit [KO:K04739]
112415393  LIPE; hormone-sensitive lipase isoform X1 [KO:K07188] [EC:3.1.1.79]
112409910  PRKCZ; LOW QUALITY PROTEIN: protein kinase C zeta type [KO:K18952] [EC:2.7.11.13]
112392344  PRKCI; protein kinase C iota type isoform X1 [KO:K06069] [EC:2.7.11.13]
112390428  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 isoform X1 [KO:K07191]
112393455  FLOT2; flotillin-2 isoform X1 [KO:K07192]
112395440  FLOT1; flotillin-1 isoform X1 [KO:K07192]
112403287  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X1 [KO:K06086]
112403958  CBL; E3 ubiquitin-protein ligase CBL [KO:K04707] [EC:2.3.2.27]
112393232  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
112412224  CRKL; crk-like protein [KO:K04438]
112392998  CRK; adapter molecule crk isoform X1 [KO:K04438]
112411538  RAPGEF1; rap guanine nucleotide exchange factor 1 [KO:K06277]
112405275  RHOQ; rho-related GTP-binding protein RhoQ isoform X1 [KO:K07194]
112410265  EXOC7; exocyst complex component 7 isoform X1 [KO:K07195]
112400253  TRIP10; cdc42-interacting protein 4 isoform X1 [KO:K07196]
112404728  SREBF1; sterol regulatory element-binding protein 1 [KO:K07197]
112408086  ACACA; acetyl-CoA carboxylase 1 isoform X1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
112397285  ACACB; acetyl-CoA carboxylase 2 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
112410253  FASN; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
112401742  PKLR; pyruvate kinase PKLR isoform X1 [KO:K12406] [EC:2.7.1.40]
112403280  HK2; hexokinase-2 [KO:K00844] [EC:2.7.1.1]
112397869  HK3; hexokinase-3 isoform X1 [KO:K00844] [EC:2.7.1.1]
112413526  HK1; hexokinase-1 isoform X1 [KO:K00844] [EC:2.7.1.1]
112413527  HKDC1; putative hexokinase HKDC1 isoform X1 [KO:K00844] [EC:2.7.1.1]
112401344  GCK; glucokinase isoform X1 [KO:K12407] [EC:2.7.1.2]
112405979  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
112407082  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
112412979  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
112408820  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
112411852  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
112405875  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
112394236  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
112406687  FOXO1; forkhead box protein O1 [KO:K07201]
112400037  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
112410110  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
112400500  G6PC; glucose-6-phosphatase isoform X1 [KO:K01084] [EC:3.1.3.9]
112407380  G6PC2; glucose-6-phosphatase 2 [KO:K01084] [EC:3.1.3.9]
112405403  FBP1; fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
112405442  FBP2; fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
112403085  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
112405031  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial isoform X1 [KO:K01596] [EC:4.1.1.32]
112402675  MTOR; serine/threonine-protein kinase mTOR isoform X1 [KO:K07203] [EC:2.7.11.1]
112410361  RPTOR; regulatory-associated protein of mTOR isoform X1 [KO:K07204]
112402503  RPS6KB2; ribosomal protein S6 kinase beta-2 [KO:K04688] [EC:2.7.11.1]
112408022  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
112401091  RPS6; 40S ribosomal protein S6 [KO:K02991]
112413144  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
112396716  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
112397866  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
112406614  LOW QUALITY PROTEIN: eukaryotic translation initiation factor 4E-like [KO:K03259]
112393719  EIF4E; eukaryotic translation initiation factor 4E [KO:K03259]
112411342  TSC1; hamartin isoform X1 [KO:K07206]
112409519  TSC2; tuberin isoform X1 [KO:K07207]
112405904  RHEB; GTP-binding protein Rheb [KO:K07208]
112402326  BAD; bcl2-associated agonist of cell death [KO:K02158]
112401764  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
112396342  SHC2; SHC-transforming protein 2 [KO:K17447]
112390850  SHC3; SHC-transforming protein 3 [KO:K17448]
112402165  SHC4; SHC-transforming protein 4 isoform X1 [KO:K17449]
112410317  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
112405189  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
112391586  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
112402519  HRAS; GTPase HRas isoform X1 [KO:K02833]
112391643  KRAS; GTPase KRas isoform X1 [KO:K07827]
112413065  NRAS; GTPase NRas [KO:K07828]
112402589  ARAF; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:2.7.11.1]
112398096  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
112407243  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
112393112  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
112400165  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
112412232  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
112399342  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
112396347  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 [KO:K04372] [EC:2.7.11.1]
112400432  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X1 [KO:K04372] [EC:2.7.11.1]
112402600  ELK1; ETS domain-containing protein Elk-1 isoform X1 [KO:K04375]
112399467  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
112405798  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
112410494  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
112392871  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
112403107  PTPN1; tyrosine-protein phosphatase non-receptor type 1 [KO:K05696] [EC:3.1.3.48]
112399525  PTPRF; receptor-type tyrosine-protein phosphatase F [KO:K05695] [EC:3.1.3.48]
112395723  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
112412478  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
112413113  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
112413114  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
112390763  INPPL1; LOW QUALITY PROTEIN: phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 [KO:K15909] [EC:3.1.3.86]
112411270  INPP5A; type I inositol 1,4,5-trisphosphate 5-phosphatase isoform X1 [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
nasi00010  Glycolysis / Gluconeogenesis
nasi00061  Fatty acid biosynthesis
nasi00500  Starch and sucrose metabolism
nasi04010  MAPK signaling pathway
nasi04070  Phosphatidylinositol signaling system
nasi04210  Apoptosis
KO pathway
ko04910   
LinkDB

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