KEGG   PATHWAY: mlk04910
Entry
mlk04910                    Pathway                                
Name
Insulin signaling pathway - Mustela lutreola (European mink)
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
mlk04910  Insulin signaling pathway
mlk04910

Organism
Mustela lutreola (European mink) [GN:mlk]
Gene
131817733  INS; insulin isoform X1 [KO:K04526]
131823456  INSR; insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
131827381  IRS1; insulin receptor substrate 1 [KO:K16172]
131813562  IRS2; insulin receptor substrate 2 isoform X1 [KO:K07187]
131820117  insulin receptor substrate 2-like isoform X1 [KO:K17445]
131821025  IRS4; insulin receptor substrate 4 [KO:K17446]
131823754  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
131832309  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
131810162  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
131809015  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
131824589  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
131824847  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
131819765  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
131837056  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
131815063  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
131817507  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
131825080  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
131838903  GYS2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
131817768  GYS1; glycogen [starch] synthase, muscle isoform X1 [KO:K00693] [EC:2.4.1.11]
131840593  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
131811171  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
131816316  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
131836362  PPP1R3E; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
131820492  PPP1R3B; protein phosphatase 1 regulatory subunit 3B isoform X1 [KO:K07189]
131828660  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
131807385  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
131829646  PPP1R3A; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
131821228  PPP1R3F; protein phosphatase 1 regulatory subunit 3F isoform X1 [KO:K17453]
131819361  PHKG2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform isoform X1 [KO:K00871] [EC:2.7.11.19]
131819626  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform [KO:K00871] [EC:2.7.11.19]
131821114  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
131818013  PHKB; phosphorylase b kinase regulatory subunit beta [KO:K07190]
131835976  CALML4; calmodulin-like protein 4 isoform X1 [KO:K02183]
131836771  CALM1; calmodulin-1 isoform X1 [KO:K02183]
131838058  calmodulin-like protein 3 [KO:K02183]
131839863  calmodulin-like [KO:K02183]
131808503  CALM2; calmodulin-2 [KO:K02183]
131817928  CALM3; calmodulin-3 [KO:K02183]
131810396  CALML6; calmodulin-like protein 6 [KO:K02183]
131836550  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
131814872  PYGM; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
131808290  PYGB; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
131809644  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B [KO:K13296] [EC:3.1.4.17]
131823635  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
131808844  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
131819098  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit isoform X1 [KO:K04739]
131829248  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit isoform X1 [KO:K04739]
131815899  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
131823902  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
131817615  LIPE; LOW QUALITY PROTEIN: hormone-sensitive lipase [KO:K07188] [EC:3.1.1.79]
131808860  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
131824877  PRKCI; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
131816528  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
131834413  FLOT1; flotillin-1 isoform X1 [KO:K07192]
131815937  FLOT2; flotillin-2 isoform X1 [KO:K07192]
131819799  SH2B2; SH2B adapter protein 2 isoform X1 [KO:K07193]
131828617  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X1 [KO:K06086]
131837043  CBL; E3 ubiquitin-protein ligase CBL isoform X1 [KO:K04707] [EC:2.3.2.27]
131825173  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
131811098  CRKL; crk-like protein [KO:K04438]
131816057  CRK; adapter molecule crk isoform X1 [KO:K04438]
131812612  RAPGEF1; rap guanine nucleotide exchange factor 1 isoform X1 [KO:K06277]
131808511  RHOQ; rho-related GTP-binding protein RhoQ [KO:K07194]
131816973  EXOC7; exocyst complex component 7 isoform X1 [KO:K07195]
131823394  TRIP10; cdc42-interacting protein 4 isoform X1 [KO:K07196]
131816222  SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
131816759  ACACA; acetyl-CoA carboxylase 1 isoform X1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
131811784  ACACB; acetyl-CoA carboxylase 2 isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
131815810  FASN; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
131814944  PKLR; pyruvate kinase PKLR isoform X1 [KO:K12406] [EC:2.7.1.40]
131840346  HK2; hexokinase-2 [KO:K00844] [EC:2.7.1.1]
131828882  HK1; hexokinase-1 isoform X1 [KO:K00844] [EC:2.7.1.1]
131828884  HKDC1; hexokinase HKDC1 [KO:K00844] [EC:2.7.1.1]
131831957  HK3; hexokinase-3 isoform X1 [KO:K00844] [EC:2.7.1.1]
131808931  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X1 [KO:K07198] [EC:2.7.11.31]
131831692  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
131809476  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199]
131810835  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
131838812  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
131827445  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
131829962  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
131813512  FOXO1; forkhead box protein O1 [KO:K07201]
131825299  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
131828124  G6PC2; glucose-6-phosphatase 2 isoform X1 [KO:K01084] [EC:3.1.3.9]
131815697  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
131816468  G6PC1; glucose-6-phosphatase catalytic subunit 1 isoform X1 [KO:K01084] [EC:3.1.3.9]
131812501  FBP1; fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
131812848  FBP2; fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
131836383  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
131807952  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
131810411  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
131816256  RPTOR; regulatory-associated protein of mTOR isoform X1 [KO:K07204]
131816533  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
131816894  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
131813038  RPS6; small ribosomal subunit protein eS6 [KO:K02991]
131823400  small ribosomal subunit protein eS6-like [KO:K02991]
131816196  small ribosomal subunit protein eS6-like [KO:K02991]
131824390  small ribosomal subunit protein eS6-like [KO:K02991]
131825176  small ribosomal subunit protein eS6-like [KO:K02991]
131825224  small ribosomal subunit protein eS6-like [KO:K02991]
131820306  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
131827330  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
131822113  eukaryotic translation initiation factor 4E type 2-like [KO:K03259]
131830096  EIF4E; eukaryotic translation initiation factor 4E isoform X1 [KO:K03259]
131831136  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
131833528  LOW QUALITY PROTEIN: eukaryotic translation initiation factor 4E-like [KO:K03259]
131812183  TSC1; hamartin isoform X1 [KO:K07206]
131819373  TSC2; tuberin isoform X1 [KO:K07207]
131829961  RHEB; GTP-binding protein Rheb [KO:K07208]
131814653  BAD; bcl2-associated agonist of cell death [KO:K02158]
131814353  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
131823143  SHC2; SHC-transforming protein 2 [KO:K17447]
131812476  SHC3; SHC-transforming protein 3 [KO:K17448]
131836254  SHC4; SHC-transforming protein 4 [KO:K17449]
131816784  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
131836536  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
131840500  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
131818337  HRAS; GTPase HRas isoform X1 [KO:K02833]
131838926  KRAS; GTPase KRas isoform X1 [KO:K07827]
131810307  NRAS; GTPase NRas isoform X1 [KO:K07828]
131810524  LOW QUALITY PROTEIN: GTPase NRas-like [KO:K07828]
131821130  ARAF; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:2.7.11.1]
131829849  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
131824239  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
131835957  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
131823312  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
131811758  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
131820131  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
131823229  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 isoform X1 [KO:K04372] [EC:2.7.11.1]
131808925  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X1 [KO:K04372] [EC:2.7.11.1]
131820861  ELK1; ETS domain-containing protein Elk-1 [KO:K04375]
131819736  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
131839266  SOCS2; suppressor of cytokine signaling 2 isoform X1 [KO:K04695]
131816441  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
131836594  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
131807454  PTPN1; tyrosine-protein phosphatase non-receptor type 1 isoform X1 [KO:K05696] [EC:3.1.3.48]
131810256  PTPRF; receptor-type tyrosine-protein phosphatase F isoform X1 [KO:K05695] [EC:3.1.3.48]
131828723  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
131831160  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
131832665  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
131820342  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
131807867  INPPL1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 isoform X1 [KO:K15909] [EC:3.1.3.86]
131830513  INPP5A; inositol polyphosphate-5-phosphatase A 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
mlk00010  Glycolysis / Gluconeogenesis
mlk00061  Fatty acid biosynthesis
mlk00500  Starch and sucrose metabolism
mlk04010  MAPK signaling pathway
mlk04070  Phosphatidylinositol signaling system
mlk04210  Apoptosis
KO pathway
ko04910   
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