KEGG   PATHWAY: ko04910
Entry
ko04910                     Pathway                                

Name
Insulin signaling pathway
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
ko04910  Insulin signaling pathway
ko04910

Disease
H00069  Glycogen storage disease
H00410  Maturity onset diabetes of the young (MODY)
H00420  Familial partial lipodystrophy
H00512  Permanent neonatal diabetes mellitus
H00719  Leprechaunism
H00896  Lymphangioleiomyomatosis
H00915  Tuberous sclerosis complex
H00942  Rabson-Mendenhall syndrome
H01102  Pituitary adenomas
H01154  Wolff-Parkinson-White (WPW) syndrome
H01228  Insulin-resistant diabetes mellitus with acanthosis nigricans
H01251  Focal cortical dysplasia of Taylor
H01267  Familial hyperinsulinemic hypoglycemia
H01760  Hepatic glycogen storage disease
H01762  Muscle glycogen storage disease
H01943  Glycogen storage disease type V
H01944  Glycogen storage disease type VI
H01948  Glycogen storage disease type IX
H01949  Glycogen storage disease type 0b
H01950  Glycogen storage disease type 0a
H01956  Glycogen storage disease of heart
Orthology
K04526  insulin
K04527  insulin receptor [EC:2.7.10.1]
K16172  insulin receptor substrate 1
K07187  insulin receptor substrate 2
K17445  insulin receptor substrate 3
K17446  insulin receptor substrate 4
K02649  phosphoinositide-3-kinase regulatory subunit alpha/beta/delta
K00922  phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153]
K06276  3-phosphoinositide dependent protein kinase-1 [EC:2.7.11.1]
K04456  RAC serine/threonine-protein kinase [EC:2.7.11.1]
K03083  glycogen synthase kinase 3 beta [EC:2.7.11.26]
K00693  glycogen synthase [EC:2.4.1.11]
K06269  serine/threonine-protein phosphatase PP1 catalytic subunit [EC:3.1.3.16]
K07189  protein phosphatase 1 regulatory subunit 3A/B/C/D/E
K17453  protein phosphatase 1 regulatory subunit 3F
K00871  phosphorylase kinase gamma subunit [EC:2.7.11.19]
K07190  phosphorylase kinase alpha/beta subunit
K02183  calmodulin
K00688  glycogen phosphorylase [EC:2.4.1.1]
K13296  cGMP-inhibited 3',5'-cyclic phosphodiesterase B [EC:3.1.4.17]
K04345  protein kinase A [EC:2.7.11.11]
K04739  cAMP-dependent protein kinase regulator
K07188  hormone-sensitive lipase [EC:3.1.1.79]
K18952  atypical protein kinase C zeta type [EC:2.7.11.13]
K06069  atypical protein kinase C iota type [EC:2.7.11.13]
K07191  MFS transporter, SP family, solute carrier family 2 (facilitated glucose transporter), member 4
K07192  flotillin
K07193  SH2B adapter protein 2
K06086  sorbin and SH3 domain containing 1
K04707  E3 ubiquitin-protein ligase CBL [EC:2.3.2.27]
K22517  E3 ubiquitin-protein ligase CBL-B [EC:2.3.2.27]
K04438  proto-oncogene C-crk
K06277  Rap guanine nucleotide exchange factor 1
K07194  Ras homolog gene family, member Q
K07195  exocyst complex component 7
K07196  thyroid hormone receptor interactor 10
K07197  sterol regulatory element-binding transcription factor 1
K11262  acetyl-CoA carboxylase / biotin carboxylase 1 [EC:6.4.1.2 6.3.4.14 2.1.3.15]
K01946  acetyl-CoA carboxylase / biotin carboxylase 2 [EC:6.4.1.2 6.3.4.14 2.1.3.15]
K00665  fatty acid synthase, animal type [EC:2.3.1.85]
K12406  pyruvate kinase isozymes R/L [EC:2.7.1.40]
K00844  hexokinase [EC:2.7.1.1]
K12407  glucokinase [EC:2.7.1.2]
K07198  5'-AMP-activated protein kinase, catalytic alpha subunit [EC:2.7.11.11]
K07199  5'-AMP-activated protein kinase, regulatory beta subunit
K07200  5'-AMP-activated protein kinase, regulatory gamma subunit
K07201  forkhead box protein O1
K07202  alpha peroxisome proliferator-activated receptor gamma coactivator 1-alpha
K01084  glucose-6-phosphatase [EC:3.1.3.9]
K03841  fructose-1,6-bisphosphatase I [EC:3.1.3.11]
K01596  phosphoenolpyruvate carboxykinase (GTP) [EC:4.1.1.32]
K07203  serine/threonine-protein kinase mTOR [EC:2.7.11.1]
K07204  regulatory associated protein of mTOR
K04688  ribosomal protein S6 kinase beta [EC:2.7.11.1]
K02991  small subunit ribosomal protein S6e
K07205  eukaryotic translation initiation factor 4E binding protein 1
K03259  translation initiation factor 4E
K07206  tuberous sclerosis 1
K07207  tuberous sclerosis 2
K07208  Ras homolog enriched in brain
K02158  Bcl-2-antagonist of cell death
K06279  SHC-transforming protein 1
K17447  SHC-transforming protein 2
K17448  SHC-transforming protein 3
K17449  SHC-transforming protein 4
K04364  growth factor receptor-binding protein 2
K03099  son of sevenless
K02833  GTPase HRas
K07827  GTPase KRas
K07828  GTPase NRas
K08845  A-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K04365  B-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K04366  RAF proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K04368  mitogen-activated protein kinase kinase 1 [EC:2.7.12.2]
K04369  mitogen-activated protein kinase kinase 2 [EC:2.7.12.2]
K04371  mitogen-activated protein kinase 1/3 [EC:2.7.11.24]
K04372  MAP kinase interacting serine/threonine kinase [EC:2.7.11.1]
K04375  ETS domain-containing protein Elk-1
K04694  suppressor of cytokine signaling 1
K04695  suppressor of cytokine signaling 2
K04696  suppressor of cytokine signaling 3
K04697  suppressor of cytokine signaling 4
K05696  tyrosine-protein phosphatase non-receptor type 1 [EC:3.1.3.48]
K05695  receptor-type tyrosine-protein phosphatase F [EC:3.1.3.48]
K04440  mitogen-activated protein kinase 8/9/10 (c-Jun N-terminal kinase) [EC:2.7.11.24]
K07209  inhibitor of nuclear factor kappa-B kinase subunit beta [EC:2.7.11.10]
K15909  phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 2 [EC:3.1.3.86]
K01106  inositol polyphosphate 5-phosphatase INPP5A [EC:3.1.3.56]
Compound
C00031  D-Glucose
C00369  Starch
C00575  3',5'-Cyclic AMP
C05981  Phosphatidylinositol-3,4,5-trisphosphate
Reference
  Authors
Ogawa W, Kasuga M.
  Title
[Mechanism of insulin action and diabetes mellitus]
  Journal
Seikagaku 75:1332-44 (2003)
Reference
  Authors
Bevan P.
  Title
Insulin signalling.
  Journal
J Cell Sci 114:1429-30 (2001)
Reference
  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
  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
  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
  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
  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
  Authors
Ruggero D, Sonenberg N.
  Title
The Akt of translational control.
  Journal
Oncogene 24:7426-34 (2005)
DOI:10.1038/sj.onc.1209098
Reference
  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
  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
  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
  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
  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
  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
ko00010  Glycolysis / Gluconeogenesis
ko00061  Fatty acid biosynthesis
ko00500  Starch and sucrose metabolism
ko04010  MAPK signaling pathway
ko04070  Phosphatidylinositol signaling system
ko04210  Apoptosis

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