KEGG   PATHWAY: hsa04910Help
Entry
hsa04910                    Pathway                                

Name
Insulin signaling pathway - Homo sapiens (human)
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
BRITE hierarchy
Pathway map
Insulin signaling pathway
hsa04910

All organismsOrtholog table
Module
PI3K-Akt signaling [PATH:hsa04910]
Disease
H00069  
Glycogen storage diseases (GSD)
H00410  
Maturity onset diabetes of the young (MODY)
H00420  
Familial partial lipodystrophy (FPL)
H00512  
Permanent neonatal diabetes mellitus (PNDM)
H00719  
Leprechaunism
H00896  
Lymphangioleiomyomatosis (LAM)
H00915  
Tuberous sclerosis complex (TSC)
H00942  
Rabson-Mendenhall syndrome
H01102  
Pituitary adenomas
H01154  
Wolff-Parkinson-White (WPW) syndrome
H01228  
Insulin-resistant diabetes mellitus with acanthosis nigricans (IRAN)
H01251  
Focal cortical dysplasia of Taylor
H01267  
Familial hyperinsulinemic hypoglycemia (HHF)
Drug
D00085  
Insulin (JAN/USP)
D00231  
Amrinone (JAN/INN)
D00417  
Milrinone (JAN/USP/INN)
D00595  
Buformin (USAN/INN)
D00944  
Metformin hydrochloride (JP16/USP)
D01133  
Pimobendan (JAN/USAN/INN)
D01198  
Toborinone (JAN/USAN/INN)
D01690  
Vesnarinone (JAN/USAN/INN)
D01896  
Cilostazol (JP16/USAN/INN)
D02084  
Inamrinone ethylenelactate
D02085  
Milrinone lactate
D02206  
Buformin hydrochloride (JP16)
D03230  
Insulin human (genetical recombination) (JP16)
D03250  
Insulin glargine (genetical recombination) (JP16)
D03647  
Dapiclermin (USAN/INN)
D04004  
Enoximone (USAN/INN)
D04050  
Ertiprotafib (USAN/INN)
D04475  
Insulin aspart (genetical recombination) (JAN)
D04477  
Insulin lispro (genetical recombination) (JAN)
D04508  
Imazodan hydrochloride (USAN)
D04529  
Indolidan (USAN/INN)
D04537  
Ingliforib (USAN/INN)
D04539  
Insulin detemir (genetical recombination) (JAN)
D04540  
Insulin glulisine (genetical recombination) (JAN)
D04541  
Insulin human, isophane (USP)
D04542  
Insulin human zinc (USP)
D04543  
Insulin human zinc, extended (USP)
D04544  
Insulin I 125 (USAN)
D04545  
Insulin I 131 (USAN)
D04546  
Insulin, dalanated (USAN)
D04547  
Isophane insulin injection (aqueous suspension) (JAN)
D04548  
Insulin, neutral (USAN)
D04549  
Insulin zinc, extended (USP)
D04550  
Insulin zinc, prompt (USP)
D04551  
Insulin zinc (USP)
D04628  
Isomazole hydrochloride (USAN)
D04720  
Levosimendan (USAN/INN)
D04751  
Lixazinone sulfate (USAN)
D04966  
Metformin (USAN/INN)
D05622  
Proinsulin human (USAN)
D08080  
Insulin injection, biphasic isophane (BAN)
D08351  
Phenformin (BAN)
D08352  
Phenformin hydrochloride
D09727  
Insulin degludec (genetical recombination) (JAN)
Organism
Homo sapiens (human) [GN:hsa]
Gene
3630  
INS; insulin [KO:K04526]
3643  
INSR; insulin receptor [KO:K04527] [EC:2.7.10.1]
3667  
IRS1; insulin receptor substrate 1 [KO:K16172]
8660  
IRS2; insulin receptor substrate 2 [KO:K07187]
8471  
IRS4; insulin receptor substrate 4 [KO:K17446]
5295  
PIK3R1; phosphoinositide-3-kinase, regulatory subunit 1 (alpha) [KO:K02649]
23533  
PIK3R5; phosphoinositide-3-kinase, regulatory subunit 5 [KO:K02649]
5296  
PIK3R2; phosphoinositide-3-kinase, regulatory subunit 2 (beta) [KO:K02649]
8503  
PIK3R3; phosphoinositide-3-kinase, regulatory subunit 3 (gamma) [KO:K02649]
5290  
PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
5293  
PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
5291  
PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
5294  
PIK3CG; phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit gamma [KO:K00922] [EC:2.7.1.153]
5170  
PDPK1; 3-phosphoinositide dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
207  
AKT1; v-akt murine thymoma viral oncogene homolog 1 [KO:K04456] [EC:2.7.11.1]
208  
AKT2; v-akt murine thymoma viral oncogene homolog 2 [KO:K04456] [EC:2.7.11.1]
10000  
AKT3; v-akt murine thymoma viral oncogene homolog 3 [KO:K04456] [EC:2.7.11.1]
2932  
GSK3B; glycogen synthase kinase 3 beta [KO:K03083] [EC:2.7.11.26]
2998  
GYS2; glycogen synthase 2 (liver) [KO:K00693] [EC:2.4.1.11]
2997  
GYS1; glycogen synthase 1 (muscle) [KO:K00693] [EC:2.4.1.11]
5499  
PPP1CA; protein phosphatase 1, catalytic subunit, alpha isozyme [KO:K06269] [EC:3.1.3.16]
5500  
PPP1CB; protein phosphatase 1, catalytic subunit, beta isozyme [KO:K06269] [EC:3.1.3.16]
5501  
PPP1CC; protein phosphatase 1, catalytic subunit, gamma isozyme [KO:K06269] [EC:3.1.3.16]
5506  
PPP1R3A; protein phosphatase 1, regulatory subunit 3A [KO:K07189]
5507  
PPP1R3C; protein phosphatase 1, regulatory subunit 3C [KO:K07189]
5509  
PPP1R3D; protein phosphatase 1, regulatory subunit 3D [KO:K07189]
79660  
PPP1R3B; protein phosphatase 1, regulatory subunit 3B [KO:K07189]
90673  
PPP1R3E; protein phosphatase 1, regulatory subunit 3E [KO:K07189]
89801  
PPP1R3F; protein phosphatase 1, regulatory subunit 3F [KO:K17453]
5260  
PHKG1; phosphorylase kinase, gamma 1 (muscle) [KO:K00871] [EC:2.7.11.19]
5261  
PHKG2; phosphorylase kinase, gamma 2 (testis) [KO:K00871] [EC:2.7.11.19]
5257  
PHKB; phosphorylase kinase, beta [KO:K07190]
5256  
PHKA2; phosphorylase kinase, alpha 2 (liver) [KO:K07190]
5255  
PHKA1; phosphorylase kinase, alpha 1 (muscle) [KO:K07190]
810  
CALML3; calmodulin-like 3 [KO:K02183]
805  
CALM2; calmodulin 2 (phosphorylase kinase, delta) [KO:K02183]
808  
CALM3; calmodulin 3 (phosphorylase kinase, delta) [KO:K02183]
801  
CALM1; calmodulin 1 (phosphorylase kinase, delta) [KO:K02183]
163688  
CALML6; calmodulin-like 6 [KO:K02183]
51806  
CALML5; calmodulin-like 5 [KO:K02183]
5836  
PYGL; phosphorylase, glycogen, liver [KO:K00688] [EC:2.4.1.1]
5837  
PYGM; phosphorylase, glycogen, muscle [KO:K00688] [EC:2.4.1.1]
5834  
PYGB; phosphorylase, glycogen [KO:K00688] [EC:2.4.1.1]
5139  
PDE3A; phosphodiesterase 3A, cGMP-inhibited [KO:K13296] [EC:3.1.4.17]
5140  
PDE3B; phosphodiesterase 3B, cGMP-inhibited [KO:K13296] [EC:3.1.4.17]
5566  
PRKACA; protein kinase, cAMP-dependent, catalytic, alpha [KO:K04345] [EC:2.7.11.11]
5567  
PRKACB; protein kinase, cAMP-dependent, catalytic, beta [KO:K04345] [EC:2.7.11.11]
5568  
PRKACG; protein kinase, cAMP-dependent, catalytic, gamma [KO:K04345] [EC:2.7.11.11]
5613  
PRKX; protein kinase, X-linked [KO:K04345] [EC:2.7.11.11]
5573  
PRKAR1A; protein kinase, cAMP-dependent, regulatory, type I, alpha [KO:K04739]
5576  
PRKAR2A; protein kinase, cAMP-dependent, regulatory, type II, alpha [KO:K04739]
5577  
PRKAR2B; protein kinase, cAMP-dependent, regulatory, type II, beta [KO:K04739]
5575  
PRKAR1B; protein kinase, cAMP-dependent, regulatory, type I, beta [KO:K04739]
3991  
LIPE; lipase, hormone-sensitive [KO:K07188] [EC:3.1.1.79]
5584  
PRKCI; protein kinase C, iota [KO:K06069] [EC:2.7.11.13]
5590  
PRKCZ; protein kinase C, zeta [KO:K06069] [EC:2.7.11.13]
6517  
SLC2A4; solute carrier family 2 (facilitated glucose transporter), member 4 [KO:K07191]
2319  
FLOT2; flotillin 2 [KO:K07192]
10211  
FLOT1; flotillin 1 [KO:K07192]
10603  
SH2B2; SH2B adaptor protein 2 [KO:K07193]
10580  
SORBS1; sorbin and SH3 domain containing 1 [KO:K06086]
23624  
CBLC; Cbl proto-oncogene C, E3 ubiquitin protein ligase [KO:K04707] [EC:6.3.2.19]
867  
CBL; Cbl proto-oncogene, E3 ubiquitin protein ligase [KO:K04707] [EC:6.3.2.19]
868  
CBLB; Cbl proto-oncogene B, E3 ubiquitin protein ligase [KO:K04707] [EC:6.3.2.19]
1398  
CRK; v-crk avian sarcoma virus CT10 oncogene homolog [KO:K04438]
1399  
CRKL; v-crk avian sarcoma virus CT10 oncogene homolog-like [KO:K04438]
2889  
RAPGEF1; Rap guanine nucleotide exchange factor (GEF) 1 [KO:K06277]
23433  
RHOQ; ras homolog family member Q [KO:K07194]
23265  
EXOC7; exocyst complex component 7 [KO:K07195]
9322  
TRIP10; thyroid hormone receptor interactor 10 [KO:K07196]
6720  
SREBF1; sterol regulatory element binding transcription factor 1 [KO:K07197]
31  
ACACA; acetyl-CoA carboxylase alpha [KO:K11262] [EC:6.3.4.14 6.4.1.2]
32  
ACACB; acetyl-CoA carboxylase beta [KO:K11262] [EC:6.3.4.14 6.4.1.2]
2194  
FASN; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
5313  
PKLR; pyruvate kinase, liver and RBC [KO:K12406] [EC:2.7.1.40]
3101  
HK3; hexokinase 3 (white cell) [KO:K00844] [EC:2.7.1.1]
3098  
HK1; hexokinase 1 [KO:K00844] [EC:2.7.1.1]
3099  
HK2; hexokinase 2 [KO:K00844] [EC:2.7.1.1]
80201  
HKDC1; hexokinase domain containing 1 [KO:K00844] [EC:2.7.1.1]
2645  
GCK; glucokinase (hexokinase 4) [KO:K12407] [EC:2.7.1.2]
5562  
PRKAA1; protein kinase, AMP-activated, alpha 1 catalytic subunit [KO:K07198] [EC:2.7.11.11]
5563  
PRKAA2; protein kinase, AMP-activated, alpha 2 catalytic subunit [KO:K07198] [EC:2.7.11.11]
5564  
PRKAB1; protein kinase, AMP-activated, beta 1 non-catalytic subunit [KO:K07199]
5565  
PRKAB2; protein kinase, AMP-activated, beta 2 non-catalytic subunit [KO:K07199]
5571  
PRKAG1; protein kinase, AMP-activated, gamma 1 non-catalytic subunit [KO:K07200]
53632  
PRKAG3; protein kinase, AMP-activated, gamma 3 non-catalytic subunit [KO:K07200]
51422  
PRKAG2; protein kinase, AMP-activated, gamma 2 non-catalytic subunit [KO:K07200]
2308  
FOXO1; forkhead box O1 [KO:K07201]
10891  
PPARGC1A; peroxisome proliferator-activated receptor gamma, coactivator 1 alpha [KO:K07202]
2538  
G6PC; glucose-6-phosphatase, catalytic subunit [KO:K01084] [EC:3.1.3.9]
57818  
G6PC2; glucose-6-phosphatase, catalytic, 2 [KO:K01084] [EC:3.1.3.9]
92579  
G6PC3; glucose 6 phosphatase, catalytic, 3 [KO:K01084] [EC:3.1.3.9]
2203  
FBP1; fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
8789  
FBP2; fructose-1,6-bisphosphatase 2 [KO:K03841] [EC:3.1.3.11]
5105  
PCK1; phosphoenolpyruvate carboxykinase 1 (soluble) [KO:K01596] [EC:4.1.1.32]
5106  
PCK2; phosphoenolpyruvate carboxykinase 2 (mitochondrial) [KO:K01596] [EC:4.1.1.32]
2475  
MTOR; mechanistic target of rapamycin (serine/threonine kinase) [KO:K07203]
57521  
RPTOR; regulatory associated protein of MTOR, complex 1 [KO:K07204]
6198  
RPS6KB1; ribosomal protein S6 kinase, 70kDa, polypeptide 1 [KO:K04688] [EC:2.7.11.1]
6199  
RPS6KB2; ribosomal protein S6 kinase, 70kDa, polypeptide 2 [KO:K04688] [EC:2.7.11.1]
6194  
RPS6; ribosomal protein S6 [KO:K02991]
1978  
EIF4EBP1; eukaryotic translation initiation factor 4E binding protein 1 [KO:K07205]
1977  
EIF4E; eukaryotic translation initiation factor 4E [KO:K03259]
9470  
EIF4E2; eukaryotic translation initiation factor 4E family member 2 [KO:K03259]
253314  
EIF4E1B; eukaryotic translation initiation factor 4E family member 1B [KO:K03259]
7248  
TSC1; tuberous sclerosis 1 [KO:K07206]
7249  
TSC2; tuberous sclerosis 2 [KO:K07207]
6009  
RHEB; Ras homolog enriched in brain [KO:K07208]
572  
BAD; BCL2-associated agonist of cell death [KO:K02158]
6464  
SHC1; SHC (Src homology 2 domain containing) transforming protein 1 [KO:K06279]
25759  
SHC2; SHC (Src homology 2 domain containing) transforming protein 2 [KO:K17447]
53358  
SHC3; SHC (Src homology 2 domain containing) transforming protein 3 [KO:K17448]
399694  
SHC4; SHC (Src homology 2 domain containing) family, member 4 [KO:K17449]
2885  
GRB2; growth factor receptor-bound protein 2 [KO:K04364]
6654  
SOS1; son of sevenless homolog 1 (Drosophila) [KO:K03099]
6655  
SOS2; son of sevenless homolog 2 (Drosophila) [KO:K03099]
3265  
HRAS; Harvey rat sarcoma viral oncogene homolog [KO:K02833]
3845  
KRAS; Kirsten rat sarcoma viral oncogene homolog [KO:K07827]
4893  
NRAS; neuroblastoma RAS viral (v-ras) oncogene homolog [KO:K07828]
369  
ARAF; A-Raf proto-oncogene, serine/threonine kinase [KO:K08845] [EC:2.7.11.1]
673  
BRAF; B-Raf proto-oncogene, serine/threonine kinase [KO:K04365] [EC:2.7.11.1]
5894  
RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1]
5604  
MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
5605  
MAP2K2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
5594  
MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
5595  
MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
8569  
MKNK1; MAP kinase interacting serine/threonine kinase 1 [KO:K04372] [EC:2.7.11.1]
2872  
MKNK2; MAP kinase interacting serine/threonine kinase 2 [KO:K04372] [EC:2.7.11.1]
2002  
ELK1; ELK1, member of ETS oncogene family [KO:K04375]
8651  
SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
8835  
SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
9021  
SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
122809  
SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
5770  
PTPN1; protein tyrosine phosphatase, non-receptor type 1 [KO:K05696] [EC:3.1.3.48]
5792  
PTPRF; protein tyrosine phosphatase, receptor type, F [KO:K05695] [EC:3.1.3.48]
5599  
MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
5602  
MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
5601  
MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
3551  
IKBKB; inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta [KO:K07209] [EC:2.7.11.10]
3636  
INPPL1; inositol polyphosphate phosphatase-like 1 [KO:K15909] [EC:3.1.3.86]
51763  
INPP5K; inositol polyphosphate-5-phosphatase K [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
  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)
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)
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)
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)
Reference
  Authors
Saltiel AR, Kahn CR.
  Title
Insulin signalling and the regulation of glucose and lipid metabolism.
  Journal
Nature 414:799-806 (2001)
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)
Reference
  Authors
Ruggero D, Sonenberg N.
  Title
The Akt of translational control.
  Journal
Oncogene 24:7426-34 (2005)
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)
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)
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)
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)
Reference
  Authors
Ferre P, Foufelle F
  Title
SREBP-1c transcription factor and lipid homeostasis: clinical perspective.
  Journal
Horm Res 68:72-82 (2007)
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)
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)
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)
KO pathway
 

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