KEGG PATHWAY: hsa04910

PATHWAY: hsa04910

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

Pathway map

hsa04910

Insulin signaling pathway

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 lactate
D02085	Milrinone lactate
D02206	Buformin hydrochloride (JP16)
D03230	Insulin human (genetical recombination) (JP16)
D03250	Insulin glargine (genetical recombination) (JAN)
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:K07187]
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 (protein kinase B, gamma) [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]
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, E3 ubiquitin protein ligase C [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, E3 ubiquitin protein ligase B [KO:K04707] [EC:6.3.2.19]
1398	CRK; v-crk sarcoma virus CT10 oncogene homolog (avian) [KO:K04438]
1399	CRKL; v-crk sarcoma virus CT10 oncogene homolog (avian)-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]
101060511	5'-AMP-activated protein kinase subunit beta-2-like; K07199 5'-AMP-activated protein kinase, regulatory beta 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]
25759	SHC2; SHC (Src homology 2 domain containing) transforming protein 2 [KO:K06279]
399694	SHC4; SHC (Src homology 2 domain containing) family, member 4 [KO:K06279]
53358	SHC3; SHC (Src homology 2 domain containing) transforming protein 3 [KO:K06279]
6464	SHC1; SHC (Src homology 2 domain containing) transforming protein 1 [KO:K06279]
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; v-Ha-ras Harvey rat sarcoma viral oncogene homolog [KO:K02833]
3845	KRAS; v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog [KO:K07827]
4893	NRAS; neuroblastoma RAS viral (v-ras) oncogene homolog [KO:K07828]
369	ARAF; v-raf murine sarcoma 3611 viral oncogene homolog [KO:K08845] [EC:2.7.11.1]
673	BRAF; v-raf murine sarcoma viral oncogene homolog B1 [KO:K04365] [EC:2.7.11.1]
5894	RAF1; v-raf-1 murine leukemia viral oncogene homolog 1 [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

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)

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)

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)

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

PMID:11742412

Authors

Saltiel AR, Kahn CR.

Title

Insulin signalling and the regulation of glucose and lipid metabolism.

Journal

Nature 414:799-806 (2001)

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)

Reference

PMID:16288289

Authors

Ruggero D, Sonenberg N.

Title

The Akt of translational control.

Journal

Oncogene 24:7426-34 (2005)

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)

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

PMID:15229476

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

PMID:17344645

Authors

Ferre P, Foufelle F

Title

SREBP-1c transcription factor and lipid homeostasis: clinical perspective.

Journal

Horm Res 68:72-82 (2007)

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)

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)

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)

KO pathway

ko04910

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Ontology (1)   
   KEGG BRITE (1)   
Pathway (1)   
   BioSystems (1)   
Disease (13)   
   KEGG DISEASE (13)   
Drug (44)   
   KEGG DRUG (44)   
Genome (1)   
   KEGG GENOME (1)   
Gene (140)   
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