KEGG PATHWAY: ko04910

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

Orthology

K00665

FASN; fatty acid synthase, animal type [EC:2.3.1.85]

K00688

PYG, glgP; glycogen phosphorylase [EC:2.4.1.1]

K00693

GYS; glycogen synthase [EC:2.4.1.11]

K00844

HK; hexokinase [EC:2.7.1.1]

K00871

PHKG; phosphorylase kinase gamma subunit [EC:2.7.11.19]

K00922

PIK3CA_B_D; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153]

K01084

G6PC; glucose-6-phosphatase [EC:3.1.3.9]

K01106

INPP5A; inositol polyphosphate 5-phosphatase INPP5A [EC:3.1.3.56]

K01596

E4.1.1.32, pckA, PCK; phosphoenolpyruvate carboxykinase (GTP) [EC:4.1.1.32]

K01946

ACACB; acetyl-CoA carboxylase / biotin carboxylase 2 [EC:6.4.1.2 6.3.4.14 2.1.3.15]

K02158

BAD; Bcl-2-antagonist of cell death

K02183

CALM; calmodulin

K02649

PIK3R1_2_3; phosphoinositide-3-kinase regulatory subunit alpha/beta/delta

K02833

HRAS; GTPase HRas

K02991

RP-S6e, RPS6; small subunit ribosomal protein S6e

K03083

GSK3B; glycogen synthase kinase 3 beta [EC:2.7.11.26]

K03099

SOS; son of sevenless

K03259

EIF4E; translation initiation factor 4E

K03841

FBP; fructose-1,6-bisphosphatase I [EC:3.1.3.11]

K04345

PKA; protein kinase A [EC:2.7.11.11]

K04364

GRB2; growth factor receptor-bound protein 2

K04365

BRAF; B-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]

K04366

RAF1; RAF proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]

K04368

MAP2K1, MEK1; mitogen-activated protein kinase kinase 1 [EC:2.7.12.2]

K04369

MAP2K2, MEK2; mitogen-activated protein kinase kinase 2 [EC:2.7.12.2]

K04371

ERK, MAPK1_3; mitogen-activated protein kinase 1/3 [EC:2.7.11.24]

K04372

MKNK, MNK; MAP kinase interacting serine/threonine kinase [EC:2.7.11.1]

K04375

ELK1; ETS domain-containing protein Elk-1

K04438

CRK, CRKII; C-crk adapter molecule crk

K04440

JNK; mitogen-activated protein kinase 8/9/10 (c-Jun N-terminal kinase) [EC:2.7.11.24]

K04456

AKT; RAC serine/threonine-protein kinase [EC:2.7.11.1]

K04526

INS; insulin

K04527

INSR, CD220; insulin receptor [EC:2.7.10.1]

K04688

RPS6KB; ribosomal protein S6 kinase beta [EC:2.7.11.1]

K04694

SOCS1, JAB; suppressor of cytokine signaling 1

K04695

SOCS2, CIS2; suppressor of cytokine signaling 2

K04696

SOCS3, CIS3; suppressor of cytokine signaling 3

K04697

SOCS4; suppressor of cytokine signaling 4

K04707

CBL; E3 ubiquitin-protein ligase CBL [EC:2.3.2.27]

K04739

PRKAR; cAMP-dependent protein kinase regulator

K05695

PTPRF, LAR; receptor-type tyrosine-protein phosphatase F [EC:3.1.3.48]

K05696

PTPN1, PTP1B; tyrosine-protein phosphatase non-receptor type 1 [EC:3.1.3.48]

K06069

PRKCI; atypical protein kinase C iota type [EC:2.7.11.13]

K06086

SORBS1, SH3D5, PONSIN, CAP; sorbin and SH3 domain containing protein 1

K06269

PPP1C; serine/threonine-protein phosphatase PP1 catalytic subunit [EC:3.1.3.16]

K06276

PDPK1; 3-phosphoinositide dependent protein kinase-1 [EC:2.7.11.1]

K06277

RAPGEF1, GRF2; Rap guanine nucleotide exchange factor 1

K06279

SHC1; SHC-transforming protein 1

K07187

IRS2; insulin receptor substrate 2

K07188

LIPE, HSL; hormone-sensitive lipase [EC:3.1.1.79]

K07189

PPP1R3; protein phosphatase 1 regulatory subunit 3A/B/C/D/E

K07190

PHKA_B; phosphorylase kinase alpha/beta subunit

K07191

SLC2A4, GLUT4; MFS transporter, SP family, solute carrier family 2 (facilitated glucose transporter), member 4

K07192

FLOT; flotillin

K07193

SH2B, APS; SH2B adapter protein 2

K07194

RHOQ, TC10; Ras homolog gene family, member Q

K07195

EXOC7, EXO70; exocyst complex component 7

K07196

TRIP10, CIP4; thyroid hormone receptor interactor 10

K07197

SREBP1, SREBF1; sterol regulatory element-binding transcription factor 1

K07198

PRKAA, AMPK; 5'-AMP-activated protein kinase, catalytic alpha subunit [EC:2.7.11.31]

K07199

PRKAB; 5'-AMP-activated protein kinase, regulatory beta subunit

K07200

PRKAG; 5'-AMP-activated protein kinase, regulatory gamma subunit

K07201

FOXO1; forkhead box protein O1

K07202

PPARGC1A, PGC1A; alpha peroxisome proliferator-activated receptor gamma coactivator 1-alpha

K07203

MTOR, FRAP, TOR; serine/threonine-protein kinase mTOR [EC:2.7.11.1]

K07204

RAPTOR; regulatory associated protein of mTOR

K07205

EIF4EBP1; eukaryotic translation initiation factor 4E binding protein 1

K07206

TSC1; tuberous sclerosis 1

K07207

TSC2; tuberous sclerosis 2

K07208

RHEB; Ras homolog enriched in brain

K07209

IKBKB, IKKB; inhibitor of nuclear factor kappa-B kinase subunit beta [EC:2.7.11.10]

K07827

KRAS, KRAS2; GTPase KRas

K07828

NRAS; GTPase NRas

K08845

ARAF, ARAF1; A-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]

K11262

ACACA; acetyl-CoA carboxylase / biotin carboxylase 1 [EC:6.4.1.2 6.3.4.14 2.1.3.15]

K12406

PKLR; pyruvate kinase isozymes R/L [EC:2.7.1.40]

K12407

GCK; glucokinase [EC:2.7.1.2]

K13296

PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [EC:3.1.4.17]

K15909

SHIP2, INPPL1; phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 2 [EC:3.1.3.86]

K16172

IRS1; insulin receptor substrate 1

K17445

IRS3; insulin receptor substrate 3

K17446

IRS4; insulin receptor substrate 4

K17447

SHC2; SHC-transforming protein 2

K17448

SHC3; SHC-transforming protein 3

K17449

SHC4; SHC-transforming protein 4

K17453

PPP1R3F, R3F; protein phosphatase 1 regulatory subunit 3F

K18952

PRKCZ; atypical protein kinase C zeta type [EC:2.7.11.13]

K22517

CBLB; E3 ubiquitin-protein ligase CBL-B [EC:2.3.2.27]

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