KEGG   PATHWAY: rno04910Help
Entry
rno04910                    Pathway                                

Name
Insulin signaling pathway - Rattus norvegicus (rat)
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
rno04910

All organismsOrtholog table
Module
PI3K-Akt signaling [PATH:rno04910]
Organism
Rattus norvegicus (rat) [GN:rno]
Gene
24506  
Ins2; insulin 2 [KO:K04526]
24505  
Ins1; insulin 1 [KO:K04526]
24954  
Insr; insulin receptor [KO:K04527] [EC:2.7.10.1]
25467  
Irs1; insulin receptor substrate 1 [KO:K16172]
29376  
Irs2; insulin receptor substrate 2 [KO:K07187]
84021  
Irs3; insulin receptor substrate 3 [KO:K17445]
315350  
Irs4; insulin receptor substrate 4 [KO:K17446]
25513  
Pik3r1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
60664  
Pik3r3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
29741  
Pik3r2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
497931  
Pik3r5; phosphoinositide-3-kinase, regulatory subunit 5 [KO:K02649]
85243  
Pik3cb; phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
170911  
Pik3ca; phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
366508  
Pik3cd; phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
298947  
Pik3cg; phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit gamma [KO:K00922] [EC:2.7.1.153]
81745  
Pdpk1; 3-phosphoinositide dependent protein kinase-1 [KO:K06276] [EC:2.7.11.1]
24185  
Akt1; AKT serine/threonine kinase 1 [KO:K04456] [EC:2.7.11.1]
25233  
Akt2; AKT serine/threonine kinase 2 [KO:K04456] [EC:2.7.11.1]
29414  
Akt3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1]
84027  
Gsk3b; glycogen synthase kinase 3 beta [KO:K03083] [EC:2.7.11.26]
25623  
Gys2; glycogen synthase 2 [KO:K00693] [EC:2.4.1.11]
690987  
Gys1; glycogen synthase 1 [KO:K00693] [EC:2.4.1.11]
24668  
Ppp1ca; protein phosphatase 1 catalytic subunit alpha [KO:K06269] [EC:3.1.3.16]
24669  
Ppp1cc; protein phosphatase 1 catalytic subunit gamma [KO:K06269] [EC:3.1.3.16]
25594  
Ppp1cb; protein phosphatase 1 catalytic subunit beta [KO:K06269] [EC:3.1.3.16]
192280  
Ppp1r3b; protein phosphatase 1, regulatory subunit 3B [KO:K07189]
309513  
Ppp1r3c; protein phosphatase 1, regulatory subunit 3C [KO:K07189]
500036  
Ppp1r3a; protein phosphatase 1, regulatory subunit 3A [KO:K07189]
689995  
Ppp1r3d; protein phosphatase 1, regulatory subunit 3D [KO:K07189]
691447  
Ppp1r3e; protein phosphatase 1, regulatory subunit 3E [KO:K07189]
363453  
Ppp1r3f; protein phosphatase 1 regulatory subunit 3F [KO:K17453]
140671  
Phkg2; phosphorylase kinase catalytic subunit gamma 2 [KO:K00871] [EC:2.7.11.19]
29353  
Phkg1; phosphorylase kinase, gamma 1 [KO:K00871] [EC:2.7.11.19]
64561  
Phka1; phosphorylase kinase, alpha 1 [KO:K07190]
361377  
Phkb; phosphorylase kinase regulatory subunit beta [KO:K07190]
678739  
Phka2; phosphorylase kinase, alpha 2 [KO:K07190]
50663  
Calm2; calmodulin 2 [KO:K02183]
24242  
Calm1; calmodulin 1 [KO:K02183]
24244  
Calm3; calmodulin 3 [KO:K02183]
364774  
Calml5; calmodulin-like 5 [KO:K02183]
307100  
Calml3; calmodulin-like 3 [KO:K02183]
691455  
Calml4; calmodulin-like 4 [KO:K02183]
64035  
Pygl; phosphorylase, glycogen, liver [KO:K00688] [EC:2.4.1.1]
25739  
Pygb; phosphorylase, glycogen; brain [KO:K00688] [EC:2.4.1.1]
24701  
Pygm; phosphorylase, glycogen, muscle [KO:K00688] [EC:2.4.1.1]
29516  
Pde3b; phosphodiesterase 3B [KO:K13296] [EC:3.1.4.17]
25636  
Prkaca; protein kinase cAMP-activated catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
293508  
Prkacb; protein kinase cAMP-activated catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
25725  
Prkar1a; protein kinase cAMP-dependent type 1 regulatory subunit alpha [KO:K04739]
29699  
Prkar2a; protein kinase cAMP-dependent type 2 regulatory subunit alpha [KO:K04739]
24679  
Prkar2b; protein kinase cAMP-dependent type 2 regulatory subunit beta [KO:K04739]
25330  
Lipe; lipase E, hormone sensitive type [KO:K07188] [EC:3.1.1.79]
25522  
Prkcz; protein kinase C, zeta [KO:K18952] [EC:2.7.11.13]
84006  
Prkci; protein kinase C, iota [KO:K06069] [EC:2.7.11.13]
25139  
Slc2a4; solute carrier family 2 member 4 [KO:K07191]
83764  
Flot2; flotillin 2 [KO:K07192]
64665  
Flot1; flotillin 1 [KO:K07192]
114203  
Sh2b2; SH2B adaptor protein 2 [KO:K07193]
686098  
Sorbs1; sorbin and SH3 domain containing 1 [KO:K06086]
292699  
Cblc; Cbl proto-oncogene C [KO:K04707] [EC:2.3.2.27]
171136  
Cblb; Cbl proto-oncogene B [KO:K04707] [EC:2.3.2.27]
500985  
Cbl; Cbl proto-oncogene [KO:K04707] [EC:2.3.2.27]
54245  
Crk; CRK proto-oncogene, adaptor protein [KO:K04438]
287942  
Crkl; v-crk avian sarcoma virus CT10 oncogene homolog-like [KO:K04438]
crk-like protein-like [KO:K04438]
63881  
Rapgef1; Rap guanine nucleotide exchange factor 1 [KO:K06277]
85428  
Rhoq; ras homolog family member Q [KO:K07194]
64632  
Exoc7; exocyst complex component 7 [KO:K07195]
exocyst complex component 7-like [KO:K07195]
116717  
Trip10; thyroid hormone receptor interactor 10 [KO:K07196]
78968  
Srebf1; sterol regulatory element binding transcription factor 1 [KO:K07197]
60581  
Acaca; acetyl-CoA carboxylase alpha [KO:K11262] [EC:6.3.4.14 6.4.1.2]
116719  
Acacb; acetyl-CoA carboxylase beta [KO:K01946] [EC:6.3.4.14 6.4.1.2]
50671  
Fasn; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
24651  
Pklr; pyruvate kinase, liver and RBC [KO:K12406] [EC:2.7.1.40]
25058  
Hk1; hexokinase 1 [KO:K00844] [EC:2.7.1.1]
25059  
Hk2; hexokinase 2 [KO:K00844] [EC:2.7.1.1]
25060  
Hk3; hexokinase 3 [KO:K00844] [EC:2.7.1.1]
hexokinase 1-like [KO:K00844] [EC:2.7.1.1]
24385  
Gck; glucokinase [KO:K12407] [EC:2.7.1.2]
65248  
Prkaa1; protein kinase AMP-activated catalytic subunit alpha 1 [KO:K07198] [EC:2.7.11.11]
78975  
Prkaa2; protein kinase AMP-activated catalytic subunit alpha 2 [KO:K07198] [EC:2.7.11.11]
83803  
Prkab1; protein kinase AMP-activated non-catalytic subunit beta 1 [KO:K07199]
64562  
Prkab2; protein kinase AMP-activated non-catalytic subunit beta 2 [KO:K07199]
25520  
Prkag1; protein kinase AMP-activated non-catalytic subunit gamma 1 [KO:K07200]
373545  
Prkag2; protein kinase AMP-activated non-catalytic subunit gamma 2 [KO:K07200]
301518  
Prkag3; protein kinase AMP-activated non-catalytic subunit gamma 3 [KO:K07200]
84482  
Foxo1; forkhead box O1 [KO:K07201]
83516  
Ppargc1a; PPARG coactivator 1 alpha [KO:K07202]
25634  
G6pc; glucose-6-phosphatase, catalytic subunit [KO:K01084] [EC:3.1.3.9]
681817  
G6pc2; glucose-6-phosphatase catalytic subunit 2 [KO:K01084] [EC:3.1.3.9]
303565  
G6pc3; glucose 6 phosphatase catalytic subunit 3 [KO:K01084] [EC:3.1.3.9]
24362  
Fbp1; fructose-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
114508  
Fbp2; fructose-bisphosphatase 2 [KO:K03841] [EC:3.1.3.11]
362282  
Pck1; phosphoenolpyruvate carboxykinase 1 [KO:K01596] [EC:4.1.1.32]
361042  
Pck2; phosphoenolpyruvate carboxykinase 2 (mitochondrial) [KO:K01596] [EC:4.1.1.32]
56718  
Mtor; mechanistic target of rapamycin [KO:K07203] [EC:2.7.11.1]
287871  
Rptor; regulatory associated protein of MTOR, complex 1 [KO:K07204]
83840  
Rps6kb1; ribosomal protein S6 kinase B1 [KO:K04688] [EC:2.7.11.1]
361696  
Rps6kb2; ribosomal protein S6 kinase, polypeptide 2 [KO:K04688] [EC:2.7.11.1]
29304  
Rps6; ribosomal protein S6 [KO:K02991]
40S ribosomal protein S6-like [KO:K02991]
116636  
Eif4ebp1; eukaryotic translation initiation factor 4E binding protein 1 [KO:K07205]
117045  
Eif4e; eukaryotic translation initiation factor 4E [KO:K03259]
363275  
Eif4e2; eukaryotic translation initiation factor 4E family member 2 [KO:K03259]
686104  
Eif4e1b; eukaryotic translation initiation factor 4E family member 1B [KO:K03259]
60445  
Tsc1; tuberous sclerosis 1 [KO:K07206]
24855  
Tsc2; tuberous sclerosis 2 [KO:K07207]
26954  
Rheb; Ras homolog enriched in brain [KO:K07208]
64639  
Bad; BCL2-associated agonist of cell death [KO:K02158]
85385  
Shc1; SHC adaptor protein 1 [KO:K06279]
314612  
Shc2; SHC adaptor protein 2 [KO:K17447]
114858  
Shc3; SHC adaptor protein 3 [KO:K17448]
679845  
Shc4; SHC adaptor protein 4 [KO:K17449]
81504  
Grb2; growth factor receptor bound protein 2 [KO:K04364]
85384  
Sos2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO:K03099]
313845  
Sos1; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO:K03099]
293621  
Hras; Harvey rat sarcoma virus oncogene [KO:K02833]
24525  
Kras; KRAS proto-oncogene, GTPase [KO:K07827]
24605  
Nras; neuroblastoma RAS viral oncogene homolog [KO:K07828]
64363  
Araf; A-Raf proto-oncogene, serine/threonine kinase [KO:K08845] [EC:2.7.11.1]
114486  
Braf; B-Raf proto-oncogene, serine/threonine kinase [KO:K04365] [EC:2.7.11.1]
24703  
Raf1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1]
170851  
Map2k1; mitogen activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
58960  
Map2k2; mitogen activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
116590  
Mapk1; mitogen activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
50689  
Mapk3; mitogen activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
299618  
Mknk2; MAP kinase-interacting serine/threonine kinase 2 [KO:K04372] [EC:2.7.11.1]
500526  
Mknk1; MAP kinase-interacting serine/threonine kinase 1 [KO:K04372] [EC:2.7.11.1]
314436  
Elk1; ELK1, ETS transcription factor [KO:K04375]
252971  
Socs1; suppressor of cytokine signaling 1 [KO:K04694]
84607  
Socs2; suppressor of cytokine signaling 2 [KO:K04695]
89829  
Socs3; suppressor of cytokine signaling 3 [KO:K04696]
305828  
Socs4; suppressor of cytokine signaling 4 [KO:K04697]
24697  
Ptpn1; protein tyrosine phosphatase, non-receptor type 1 [KO:K05696] [EC:3.1.3.48]
360406  
Ptprf; protein tyrosine phosphatase, receptor type, F [KO:K05695] [EC:3.1.3.48]
25272  
Mapk10; mitogen activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
50658  
Mapk9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
116554  
Mapk8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
84351  
Ikbkb; inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta [KO:K07209] [EC:2.7.11.10]
65038  
Inppl1; inositol polyphosphate phosphatase-like 1 [KO:K15909] [EC:3.1.3.86]
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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