KEGG   PATHWAY: rno04910
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
Pathway map
rno04910  Insulin signaling pathway
rno04910

Organism
Rattus norvegicus (rat) [GN:rno]
Gene
24506  Ins2; insulin-2 preproprotein [KO:K04526]
24505  Ins1; insulin-1 preproprotein [KO:K04526]
24954  Insr; insulin receptor preproprotein [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; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
60664  Pik3r3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
29741  Pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
85243  Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
170911  Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
366508  Pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
134484121  LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform-like [KO:K00922] [EC:2.7.1.153]
81745  Pdpk1; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
24185  Akt1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
25233  Akt2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
29414  Akt3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
84027  Gsk3b; glycogen synthase kinase-3 beta [KO:K03083] [EC:2.7.11.26]
25623  Gys2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
690987  Gys1; glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
24668  Ppp1ca; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
24669  Ppp1cc; serine/threonine-protein phosphatase PP1-gamma catalytic subunit isoform 1 [KO:K06269] [EC:3.1.3.16]
25594  Ppp1cb; serine/threonine-protein phosphatase PP1-beta catalytic subunit [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 b kinase gamma catalytic chain, liver/testis isoform [KO:K00871] [EC:2.7.11.19]
29353  Phkg1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform [KO:K00871] [EC:2.7.11.19]
64561  Phka1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform [KO:K07190]
361377  Phkb; phosphorylase b kinase regulatory subunit beta isoform 1 [KO:K07190]
678739  Phka2; phosphorylase b kinase regulatory subunit alpha, liver isoform [KO:K07190]
364774  Calml5; calmodulin-like protein 5 [KO:K02183]
307100  Calml3; calmodulin-like protein 3 [KO:K02183]
691455  Calml4; calmodulin-like protein 4 [KO:K02183]
24242  Calm1; calmodulin-1 [KO:K02183]
24244  Calm3; calmodulin-3 [KO:K02183]
50663  Calm2; calmodulin-2 [KO:K02183]
64035  Pygl; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
25739  Pygb; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
24701  Pygm; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
29516  Pde3b; cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B [KO:K13296] [EC:3.1.4.17]
25636  Prkaca; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
293508  Prkacb; cAMP-dependent protein kinase catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
25725  Prkar1a; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
29699  Prkar2a; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
24679  Prkar2b; cAMP-dependent protein kinase type II-beta regulatory subunit [KO:K04739]
25521  Prkar1b; cAMP-dependent protein kinase type I-beta regulatory subunit isoform 2 [KO:K04739]
25330  Lipe; hormone-sensitive lipase [KO:K07188] [EC:3.1.1.79]
25522  Prkcz; protein kinase C zeta type [KO:K18952] [EC:2.7.11.13]
84006  Prkci; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
25139  Slc2a4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
83764  Flot2; flotillin-2 isoform 2 [KO:K07192]
64665  Flot1; flotillin-1 [KO:K07192]
114203  Sh2b2; SH2B adapter protein 2 [KO:K07193]
686098  Sorbs1; sorbin and SH3 domain-containing protein 1 [KO:K06086]
500985  Cbl; E3 ubiquitin-protein ligase CBL [KO:K04707] [EC:2.3.2.27]
171136  Cblb; E3 ubiquitin-protein ligase CBL-B [KO:K22517] [EC:2.3.2.27]
54245  Crk; adapter molecule crk [KO:K04438]
287942  Crkl; crk-like protein [KO:K04438]
63881  Rapgef1; rap guanine nucleotide exchange factor 1 isoform X25 [KO:K06277]
64632  Exoc7; exocyst complex component 7 [KO:K07195]
116717  Trip10; cdc42-interacting protein 4 [KO:K07196]
78968  Srebf1; sterol regulatory element-binding protein 1 isoform 1 precursor [KO:K07197]
60581  Acaca; acetyl-CoA carboxylase 1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
116719  Acacb; acetyl-CoA carboxylase 2 precursor [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
50671  Fasn; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
24651  Pklr; pyruvate kinase PKLR [KO:K12406] [EC:2.7.1.40]
25058  Hk1; hexokinase-1 isoform 2 [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]
100364027  Hkdc1; hexokinase HKDC1 isoform X1 [KO:K00844] [EC:2.7.1.1]
24385  Gck; hexokinase-4 isoform 2 [KO:K12407] [EC:2.7.1.2]
65248  Prkaa1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 [KO:K07198] [EC:2.7.11.31]
78975  Prkaa2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
83803  Prkab1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
64562  Prkab2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
25520  Prkag1; 5'-AMP-activated protein kinase subunit gamma-1 [KO:K07200]
301518  Prkag3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
84482  Foxo1; forkhead box protein O1 [KO:K07201]
83516  Ppargc1a; peroxisome proliferator-activated receptor gamma coactivator 1-alpha [KO:K07202]
25634  G6pc1; glucose-6-phosphatase catalytic subunit 1 [KO:K01084] [EC:3.1.3.9]
303565  G6pc3; glucose-6-phosphatase 3 [KO:K01084] [EC:3.1.3.9]
24362  Fbp1; fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
114508  Fbp2; fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
362282  Pck1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
361042  Pck2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
56718  Mtor; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
287871  Rptor; regulatory-associated protein of mTOR [KO:K07204]
83840  Rps6kb1; ribosomal protein S6 kinase beta-1 [KO:K04688] [EC:2.7.11.1]
361696  Rps6kb2; ribosomal protein S6 kinase beta-2 [KO:K04688] [EC:2.7.11.1]
29304  Rps6; small ribosomal subunit protein eS6 [KO:K02991]
116636  Eif4ebp1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
117045  Eif4e; eukaryotic translation initiation factor 4E [KO:K03259]
686104  Eif4e1b; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
363275  Eif4e2; eukaryotic translation initiation factor 4E type 2 isoform 1 [KO:K03259]
60445  Tsc1; hamartin [KO:K07206]
24855  Tsc2; tuberin [KO:K07207]
26954  Rheb; GTP-binding protein Rheb [KO:K07208]
64639  Bad; bcl2-associated agonist of cell death [KO:K02158]
85385  Shc1; SHC-transforming protein 1 isoform b [KO:K06279]
314612  Shc2; SHC-transforming protein 2 [KO:K17447]
114858  Shc3; SHC-transforming protein 3 [KO:K17448]
679845  Shc4; SHC-transforming protein 4 [KO:K17449]
81504  Grb2; growth factor receptor-bound protein 2 [KO:K04364]
85384  Sos2; son of sevenless homolog 2 [KO:K03099]
313845  Sos1; son of sevenless homolog 1 [KO:K03099]
293621  Hras; GTPase HRas [KO:K02833]
367858  Hrasl1; HRas proto-oncogene, GTPase like 1 [KO:K02833]
24525  Kras; GTPase KRas [KO:K07827]
24605  Nras; GTPase NRas [KO:K07828]
64363  Araf; serine/threonine-protein kinase A-Raf isoform 1 [KO:K08845] [EC:2.7.11.1]
114486  Braf; serine/threonine-protein kinase B-raf isoform X2 [KO:K04365] [EC:2.7.11.1]
24703  Raf1; RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:2.7.11.1]
170851  Map2k1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
58960  Map2k2; dual specificity 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-protein kinase 2 [KO:K04372] [EC:2.7.11.1]
500526  Mknk1; MAP kinase-interacting serine/threonine-protein kinase 1 [KO:K04372] [EC:2.7.11.1]
314436  Elk1; ETS domain-containing protein Elk-1 [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; tyrosine-protein phosphatase non-receptor type 1 [KO:K05696] [EC:3.1.3.48]
360406  Ptprf; receptor-type tyrosine-protein phosphatase F precursor [KO:K05695] [EC:3.1.3.48]
25272  Mapk10; mitogen-activated protein kinase 10 isoform 2 [KO:K04440] [EC:2.7.11.24]
50658  Mapk9; mitogen-activated protein kinase 9 isoform 2 [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 nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
65038  Inppl1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 isoform 1 [KO:K15909] [EC:3.1.3.86]
365382  Inpp5a; inositol polyphosphate-5-phosphatase A [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)
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
Related
pathway
rno00010  Glycolysis / Gluconeogenesis
rno00061  Fatty acid biosynthesis
rno00500  Starch and sucrose metabolism
rno04010  MAPK signaling pathway
rno04070  Phosphatidylinositol signaling system
rno04210  Apoptosis
KO pathway
ko04910   
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