KEGG   PATHWAY: emc04910
Entry
emc04910                    Pathway                                
Name
Insulin signaling pathway - Eublepharis macularius (Leopard gecko)
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
emc04910  Insulin signaling pathway
emc04910

Organism
Eublepharis macularius (Leopard gecko) [GN:emc]
Gene
129324677  INS; insulin [KO:K04526]
129330829  insulin receptor-like isoform X1 [KO:K04527] [EC:2.7.10.1]
129340365  insulin receptor substrate 1-like isoform X1 [KO:K16172]
129332056  IRS1; insulin receptor substrate 1 [KO:K16172]
129341159  IRS4; insulin receptor substrate 4 [KO:K07187]
129325940  IRS2; insulin receptor substrate 2 [KO:K07187]
129334239  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
129329994  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta isoform X1 [KO:K02649]
129331257  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
129340355  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform-like isoform X1 [KO:K00922] [EC:2.7.1.153]
129331860  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
129332202  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
129345006  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
129340664  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
129323978  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
129329530  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
129342846  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
129345278  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
129335851  GYS2; LOW QUALITY PROTEIN: glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
129338923  GYS1; glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
129329374  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
129323844  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
129341454  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
129334287  PPP1R3B; protein phosphatase 1 regulatory subunit 3B isoform X1 [KO:K07189]
129339991  PPP1R3E; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
129329651  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
129341879  protein phosphatase 1 regulatory subunit 3C-B-like [KO:K07189]
129344330  protein phosphatase 1 regulatory subunit 3E-like [KO:K07189]
129332835  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
129346031  PPP1R3F; protein phosphatase 1 regulatory subunit 3F [KO:K17453]
129338754  PHKG2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform [KO:K00871] [EC:2.7.11.19]
129344649  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform [KO:K00871] [EC:2.7.11.19]
129340882  PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
129325497  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
129343941  PHKB; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
129345633  CALML4; calmodulin-like protein 4 [KO:K02183]
129334948  calmodulin-A-like [KO:K02183]
129335564  uncharacterized protein LOC129335564 [KO:K02183]
129335565  calmodulin, flagellar-like [KO:K02183]
129324040  CALM1; calmodulin-1 [KO:K02183]
129342822  CALM3; calmodulin-3 isoform X1 [KO:K02183]
129332838  CALM2; calmodulin-2 [KO:K02183]
129338701  calmodulin-1 [KO:K02183]
129344686  CALML6; calmodulin-like protein 6 [KO:K02183]
129333610  PYGB; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
129323490  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
129337126  PYGM; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
129324274  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B isoform X1 [KO:K13296] [EC:3.1.4.17]
129329909  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
129327293  cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
129328134  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
129328335  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
129340688  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit [KO:K04739]
129336230  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit [KO:K04739]
129343552  LIPE; hormone-sensitive lipase isoform X1 [KO:K07188] [EC:3.1.1.79]
129344516  PRKCZ; protein kinase C zeta type [KO:K18952] [EC:2.7.11.13]
129332345  PRKCI; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
129340375  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 isoform X1 [KO:K07191]
129328617  FLOT1; flotillin-1 isoform X1 [KO:K07192]
129345088  FLOT2; flotillin-2 isoform X1 [KO:K07192]
129344980  SH2B2; SH2B adapter protein 2 [KO:K07193]
129332821  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X1 [KO:K06086]
129342107  CBL; E3 ubiquitin-protein ligase CBL [KO:K04707] [EC:2.3.2.27]
129343170  CBLC; E3 ubiquitin-protein ligase CBL-C isoform X1 [KO:K04707] [EC:2.3.2.27]
129325718  CBLB; E3 ubiquitin-protein ligase CBL-B [KO:K22517] [EC:2.3.2.27]
129340736  crk-like protein [KO:K04438]
129341313  CRKL; crk-like protein [KO:K04438]
129344785  CRK; adapter molecule crk isoform X1 [KO:K04438]
129341999  RAPGEF1; rap guanine nucleotide exchange factor 1 [KO:K06277]
129332743  RHOQ; rho-related GTP-binding protein RhoQ [KO:K07194]
129327361  EXOC7; exocyst complex component 7 isoform X1 [KO:K07195]
129345980  TRIP10; cdc42-interacting protein 4 isoform X1 [KO:K07196]
129338470  SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
129345034  ACACA; acetyl-CoA carboxylase 1 isoform X1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
129341574  ACACB; acetyl-CoA carboxylase 2 isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
129327360  FASN; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
129339682  PKLR; pyruvate kinase PKLR isoform X1 [KO:K12406] [EC:2.7.1.40]
129327614  HK3; hexokinase-3 [KO:K00844] [EC:2.7.1.1]
129342029  hexokinase-2 [KO:K00844] [EC:2.7.1.1]
129332164  HK1; hexokinase-1 [KO:K00844] [EC:2.7.1.1]
129332165  hexokinase HKDC1 [KO:K00844] [EC:2.7.1.1]
129342642  GCK; hexokinase-4 isoform X1 [KO:K12407] [EC:2.7.1.2]
129334389  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 [KO:K07198] [EC:2.7.11.31]
129331417  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X1 [KO:K07198] [EC:2.7.11.31]
129341507  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
129330974  5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
129328087  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
129323970  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
129337557  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
129341615  FOXO1; forkhead box protein O1 [KO:K07201]
129343672  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha [KO:K07202]
129340646  glucose-6-phosphatase catalytic subunit 1-like [KO:K01084] [EC:3.1.3.9]
129324784  G6PC2; glucose-6-phosphatase 2 [KO:K01084] [EC:3.1.3.9]
129338511  glucose-6-phosphatase catalytic subunit 1-like [KO:K01084] [EC:3.1.3.9]
129338885  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
129334284  fructose-1,6-bisphosphatase 1-like [KO:K03841] [EC:3.1.3.11]
129335202  fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
129331412  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
129338457  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial isoform X1 [KO:K01596] [EC:4.1.1.32]
129344458  MTOR; serine/threonine-protein kinase mTOR isoform X1 [KO:K07203] [EC:2.7.11.1]
129328073  RPTOR; regulatory-associated protein of mTOR isoform X1 [KO:K07204]
129323741  RPS6KB2; ribosomal protein S6 kinase beta-2 [KO:K04688] [EC:2.7.11.1]
129344466  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
129334423  RPS6; 40S ribosomal protein S6 [KO:K02991]
129342005  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
129327613  EIF4E1B; LOW QUALITY PROTEIN: eukaryotic translation initiation factor 4E type 1B [KO:K03259]
129336999  EIF4E; eukaryotic translation initiation factor 4E [KO:K03259]
129332870  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
129342094  TSC1; hamartin isoform X1 [KO:K07206]
129340080  TSC2; tuberin isoform X1 [KO:K07207]
129337580  RHEB; GTP-binding protein Rheb [KO:K07208]
129340405  BAD; bcl2-associated agonist of cell death [KO:K02158]
129339940  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
129329904  SHC2; SHC-transforming protein 2 [KO:K17447]
129335216  SHC3; SHC-transforming protein 3 [KO:K17448]
129345563  SHC4; SHC-transforming protein 4 [KO:K17449]
129328224  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
129324492  SOS2; son of sevenless homolog 2 [KO:K03099]
129333455  SOS1; son of sevenless homolog 1 [KO:K03099]
129324311  HRAS; GTPase HRas [KO:K02833]
129336091  KRAS; GTPase KRas isoform X1 [KO:K07827]
129338629  GTPase HRas-like [KO:K07827]
129330049  NRAS; GTPase NRas [KO:K07828]
129346271  ARAF; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
129336309  BRAF; serine/threonine-protein kinase B-raf [KO:K04365] [EC:2.7.11.1]
129328096  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
129345582  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
129330130  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
129341079  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
129338355  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
129330866  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 [KO:K04372] [EC:2.7.11.1]
129331316  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 [KO:K04372] [EC:2.7.11.1]
129346612  ELK1; ETS domain-containing protein Elk-1 [KO:K04375]
129340247  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
129335717  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
129328279  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
129340151  suppressor of cytokine signaling 3-like [KO:K04696]
129323632  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
129330251  PTPN1; tyrosine-protein phosphatase non-receptor type 1 [KO:K05696] [EC:3.1.3.48]
129329844  PTPRF; receptor-type tyrosine-protein phosphatase F isoform X1 [KO:K05695] [EC:3.1.3.48]
129328129  MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
129336678  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
129331890  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
129342159  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
129325733  INPPL1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 [KO:K15909] [EC:3.1.3.86]
129332305  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
emc00010  Glycolysis / Gluconeogenesis
emc00061  Fatty acid biosynthesis
emc00500  Starch and sucrose metabolism
emc04010  MAPK signaling pathway
emc04070  Phosphatidylinositol signaling system
emc04210  Apoptosis
KO pathway
ko04910   
LinkDB

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