KEGG   PATHWAY: ppug04910
Entry
ppug04910                   Pathway                                
Name
Insulin signaling pathway - Pungitius pungitius (ninespine stickleback)
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
ppug04910  Insulin signaling pathway
ppug04910

Organism
Pungitius pungitius (ninespine stickleback) [GN:ppug]
Gene
119193899  prkar2ab; protein kinase, cAMP-dependent, regulatory, type II, alpha, B [KO:K04739]
119194038  pck1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
119194691  [KO:K06269] [EC:3.1.3.16]
119194767  socs4; suppressor of cytokine signaling 4 [KO:K04697]
119194812  [KO:K02183]
119195101  cbl; E3 ubiquitin-protein ligase CBL [KO:K04707] [EC:2.3.2.27]
119195521  [KO:K04739]
119195764  map2k1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
119195920  kras; GTPase KRas isoform X1 [KO:K07827]
119196409  [KO:K02833]
119196452  [KO:K07189]
119196715  calml4b; calmodulin-like protein 4 [KO:K02183]
119197023  lipeb; hormone-sensitive lipase isoform X1 [KO:K07188] [EC:3.1.1.79]
119197253  flot1b; flotillin-1b [KO:K07192]
119197382  shc1; SHC-transforming protein 1 isoform X1 [KO:K06279]
119198660  pck2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
119198785  [KO:K07200]
119202427  prkcz; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
119206876  prkacbb; protein kinase, cAMP-dependent, catalytic, beta b [KO:K04345] [EC:2.7.11.11]
119209207  crk; adapter molecule crk [KO:K04438]
119209321  [KO:K00922] [EC:2.7.1.153]
119209332  pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
119209338  [KO:K07200]
119209359  eif4e2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
119209392  [KO:K05695] [EC:3.1.3.48]
119209420  [KO:K02649]
119209473  prkci; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
119209490  insra; insulin receptor a [KO:K04527] [EC:2.7.10.1]
119209615  rheb; GTP-binding protein Rheb [KO:K07208]
119209642  map2k2b; dual specificity mitogen-activated protein kinase kinase 2b [KO:K04369] [EC:2.7.12.2]
119209826  prkab2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
119210020  [KO:K03259]
119210253  foxo1a; forkhead box protein O1-A [KO:K07201]
119210316  socs2; suppressor of cytokine signaling 2 [KO:K04695]
119210463  inppl1b; inositol polyphosphate phosphatase-like 1b [KO:K15909] [EC:3.1.3.86]
119210797  braf; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
119210841  [KO:K07193]
119210947  mapk9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
119211112  akt2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
119212017  calm3a; calmodulin 3a (phosphorylase kinase, delta) [KO:K02183]
119212533  [KO:K04440] [EC:2.7.11.24]
119212666  [KO:K06269] [EC:3.1.3.16]
119212915  [KO:K01084] [EC:3.1.3.9]
119212917  g6pc1a.2; glucose-6-phosphatase catalytic subunit 1 [KO:K01084] [EC:3.1.3.9]
119212944  g6pc3; glucose-6-phosphatase 3 [KO:K01084] [EC:3.1.3.9]
119213046  exoc7; exocyst complex component 7 isoform X1 [KO:K07195]
119213100  pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
119213101  fasn; fatty acid synthase isoform X1 [KO:K00665] [EC:2.3.1.85]
119213165  pdpk1b; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
119213224  socs3b; suppressor of cytokine signaling 3b [KO:K04696]
119213322  [KO:K04739]
119213401  phkg2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform [KO:K00871] [EC:2.7.11.19]
119213781  mapk8a; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
119213835  [KO:K01106] [EC:3.1.3.56]
119213889  akt3a; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
119213930  [KO:K07187]
119214039  calm2a; calmodulin 2a (phosphorylase kinase, delta) [KO:K02183]
119214056  inppl1a; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2A [KO:K15909] [EC:3.1.3.86]
119214279  rhoq; rho-related GTP-binding protein RhoQ [KO:K07194]
119214456  eif4e1c; eukaryotic translation initiation factor 4E family member 1c [KO:K03259]
119214501  ppp1r3ca; protein phosphatase 1, regulatory subunit 3Ca [KO:K07189]
119214646  [KO:K06086]
119215070  si:ch211-284e13.4; insulin receptor substrate 1-B [KO:K16172]
119215349  ins; insulin [KO:K04526]
119215469  [KO:K04707] [EC:2.3.2.27]
119215503  rps6kb1a; ribosomal protein S6 kinase beta-1 [KO:K04688] [EC:2.7.11.1]
119215536  [KO:K07192]
119215623  [KO:K04438]
119215831  [KO:K07201]
119215860  acaca; acetyl-CoA carboxylase 1 isoform X2 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
119215861  [KO:K00844] [EC:2.7.1.1]
119216287  prkacba; protein kinase, cAMP-dependent, catalytic, beta a isoform X1 [KO:K04345] [EC:2.7.11.11]
119216703  map2k2a; dual specificity mitogen-activated protein kinase kinase 2a [KO:K04369] [EC:2.7.12.2]
119216728  shc2; LOW QUALITY PROTEIN: SHC-transforming protein 2 [KO:K17447]
119216846  mknk1; MAP kinase-interacting serine/threonine-protein kinase 1 [KO:K04372] [EC:2.7.11.1]
119216881  ptprfa; protein tyrosine phosphatase receptor type Fa isoform X1 [KO:K05695] [EC:3.1.3.48]
119216917  [KO:K02649]
119216976  pik3r3b; phosphoinositide-3-kinase, regulatory subunit 3b (gamma) isoform X1 [KO:K02649]
119217013  prkaa2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X1 [KO:K07198] [EC:2.7.11.31]
119217034  mknk2b; MAP kinase-interacting serine/threonine-protein kinase 2b isoform X1 [KO:K04372] [EC:2.7.11.1]
119217096  [KO:K00922] [EC:2.7.1.153]
119217181  insrb; insulin receptor b [KO:K04527] [EC:2.7.10.1]
119217373  [KO:K04694]
119217409  tsc2; tuberin isoform X1 [KO:K07207]
119217415  rptor; regulatory-associated protein of mTOR [KO:K07204]
119217531  [KO:K03099]
119217641  [KO:K04345] [EC:2.7.11.11]
119217796  [KO:K07192]
119217882  [KO:K00844] [EC:2.7.1.1]
119217961  akt3b; LOW QUALITY PROTEIN: RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
119218185  [KO:K04688] [EC:2.7.11.1]
119218493  rps6; 40S ribosomal protein S6 [KO:K02991]
119218636  trip10b; thyroid hormone receptor interactor 10b isoform X1 [KO:K07196]
119218887  lipea; lipase, hormone-sensitive a [KO:K07188] [EC:3.1.1.79]
119219600  flot1a; flotillin-1a isoform X1 [KO:K07192]
119219742  prkag3a; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
119219897  grb2b; growth factor receptor-bound protein 2b [KO:K04364]
119219913  mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
119219984  socs1a; suppressor of cytokine signaling 1a [KO:K04694]
119220083  srebf1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
119220127  prkacaa; protein kinase, cAMP-dependent, catalytic, alpha, genome duplicate a isoform X1 [KO:K04345] [EC:2.7.11.11]
119220132  gys1; glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
119220140  zgc:55558; GTPase KRas [KO:K07827]
119220145  prkar1aa; protein kinase, cAMP-dependent, regulatory, type I, alpha (tissue specific extinguisher 1) a [KO:K04739]
119220339  prkar1b; cAMP-dependent protein kinase type I-beta regulatory subunit isoform X1 [KO:K04739]
119220408  ppp1caa; protein phosphatase 1, catalytic subunit, alpha isozyme a [KO:K06269] [EC:3.1.3.16]
119220737  trip10a; cdc42-interacting protein 4 homolog isoform X1 [KO:K07196]
119221021  socs3a; suppressor of cytokine signaling 3a [KO:K04696]
119221840  [KO:K00871] [EC:2.7.11.19]
119221908  ptpn1; tyrosine-protein phosphatase non-receptor type 1 [KO:K05696] [EC:3.1.3.48]
119221983  raf1a; raf-1 proto-oncogene, serine/threonine kinase a isoform X1 [KO:K04366] [EC:2.7.11.1]
119222148  prkar2aa; protein kinase, cAMP-dependent, regulatory, type II, alpha A [KO:K04739]
119222180  mtor; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
119222230  si:ch211-167b20.8; protein phosphatase 1 regulatory subunit 3A isoform X1 [KO:K07189]
119222288  [KO:K06269] [EC:3.1.3.16]
119222301  badb; BCL2 associated agonist of cell death b isoform X1 [KO:K02158]
119222341  pygmb; phosphorylase, glycogen, muscle b [KO:K00688] [EC:2.4.1.1]
119222591  [KO:K07191]
119222704  [KO:K00922] [EC:2.7.1.153]
119222804  ppargc1a; LOW QUALITY PROTEIN: peroxisome proliferator-activated receptor gamma coactivator 1-alpha [KO:K07202]
119222823  elk1; ETS domain-containing protein Elk-3 [KO:K04375]
119222867  [KO:K07187]
119222871  phka1a; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
119223188  pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
119223385  eif4e2rs1; eukaryotic translation initiation factor 4E family member 2 related sequence 1 [KO:K03259]
119223684  ppp1r3da; protein phosphatase 1, regulatory subunit 3Da [KO:K07189]
119224577  inpp5l; inositol polyphosphate-5-phosphatase A [KO:K01106] [EC:3.1.3.56]
119224672  [KO:K02649]
119224747  araf; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:2.7.11.1]
119224780  acacb; LOW QUALITY PROTEIN: acetyl-CoA carboxylase 2 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
119224898  mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
119224902  fbp1a; fructose-1,6-bisphosphatase 1a [KO:K03841] [EC:3.1.3.11]
119224904  fbp2; fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
119224939  ikbkb; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
119224965  eif4ebp1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
119225005  prkab1b; 5'-AMP-activated protein kinase subunit beta-1b isoform X1 [KO:K07199]
119225013  ppp1cc; serine/threonine-protein phosphatase PP1-gamma catalytic subunit A [KO:K06269] [EC:3.1.3.16]
119225108  hk2; hexokinase-2 [KO:K00844] [EC:2.7.1.1]
119225121  ppp1r3c2b; protein phosphatase 1 regulatory subunit 3C-B-like [KO:K07189]
119225324  gck; hexokinase-4 isoform X1 [KO:K12407] [EC:2.7.1.2]
119225400  phka2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
119225456  phkb; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
119226214  mapk10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
119226252  ppp1r3b; protein phosphatase 1 regulatory subunit 3B [KO:K07189]
119226265  rapgef1b; LOW QUALITY PROTEIN: rap guanine nucleotide exchange factor 1b [KO:K06277]
119226302  pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
119226320  [KO:K07205]
119226447  prkaa1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 [KO:K07198] [EC:2.7.11.31]
119226465  pde3b; cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B isoform X1 [KO:K13296] [EC:3.1.4.17]
119226579  hk1; hexokinase-1 isoform X3 [KO:K00844] [EC:2.7.1.1]
119226595  tsc1b; TSC complex subunit 1b isoform X1 [KO:K07206]
119226598  crkl; crk-like protein [KO:K04438]
119226713  prkab1a; 5'-AMP-activated protein kinase subunit beta-1a isoform X1 [KO:K07199]
119226750  shc3; SHC-transforming protein 3 [KO:K17448]
119227055  [KO:K03841] [EC:3.1.3.11]
119227178  calm1a; calmodulin-1a [KO:K02183]
119227325  eif4eb; eukaryotic translation initiation factor 4eb isoform X1 [KO:K03259]
119227440  pygl; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
119227622  [KO:K17449]
119227697  [KO:K06269] [EC:3.1.3.16]
119227745  akt1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
119228081  sos2; son of sevenless homolog 2 isoform X1 [KO:K03099]
119228510  prkag3b; 5'-AMP-activated protein kinase subunit gamma-3b [KO:K07200]
119228572  gsk3ba; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
119228584  irs2b; insulin receptor substrate 2 [KO:K07187]
119229258  calml4a; calmodulin-like protein 4a [KO:K02183]
119229449  prkag1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
119229450  rhebl1; ras homolog, mTORC1 binding like 1 [KO:K07208]
119229541  ppp1r3db; protein phosphatase 1, regulatory subunit 3Db [KO:K07189]
119230207  rps6kb1b; ribosomal protein S6 kinase beta-1 [KO:K04688] [EC:2.7.11.1]
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
ppug00010  Glycolysis / Gluconeogenesis
ppug00061  Fatty acid biosynthesis
ppug00500  Starch and sucrose metabolism
ppug04010  MAPK signaling pathway
ppug04070  Phosphatidylinositol signaling system
ppug04210  Apoptosis
KO pathway
ko04910   

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