KEGG   PATHWAY: dnm04910
Entry
dnm04910                    Pathway                                
Name
Insulin signaling pathway - Dasypus novemcinctus (nine-banded armadillo)
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
dnm04910  Insulin signaling pathway
dnm04910

Organism
Dasypus novemcinctus (nine-banded armadillo) [GN:dnm]
Gene
101411204  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
101411403  PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X2 [KO:K07190]
101411619  PTPN1; tyrosine-protein phosphatase non-receptor type 1 [KO:K05696] [EC:3.1.3.48]
101411989  BRAF; LOW QUALITY PROTEIN: serine/threonine-protein kinase B-raf [KO:K04365] [EC:2.7.11.1]
101412091  RHOQ; rho-related GTP-binding protein RhoQ [KO:K07194]
101412233  KRAS; GTPase KRas isoform X4 [KO:K07827]
101412377  FOXO1; forkhead box protein O1 [KO:K07201]
101412620  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
101412843  CALML4; calmodulin-like protein 4 isoform X2 [KO:K02183]
101413281  TSC2; tuberin [KO:K07207]
101413809  [KO:K04345] [EC:2.7.11.11]
101414148  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 isoform X2 [KO:K07200]
101414240  [KO:K07828]
101414407  BAD; bcl2-associated agonist of cell death [KO:K02158]
101414708  TRIP10; cdc42-interacting protein 4 isoform X1 [KO:K07196]
101414843  [KO:K07190]
101416000  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X1 [KO:K04372] [EC:2.7.11.1]
101416102  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
101416233  IRS4; insulin receptor substrate 4 [KO:K17446]
101416595  CALM2; calmodulin-2 [KO:K02183]
101417330  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
101417480  SHC3; LOW QUALITY PROTEIN: SHC-transforming protein 3 [KO:K17448]
101417604  INPP5A; type I inositol 1,4,5-trisphosphate 5-phosphatase [KO:K01106] [EC:3.1.3.56]
101417843  CBL; E3 ubiquitin-protein ligase CBL isoform X1 [KO:K04707] [EC:2.3.2.27]
101417995  CALM1; calmodulin-1 [KO:K02183]
101417998  RHEB; GTP-binding protein Rheb [KO:K07208]
101418750  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
101418752  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X2 [KO:K22517] [EC:2.3.2.27]
101419022  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
101419050  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
101419167  ARAF; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
101419480  HRAS; GTPase HRas isoform X1 [KO:K02833]
101419724  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit [KO:K04739]
101420042  FLOT2; flotillin-2 isoform X1 [KO:K07192]
101420045  ELK1; ETS domain-containing protein Elk-1 [KO:K04375]
101420178  FBP2; fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
101420546  [KO:K04369] [EC:2.7.12.2]
101420683  HK2; hexokinase-2 [KO:K00844] [EC:2.7.1.1]
101421043  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
101421191  FBP1; fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
101421211  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
101421268  PPP1R3B; protein phosphatase 1 regulatory subunit 3B [KO:K07189]
101421673  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit isoform X2 [KO:K04739]
101421928  EXOC7; exocyst complex component 7 [KO:K07195]
101421932  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
101422156  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
101422567  HK3; hexokinase-3 [KO:K00844] [EC:2.7.1.1]
101422617  SHC4; SHC-transforming protein 4 [KO:K17449]
101423002  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
101423038  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
101423093  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
101423692  PRKACB; LOW QUALITY PROTEIN: cAMP-dependent protein kinase catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
101423710  MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
101423744  [KO:K02649]
101424098  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
101424862  [KO:K03259]
101424990  CRK; adapter molecule crk isoform X1 [KO:K04438]
101425165  IRS2; LOW QUALITY PROTEIN: insulin receptor substrate 2 [KO:K07187]
101425404  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
101426352  ACACB; acetyl-CoA carboxylase 2 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
101426754  [KO:K00665] [EC:2.3.1.85]
101426945  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
101426965  CALM3; calmodulin-3 [KO:K02183]
101427602  PHKG2; LOW QUALITY PROTEIN: phosphorylase b kinase gamma catalytic chain, liver/testis isoform [KO:K00871] [EC:2.7.11.19]
101428270  PRKCZ; protein kinase C zeta type [KO:K18952] [EC:2.7.11.13]
101428387  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
101428509  PPP1R3C; protein phosphatase 1 regulatory subunit 3C isoform X1 [KO:K07189]
101428799  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
101428978  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
101429195  GCK; glucokinase [KO:K12407] [EC:2.7.1.2]
101429267  [KO:K07198] [EC:2.7.11.31]
101429566  [KO:K00844] [EC:2.7.1.1]
101429909  [KO:K15909] [EC:3.1.3.86]
101429999  RAPGEF1; rap guanine nucleotide exchange factor 1 isoform X2 [KO:K06277]
101430079  PYGM; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
101430169  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
101430299  [KO:K02183]
101430411  GYS1; glycogen [starch] synthase, muscle isoform X1 [KO:K00693] [EC:2.4.1.11]
101430424  PPP1R3A; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
101430570  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
101430635  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X4 [KO:K06086]
101430817  NRAS; GTPase NRas [KO:K07828]
101430930  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 [KO:K04372] [EC:2.7.11.1]
101431600  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X2 [KO:K07190]
101431948  PYGB; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
101431970  INSR; insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
101431993  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
101432391  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
101433051  SH2B2; SH2B adapter protein 2 isoform X2 [KO:K07193]
101433237  G6PC; glucose-6-phosphatase [KO:K01084] [EC:3.1.3.9]
101433259  RPTOR; regulatory-associated protein of mTOR [KO:K07204]
101433347  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
101433544  SOS2; son of sevenless homolog 2 [KO:K03099]
101434069  MTOR; LOW QUALITY PROTEIN: serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
101434210  RPS6KB2; ribosomal protein S6 kinase beta-2 [KO:K04688] [EC:2.7.11.1]
101434873  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
101434926  CRKL; crk-like protein isoform X1 [KO:K04438]
101434958  LIPE; hormone-sensitive lipase [KO:K07188] [EC:3.1.1.79]
101435143  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform [KO:K00871] [EC:2.7.11.19]
101435185  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial isoform X2 [KO:K01596] [EC:4.1.1.32]
101435268  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
101435282  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
101435351  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
101435520  [KO:K07194]
101435614  [KO:K04739]
101435742  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
101435845  FLOT1; flotillin-1 [KO:K07192]
101436765  PKLR; pyruvate kinase PKLR [KO:K12406] [EC:2.7.1.40]
101437067  PTPRF; receptor-type tyrosine-protein phosphatase F isoform X4 [KO:K05695] [EC:3.1.3.48]
101437367  IRS1; insulin receptor substrate 1 [KO:K16172]
101437415  [KO:K02183]
101438260  SHC1; SHC-transforming protein 1 [KO:K06279]
101439255  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
101439874  [KO:K04695]
101440357  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
101440385  SREBF1; sterol regulatory element-binding protein 1 [KO:K07197]
101440515  HKDC1; putative hexokinase HKDC1 isoform X1 [KO:K00844] [EC:2.7.1.1]
101440531  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
101440900  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
101441254  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
101441439  ACACA; acetyl-CoA carboxylase 1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
101441447  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
101441748  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
101442225  GYS2; glycogen [starch] synthase, liver isoform X1 [KO:K00693] [EC:2.4.1.11]
101442591  PHKB; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
101442966  RPS6; 40S ribosomal protein S6 [KO:K02991]
101443761  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
101444276  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
101444762  PPP1CA; LOW QUALITY PROTEIN: serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
101445596  [KO:K04345] [EC:2.7.11.11]
101445813  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
101446801  TSC1; hamartin isoform X1 [KO:K07206]
101446858  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
101446957  PPP1R3E; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
101447321  SHC2; SHC-transforming protein 2 [KO:K17447]
101447724  PPP1R3F; protein phosphatase 1 regulatory subunit 3F isoform X2 [KO:K17453]
101447889  PRKCI; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
105744587  [KO:K02183]
105745292  [KO:K07201]
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
dnm00010  Glycolysis / Gluconeogenesis
dnm00061  Fatty acid biosynthesis
dnm00500  Starch and sucrose metabolism
dnm04010  MAPK signaling pathway
dnm04070  Phosphatidylinositol signaling system
dnm04210  Apoptosis
KO pathway
ko04910   

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