KEGG   PATHWAY: mmur04910
Entry
mmur04910                   Pathway                                
Name
Insulin signaling pathway - Microcebus murinus (gray mouse lemur)
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
mmur04910  Insulin signaling pathway
mmur04910

Organism
Microcebus murinus (gray mouse lemur) [GN:mmur]
Gene
105859822  INS; insulin [KO:K04526]
105869687  insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
105862871  IRS1; insulin receptor substrate 1 [KO:K16172]
105864251  IRS2; insulin receptor substrate 2 isoform X1 [KO:K07187]
105868385  insulin receptor substrate 1-like [KO:K17445]
105863379  IRS4; insulin receptor substrate 4 [KO:K17446]
105881219  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
105855026  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
105877483  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
105862660  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
105855821  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
105886063  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
105859676  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
105861093  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
105876768  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
105863738  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
105879917  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
105882789  GYS2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
105865598  GYS1; glycogen [starch] synthase, muscle isoform X1 [KO:K00693] [EC:2.4.1.11]
105867474  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
105868044  serine/threonine-protein phosphatase PP1-gamma catalytic subunit B-like [KO:K06269] [EC:3.1.3.16]
105884438  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
105856600  serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
105880930  PPP1CC; LOW QUALITY PROTEIN: serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
105855281  PPP1R3A; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
105864653  PPP1R3E; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
105857453  PPP1R3B; protein phosphatase 1 regulatory subunit 3B [KO:K07189]
105864836  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
105872005  PPP1R3C; protein phosphatase 1 regulatory subunit 3C isoform X1 [KO:K07189]
105856421  PPP1R3F; protein phosphatase 1 regulatory subunit 3F isoform X1 [KO:K17453]
105871018  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform isoform X1 [KO:K00871] [EC:2.7.11.19]
105871065  PHKG2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform [KO:K00871] [EC:2.7.11.19]
105882194  PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
105882375  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
105876207  PHKB; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
105867016  CALM2; calmodulin [KO:K02183]
105876291  CALM1; calmodulin [KO:K02183]
105869569  CALM3; calmodulin [KO:K02183]
105870055  calmodulin-like [KO:K02183]
105877681  CALML6; LOW QUALITY PROTEIN: calmodulin-like protein 6 [KO:K02183]
105858210  calmodulin-alpha-like [KO:K02183]
105873434  CALML4; calmodulin-like protein 4 [KO:K02183]
105867685  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
105860646  PYGB; LOW QUALITY PROTEIN: glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
105878488  PYGM; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
105879994  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
105867963  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
105861780  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X2 [KO:K04345] [EC:2.7.11.11]
105874939  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit isoform X1 [KO:K04739]
105861036  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit [KO:K04739]
105868353  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit isoform X1 [KO:K04739]
105861688  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
105868011  LIPE; hormone-sensitive lipase isoform X1 [KO:K07188] [EC:3.1.1.79]
105877684  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
105879189  PRKCI; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
105877856  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
105855400  FLOT1; flotillin-1 isoform X1 [KO:K07192]
105857897  FLOT2; flotillin-2 isoform X1 [KO:K07192]
105868276  SH2B2; SH2B adapter protein 2 isoform X1 [KO:K07193]
105872499  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X1 [KO:K06086]
105876096  CBL; E3 ubiquitin-protein ligase CBL [KO:K04707] [EC:2.3.2.27]
105878030  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
105877776  CRKL; crk-like protein [KO:K04438]
105857910  CRK; adapter molecule crk isoform X1 [KO:K04438]
105859859  RAPGEF1; rap guanine nucleotide exchange factor 1 isoform X1 [KO:K06277]
105866500  RHOQ; rho-related GTP-binding protein RhoQ [KO:K07194]
105878963  EXOC7; exocyst complex component 7 isoform X1 [KO:K07195]
105869680  TRIP10; cdc42-interacting protein 4 isoform X1 [KO:K07196]
105861966  SREBF1; sterol regulatory element-binding protein 1 isoform X2 [KO:K07197]
105879961  ACACA; acetyl-CoA carboxylase 1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
105866938  ACACB; acetyl-CoA carboxylase 2 isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
105878096  FASN; LOW QUALITY PROTEIN: fatty acid synthase [KO:K00665] [EC:2.3.1.85]
105873168  PKLR; pyruvate kinase PKLR isoform X1 [KO:K12406] [EC:2.7.1.40]
105883841  HK3; hexokinase-3 isoform X1 [KO:K00844] [EC:2.7.1.1]
105884567  HK2; hexokinase-2 [KO:K00844] [EC:2.7.1.1]
105870209  HK1; hexokinase-1 isoform X1 [KO:K00844] [EC:2.7.1.1]
105870210  HKDC1; putative hexokinase HKDC1 isoform X1 [KO:K00844] [EC:2.7.1.1]
105858409  GCK; glucokinase isoform X1 [KO:K12407] [EC:2.7.1.2]
105882576  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
105878394  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X2 [KO:K07198] [EC:2.7.11.31]
105866904  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
105869807  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199]
105883193  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
105869461  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
105857701  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 isoform X1 [KO:K07200]
105868033  FOXO1; forkhead box protein O1 [KO:K07201]
105856056  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
105859453  G6PC; glucose-6-phosphatase isoform X1 [KO:K01084] [EC:3.1.3.9]
105883539  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
105880680  G6PC2; glucose-6-phosphatase 2 isoform X1 [KO:K01084] [EC:3.1.3.9]
105862136  FBP1; LOW QUALITY PROTEIN: fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
105855616  fructose-1,6-bisphosphatase isozyme 2-like isoform X1 [KO:K03841] [EC:3.1.3.11]
105855618  fructose-1,6-bisphosphatase isozyme 2-like [KO:K03841] [EC:3.1.3.11]
105874534  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
105866581  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
105886039  MTOR; serine/threonine-protein kinase mTOR isoform X1 [KO:K07203] [EC:2.7.11.1]
105884979  RPTOR; LOW QUALITY PROTEIN: regulatory-associated protein of mTOR [KO:K07204]
105867475  RPS6KB2; ribosomal protein S6 kinase beta-2 [KO:K04688] [EC:2.7.11.1]
105874527  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
105874134  RPS6; 40S ribosomal protein S6 [KO:K02991]
105870389  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
105863198  LOW QUALITY PROTEIN: eukaryotic translation initiation factor 4E type 1B-like [KO:K03259]
105856581  EIF4E; eukaryotic translation initiation factor 4E [KO:K03259]
105886161  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
105857723  eukaryotic translation initiation factor 4E type 1B-like [KO:K03259]
105880452  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
105873486  eukaryotic translation initiation factor 4E type 2 [KO:K03259]
105859868  TSC1; hamartin isoform X1 [KO:K07206]
105859584  TSC2; tuberin isoform X1 [KO:K07207]
105883192  RHEB; GTP-binding protein Rheb isoform X1 [KO:K07208]
105878474  BAD; bcl2-associated agonist of cell death [KO:K02158]
105873192  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
105860825  SHC2; SHC-transforming protein 2 isoform X1 [KO:K17447]
105876163  SHC3; SHC-transforming protein 3 isoform X1 [KO:K17448]
105870730  SHC4; SHC-transforming protein 4 isoform X1 [KO:K17449]
105878936  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
105867678  SOS2; son of sevenless homolog 2 [KO:K03099]
105884529  SOS1; son of sevenless homolog 1 [KO:K03099]
105874032  HRAS; GTPase HRas [KO:K02833]
105857286  KRAS; GTPase KRas isoform X1 [KO:K07827]
105878710  NRAS; GTPase NRas [KO:K07828]
105862190  ARAF; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:2.7.11.1]
105873244  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
105882676  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
105868083  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
105873938  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
105870697  mitogen-activated protein kinase 6-like [KO:K04371] [EC:2.7.11.24]
105877796  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
105871124  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
105860751  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 [KO:K04372] [EC:2.7.11.1]
105877503  MOB3C; MOB kinase activator 3C isoform X1 [KO:K04372] [EC:2.7.11.1]
105862174  ELK1; ETS domain-containing protein Elk-1 [KO:K04375]
105882429  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
105867161  suppressor of cytokine signaling 2-like [KO:K04695]
105868494  suppressor of cytokine signaling 2-like [KO:K04695]
105868495  suppressor of cytokine signaling 2-like [KO:K04695]
105877066  SOCS2; suppressor of cytokine signaling 2 isoform X1 [KO:K04695]
109730136  uncharacterized protein LOC109730136 isoform X1 [KO:K04695]
105866738  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
105867701  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
105872274  PTPN1; tyrosine-protein phosphatase non-receptor type 1 isoform X1 [KO:K05696] [EC:3.1.3.48]
105877423  PTPRF; receptor-type tyrosine-protein phosphatase F [KO:K05695] [EC:3.1.3.48]
105860097  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
105874790  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
105864291  mitogen-activated protein kinase 10-like isoform X1 [KO:K04440] [EC:2.7.11.24]
105865754  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
105878144  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
105860386  INPPL1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 isoform X1 [KO:K15909] [EC:3.1.3.86]
109729444  type I inositol 1,4,5-trisphosphate 5-phosphatase-like isoform X1 [KO:K01106] [EC:3.1.3.56]
105866235  type I inositol 1,4,5-trisphosphate 5-phosphatase isoform X1 [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
mmur00010  Glycolysis / Gluconeogenesis
mmur00061  Fatty acid biosynthesis
mmur00500  Starch and sucrose metabolism
mmur04010  MAPK signaling pathway
mmur04070  Phosphatidylinositol signaling system
mmur04210  Apoptosis
KO pathway
ko04910   
LinkDB

DBGET integrated database retrieval system