KEGG   PATHWAY: mlx04910
Entry
mlx04910                    Pathway                                
Name
Insulin signaling pathway - Mirounga leonina (Southern elephant seal)
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
mlx04910  Insulin signaling pathway
mlx04910

Organism
Mirounga leonina (Southern elephant seal) [GN:mlx]
Gene
118015656  INS; insulin [KO:K04526]
118005442  INSR; insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
118011983  IRS1; insulin receptor substrate 1 [KO:K16172]
117999416  insulin receptor substrate 1-like [KO:K17445]
118010742  IRS4; insulin receptor substrate 4 [KO:K17446]
118016863  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
118019468  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
118006042  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
118004424  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
118020028  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
118006556  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
118021736  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
118022658  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
118002024  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
118014553  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
118007057  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
118025587  GYS2; glycogen [starch] synthase, liver isoform X1 [KO:K00693] [EC:2.4.1.11]
117998248  GYS1; glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
118007723  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
118016125  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
118018468  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
118023682  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
118010006  PPP1R3B; protein phosphatase 1 regulatory subunit 3B isoform X1 [KO:K07189]
118003368  PPP1R3E; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
118020998  PPP1R3A; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
118010390  PPP1R3F; protein phosphatase 1 regulatory subunit 3F isoform X1 [KO:K17453]
117999543  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform isoform X1 [KO:K00871] [EC:2.7.11.19]
117999585  PHKG2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform isoform X1 [KO:K00871] [EC:2.7.11.19]
118023818  PHKB; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
118026033  PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
118007336  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
118008161  CALM2; calmodulin-2 [KO:K02183]
118016596  calmodulin-1-like [KO:K02183]
118002566  CALM1; calmodulin-1 [KO:K02183]
118003137  CALML4; LOW QUALITY PROTEIN: calmodulin-like protein 4 [KO:K02183]
118012486  calmodulin-like [KO:K02183]
118019658  CALML6; calmodulin-like protein 6 [KO:K02183]
117998176  CALM3; calmodulin-3 [KO:K02183]
118020691  calmodulin-1-like [KO:K02183]
118021620  CALML3; calmodulin-like protein 3 [KO:K02183]
118021903  calmodulin-like [KO:K02183]
118016008  PYGM; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
118002384  PYGL; glycogen phosphorylase, liver form isoform X1 [KO:K00688] [EC:2.4.1.1]
118011161  PYGB; glycogen phosphorylase, brain form isoform X1 [KO:K00688] [EC:2.4.1.1]
118004181  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B isoform X1 [KO:K13296] [EC:3.1.4.17]
118005070  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
118019227  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
118024334  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit isoform X1 [KO:K04739]
118005696  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
118020618  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit [KO:K04739]
117999263  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit [KO:K04739]
117998053  LIPE; hormone-sensitive lipase isoform X1 [KO:K07188] [EC:3.1.1.79]
118020095  PRKCZ; protein kinase C zeta type [KO:K18952] [EC:2.7.11.13]
118006199  PRKCI; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
118000005  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 isoform X1 [KO:K07191]
118025269  FLOT2; flotillin-2 isoform X1 [KO:K07192]
118027363  FLOT1; flotillin-1 isoform X1 [KO:K07192]
118020204  LOW QUALITY PROTEIN: flotillin-2-like [KO:K07192]
117999452  SH2B2; SH2B adapter protein 2 isoform X1 [KO:K07193]
118024044  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X1 [KO:K06086]
118013312  CBL; E3 ubiquitin-protein ligase CBL isoform X1 [KO:K04707] [EC:2.3.2.27]
118007136  CBLB; E3 ubiquitin-protein ligase CBL-B [KO:K22517] [EC:2.3.2.27]
118025226  CRK; adapter molecule crk isoform X1 [KO:K04438]
117999812  CRKL; crk-like protein [KO:K04438]
118017569  RAPGEF1; rap guanine nucleotide exchange factor 1 isoform X1 [KO:K06277]
118008173  RHOQ; rho-related GTP-binding protein RhoQ [KO:K07194]
118024245  EXOC7; exocyst complex component 7 isoform X1 [KO:K07195]
118004898  TRIP10; cdc42-interacting protein 4 isoform X1 [KO:K07196]
118000153  SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
118024650  ACACA; acetyl-CoA carboxylase 1 isoform X1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
118018582  ACACB; acetyl-CoA carboxylase 2 isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
118024149  FASN; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
118013609  PKLR; pyruvate kinase PKLR isoform X1 [KO:K12406] [EC:2.7.1.40]
118007936  HK2; hexokinase-2 isoform X1 [KO:K00844] [EC:2.7.1.1]
118017078  HK3; hexokinase-3 isoform X1 [KO:K00844] [EC:2.7.1.1]
118018146  hexokinase HKDC1 [KO:K00844] [EC:2.7.1.1]
118018157  hexokinase-1 [KO:K00844] [EC:2.7.1.1]
118018915  hexokinase HKDC1 [KO:K00844] [EC:2.7.1.1]
118018931  hexokinase-1 [KO:K00844] [EC:2.7.1.1]
118024577  GCK; hexokinase-4 [KO:K12407] [EC:2.7.1.2]
118019366  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X1 [KO:K07198] [EC:2.7.11.31]
118006331  5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
118006463  5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
118000245  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199]
118018532  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
118008887  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
118026822  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
118012033  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 isoform X1 [KO:K07200]
118009481  FOXO1; forkhead box protein O1 [KO:K07201]
118010659  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
118024941  G6PC; glucose-6-phosphatase [KO:K01084] [EC:3.1.3.9]
118024966  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
118011813  G6PC2; glucose-6-phosphatase 2 [KO:K01084] [EC:3.1.3.9]
118023334  FBP2; fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
118023335  FBP1; fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
118023997  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] isoform X1 [KO:K01596] [EC:4.1.1.32]
118003117  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
118020008  MTOR; serine/threonine-protein kinase mTOR isoform X1 [KO:K07203] [EC:2.7.11.1]
118024187  RPTOR; regulatory-associated protein of mTOR [KO:K07204]
118016129  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
118024673  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
118015851  LOW QUALITY PROTEIN: 40S ribosomal protein S6-like [KO:K02991]
118002114  40S ribosomal protein S6-like [KO:K02991]
118017309  40S ribosomal protein S6-like [KO:K02991]
118018960  40S ribosomal protein S6-like [KO:K02991]
117999029  RPS6; 40S ribosomal protein S6 [KO:K02991]
118009966  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
118015501  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
118010310  EIF4E; eukaryotic translation initiation factor 4E [KO:K03259]
118011934  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
118017558  TSC1; hamartin isoform X1 [KO:K07206]
118021717  TSC2; tuberin isoform X1 [KO:K07207]
118026819  RHEB; GTP-binding protein Rheb [KO:K07208]
118016000  BAD; bcl2-associated agonist of cell death [KO:K02158]
118013864  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
118004996  SHC2; SHC-transforming protein 2 isoform X1 [KO:K17447]
118026255  SHC3; SHC-transforming protein 3 [KO:K17448]
118002971  SHC4; SHC-transforming protein 4 [KO:K17449]
118024273  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
118007794  SOS1; son of sevenless homolog 1 [KO:K03099]
118002069  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
118016228  HRAS; GTPase HRas isoform X1 [KO:K02833]
118025572  KRAS; GTPase KRas isoform X1 [KO:K07827]
118000495  NRAS; GTPase NRas [KO:K07828]
118009801  ARAF; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
118021159  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
118005431  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
118003336  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
118004882  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
117999637  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
117999826  MAPK1; mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:2.7.11.24]
118005009  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 isoform X1 [KO:K04372] [EC:2.7.11.1]
118019456  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X1 [KO:K04372] [EC:2.7.11.1]
118009849  ELK1; ETS domain-containing protein Elk-1 isoform X1 [KO:K04375]
118021940  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
117998887  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
118024211  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
118002023  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
118023969  PTPN1; tyrosine-protein phosphatase non-receptor type 1 isoform X1 [KO:K05696] [EC:3.1.3.48]
118019521  PTPRF; receptor-type tyrosine-protein phosphatase F isoform X1 [KO:K05695] [EC:3.1.3.48]
118022776  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
118010368  mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
118026506  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
118009921  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
118003950  INPPL1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 isoform X1 [KO:K15909] [EC:3.1.3.86]
117997970  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
mlx00010  Glycolysis / Gluconeogenesis
mlx00061  Fatty acid biosynthesis
mlx00500  Starch and sucrose metabolism
mlx04010  MAPK signaling pathway
mlx04070  Phosphatidylinositol signaling system
mlx04210  Apoptosis
KO pathway
ko04910   
LinkDB

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