Entry
Name
Insulin signaling pathway - Hippoglossus stenolepis (Pacific halibut)
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
BRITE hierarchy
Pathway map
Ortholog table
Organism
Hippoglossus stenolepis (Pacific halibut) [GN:
hsp ]
Gene
118102283 si:ch73-335l21.1; insulin receptor substrate 1-B isoform X2 [KO:K16172 ]
118114686 phosphatidylinositol 3-kinase regulatory subunit alpha-like isoform X1 [KO:K02649 ]
118117905 phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649 ]
118117936 pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649 ]
118120979 pik3r3b; phosphoinositide-3-kinase, regulatory subunit 3b (gamma) isoform X1 [KO:K02649 ]
118125392 pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649 ]
118120902 phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649 ]
118106261 pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922 ] [EC:2.7.1.153 ]
118111369 pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922 ] [EC:2.7.1.153 ]
118115119 ppp1r3c2b; protein phosphatase 1 regulatory subunit 3C-B-like [KO:K07189 ]
118110556 ppp1r3da; protein phosphatase 1, regulatory subunit 3Da [KO:K07189 ]
118111608 si:ch211-167b20.8; protein phosphatase 1 regulatory subunit 3A isoform X1 [KO:K07189 ]
118104758 ppp1r3db; protein phosphatase 1, regulatory subunit 3Db [KO:K07189 ]
118111451 phka2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190 ]
118102811 phka1a; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190 ]
118104524 phkb; phosphorylase b kinase regulatory subunit beta isoform X2 [KO:K07190 ]
118123233 prkacaa; protein kinase, cAMP-dependent, catalytic, alpha, genome duplicate a isoform X1 [KO:K04345 ] [EC:2.7.11.11 ]
118100630 cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739 ]
118123198 prkar1aa; protein kinase, cAMP-dependent, regulatory, type I, alpha (tissue specific extinguisher 1) a isoform X1 [KO:K04739 ]
118110770 prkar2aa; protein kinase, cAMP-dependent, regulatory, type II, alpha A [KO:K04739 ]
118123906 prkar1b; cAMP-dependent protein kinase type I-beta regulatory subunit isoform X1 [KO:K04739 ]
118104655 cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739 ]
118102310 solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191 ]
118125467 rapgef1b; rap guanine nucleotide exchange factor 1b isoform X1 [KO:K06277 ]
118123236 trip10a; cdc42-interacting protein 4 homolog isoform X1 [KO:K07196 ]
118123399 srebf1; sterol regulatory element-binding protein 1 isoform X3 [KO:K07197 ]
118115377 prkab1b; 5'-AMP-activated protein kinase subunit beta-1b isoform X1 [KO:K07199 ]
118117356 prkab2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199 ]
118125489 prkab1a; 5'-AMP-activated protein kinase subunit beta-1a isoform X1 [KO:K07199 ]
118117188 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200 ]
118103337 prkag3a; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200 ]
118119692 prkag3b; 5'-AMP-activated protein kinase subunit gamma-3b [KO:K07200 ]
118098708 5'-AMP-activated protein kinase subunit gamma-2-like isoform X1 [KO:K07200 ]
118102638 ppargc1a; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202 ]
118125634 rptor; LOW QUALITY PROTEIN: regulatory-associated protein of mTOR [KO:K07204 ]
118115008 eukaryotic translation initiation factor 4E-binding protein 2 [KO:K07205 ]
118125727 eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205 ]
118116198 eif4eb; LOW QUALITY PROTEIN: eukaryotic translation initiation factor 4eb [KO:K03259 ]
118117994 eif4e2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259 ]
118111847 eif4ea; eukaryotic translation initiation factor 4E-1A isoform X1 [KO:K03259 ]
118102841 eif4e2rs1; eukaryotic translation initiation factor 4E family member 2 related sequence 1 isoform X1 [KO:K03259 ]
118119063 eif4e1c; eukaryotic translation initiation factor 4E family member 1c [KO:K03259 ]
118123567 grb2b; growth factor receptor-bound protein 2b isoform X1 [KO:K04364 ]
Compound
C05981 Phosphatidylinositol-3,4,5-trisphosphate
Reference
Authors
Ogawa W, Kasuga M.
Title
[Mechanism of insulin action and diabetes mellitus]
Journal
Seikagaku 75:1332-44 (2003)
Reference
Authors
Bevan P.
Title
Insulin signalling.
Journal
J Cell Sci 114:1429-30 (2001)
Reference
Authors
Kanzaki M, Pessin JE.
Title
Insulin signaling: GLUT4 vesicles exit via the exocyst.
Journal
Reference
Authors
Moodie SA, Alleman-Sposeto J, Gustafson TA.
Title
Identification of the APS protein as a novel insulin receptor substrate.
Journal
Reference
Authors
Gual P, Le Marchand-Brustel Y, Tanti JF.
Title
Positive and negative regulation of insulin signaling through IRS-1 phosphorylation.
Journal
Reference
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
Reference
Authors
Saltiel AR, Kahn CR.
Title
Insulin signalling and the regulation of glucose and lipid metabolism.
Journal
Reference
Authors
Inoki K, Corradetti MN, Guan KL.
Title
Dysregulation of the TSC-mTOR pathway in human disease.
Journal
Reference
Authors
Ruggero D, Sonenberg N.
Title
The Akt of translational control.
Journal
Reference
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
Reference
Authors
Pullen N, Dennis PB, Andjelkovic M, Dufner A, Kozma SC, Hemmings BA, Thomas G.
Title
Phosphorylation and activation of p70s6k by PDK1.
Journal
Reference
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
Authors
Ceresa BP, Pessin JE.
Title
Insulin regulation of the Ras activation/inactivation cycle.
Journal
Mol Cell Biochem 182:23-9 (1998)
Reference
Authors
Pollak MN, Schernhammer ES, Hankinson SE.
Title
Insulin-like growth factors and neoplasia.
Journal
Reference
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
Reference
Authors
Ferre P, Foufelle F
Title
SREBP-1c transcription factor and lipid homeostasis: clinical perspective.
Journal
Reference
Authors
Raghow R, Yellaturu C, Deng X, Park EA, Elam MB
Title
SREBPs: the crossroads of physiological and pathological lipid homeostasis.
Journal
Reference
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
Reference
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
Related pathway
hsp04070 Phosphatidylinositol signaling system
KO pathway
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