RGD Reference Report - Tyrosine phosphorylation of phosphoinositide-dependent kinase 1 by the insulin receptor is necessary for insulin metabolic signaling. - Rat Genome Database

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Tyrosine phosphorylation of phosphoinositide-dependent kinase 1 by the insulin receptor is necessary for insulin metabolic signaling.

Authors: Fiory, F  Alberobello, AT  Miele, C  Oriente, F  Esposito, I  Corbo, V  Ruvo, M  Tizzano, B  Rasmussen, TE  Gammeltoft, S  Formisano, P  Beguinot, F 
Citation: Fiory F, etal., Mol Cell Biol. 2005 Dec;25(24):10803-14.
RGD ID: 1581774
Pubmed: PMID:16314505   (View Abstract at PubMed)
PMCID: PMC1316974   (View Article at PubMed Central)
DOI: DOI:10.1128/MCB.25.24.10803-10814.2005   (Journal Full-text)

In L6 myoblasts, insulin receptors with deletion of the C-terminal 43 amino acids (IR(Delta43)) exhibited normal autophosphorylation and IRS-1/2 tyrosine phosphorylation. The L6 cells expressing IR(Delta43) (L6(IRDelta43)) also showed no insulin effect on glucose uptake and glycogen synthase, accompanied by a >80% decrease in insulin induction of 3-phosphoinositide-dependent protein kinase 1 (PDK-1) activity and tyrosine phosphorylation and of protein kinase B (PKB) phosphorylation at Thr(308). Insulin induced the phosphatidylinositol 3 kinase-dependent coprecipitation of PDK-1 with wild-type IR (IR(WT)), but not IR(Delta43). Based on overlay blotting, PDK-1 directly bound IR(WT), but not IR(Delta43). Insulin-activated IR(WT), and not IR(Delta43), phosphorylated PDK-1 at tyrosines 9, 373, and 376. The IR C-terminal 43-amino-acid peptide (C-terminal peptide) inhibited in vitro PDK-1 tyrosine phosphorylation by the IR. Tyr-->Phe substitution prevented this inhibitory action. In the L6(hIR) cells, the C-terminal peptide coprecipitated with PDK-1 in an insulin-stimulated fashion. This peptide simultaneously impaired the insulin effect on PDK-1 coprecipitation with IR(WT), on PDK-1 tyrosine phosphorylation, on PKB phosphorylation at Thr(308), and on glucose uptake. Upon insulin exposure, PDK-1 membrane persistence was significantly reduced in L6(IRDelta43) compared to control cells. In L6 cells expressing IR(WT), the C-terminal peptide also impaired insulin-dependent PDK-1 membrane persistence. Thus, PDK-1 directly binds to the insulin receptor, followed by PDK-1 activation and insulin metabolic effects.

Gene Ontology Annotations    Click to see Annotation Detail View

Molecular Function

Objects Annotated

Genes (Rattus norvegicus)
Insr  (insulin receptor)
Pdpk1  (3-phosphoinositide dependent protein kinase-1)

Objects referenced in this article
Gene PDPK1 3-phosphoinositide dependent protein kinase 1 Homo sapiens
Gene Pdpk1 3-phosphoinositide dependent protein kinase 1 Mus musculus

Additional Information