RGD Reference Report - Nutrients suppress phosphatidylinositol 3-kinase/Akt signaling via raptor-dependent mTOR-mediated insulin receptor substrate 1 phosphorylation. - Rat Genome Database

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Nutrients suppress phosphatidylinositol 3-kinase/Akt signaling via raptor-dependent mTOR-mediated insulin receptor substrate 1 phosphorylation.

Authors: Tzatsos, A  Kandror, KV 
Citation: Tzatsos A and Kandror KV, Mol Cell Biol. 2006 Jan;26(1):63-76.
RGD ID: 1625606
Pubmed: PMID:16354680   (View Abstract at PubMed)
PMCID: PMC1317643   (View Article at PubMed Central)
DOI: DOI:10.1128/MCB.26.1.63-76.2006   (Journal Full-text)

Nutritional excess and/or obesity represent well-known predisposition factors for the development of non-insulin-dependent diabetes mellitus (NIDDM). However, molecular links between obesity and NIDDM are only beginning to emerge. Here, we demonstrate that nutrients suppress phosphatidylinositol 3 (PI3)-kinase/Akt signaling via Raptor-dependent mTOR (mammalian target of rapamycin)-mediated phosphorylation of insulin receptor substrate 1 (IRS-1). Raptor directly binds to and serves as a scaffold for mTOR-mediated phosphorylation of IRS-1 on Ser636/639. These serines lie close to the Y(632)MPM motif that is implicated in the binding of p85alpha/p110alpha PI3-kinase to IRS-1 upon insulin stimulation. Phosphomimicking mutations of these serines block insulin-stimulated activation of IRS-1-associated PI3-kinase. Knockdown of Raptor as well as activators of the LKB1/AMPK pathway, such as the widely used antidiabetic compound metformin, suppress IRS-1 Ser636/639 phosphorylation and reverse mTOR-mediated inhibition on PI3-kinase/Akt signaling. Thus, diabetes-related hyperglycemia hyperactivates the mTOR pathway and may lead to insulin resistance due to suppression of IRS-1-dependent PI3-kinase/Akt signaling.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
RhebRatsmall GTPase-mediated signal transduction  IDA  RGD 

Molecular Function

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
RhebRatGDP binding  IDA  RGD 
RhebRatGTP binding  IDA  RGD 
RhebRatGTPase activity  IDA  RGD 

Molecular Pathway Annotations    Click to see Annotation Detail View

RGD Manual Annotations


  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
RHEBHumanmTOR signaling pathway   ISORheb (Rattus norvegicus) RGD 
RhebRatmTOR signaling pathway   IDA  RGD 
RhebMousemTOR signaling pathway   ISORheb (Rattus norvegicus) RGD 
Objects Annotated

Genes (Rattus norvegicus)
Rheb  (Ras homolog, mTORC1 binding)

Genes (Mus musculus)
Rheb  (Ras homolog enriched in brain)

Genes (Homo sapiens)
RHEB  (Ras homolog, mTORC1 binding)


Additional Information