Gene interactions and pathways from curated databases and text-mining
Proc Natl Acad Sci U S A 2001, PMID: 11287630

A phosphatidylinositol 3-kinase/Akt/mTOR pathway mediates and PTEN antagonizes tumor necrosis factor inhibition of insulin signaling through insulin receptor substrate-1.

Ozes, O N; Akca, H; Mayo, L D; Gustin, J A; Maehama, T; Dixon, J E; Donner, D B

Tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) by the insulin receptor permits this docking protein to interact with signaling proteins that promote insulin action. Serine phosphorylation uncouples IRS-1 from the insulin receptor, thereby inhibiting its tyrosine phosphorylation and insulin signaling. For this reason, there is great interest in identifying serine/threonine kinases for which IRS-1 is a substrate. Tumor necrosis factor (TNF) inhibited insulin-promoted tyrosine phosphorylation of IRS-1 and activated the Akt/protein kinase B serine-threonine kinase, a downstream target for phosphatidylinositol 3-kinase (PI 3-kinase). The effect of TNF on insulin-promoted tyrosine phosphorylation of IRS-1 was blocked by inhibition of PI 3-kinase and the PTEN tumor suppressor, which dephosphorylates the lipids that mediate PI 3-kinase functions, whereas constitutively active Akt impaired insulin-promoted IRS-1 tyrosine phosphorylation. Conversely, TNF inhibition of IRS-1 tyrosine phosphorylation was blocked by kinase dead Akt. Inhibition of IRS-1 tyrosine phosphorylation by TNF was blocked by rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), a downstream target of Akt. mTOR induced the serine phosphorylation of IRS-1 (Ser-636/639), and such phosphorylation was inhibited by rapamycin. These results suggest that TNF impairs insulin signaling through IRS-1 by activation of a PI 3-kinase/Akt/mTOR pathway, which is antagonized by PTEN.

Diseases/Pathways annotated by Medline MESH: Insulin Resistance
Document information provided by NCBI PubMed

Text Mining Data

insulin ⊣ tumor necrosis factor: " A phosphatidylinositol 3-kinase/Akt/mTOR pathway mediates and PTEN antagonizes tumor necrosis factor inhibition of insulin signaling through insulin receptor substrate-1 "

IRS-1 ⊣ Tumor necrosis factor (TNF): " Tumor necrosis factor (TNF) inhibited insulin promoted tyrosine phosphorylation of IRS-1 and activated the Akt/protein kinase B serine-threonine kinase, a downstream target for phosphatidylinositol 3-kinase ( PI 3-kinase ) "

serine-threonine kinase → Tumor necrosis factor (TNF): " Tumor necrosis factor (TNF) inhibited insulin promoted tyrosine phosphorylation of IRS-1 and activated the Akt/protein kinase B serine-threonine kinase , a downstream target for phosphatidylinositol 3-kinase ( PI 3-kinase ) "

IRS-1 ⊣ PI 3-kinase: " The effect of TNF on insulin promoted tyrosine phosphorylation of IRS-1 was blocked by inhibition of PI 3-kinase and the PTEN tumor suppressor, which dephosphorylates the lipids that mediate PI 3-kinase functions, whereas constitutively active Akt impaired insulin promoted IRS-1 tyrosine phosphorylation "

IRS-1 — TNF: " The effect of TNF on insulin promoted tyrosine phosphorylation of IRS-1 was blocked by inhibition of PI 3-kinase and the PTEN tumor suppressor, which dephosphorylates the lipids that mediate PI 3-kinase functions, whereas constitutively active Akt impaired insulin promoted IRS-1 tyrosine phosphorylation "

IRS-1 ⊣ TNF: " Conversely, TNF inhibition of IRS-1 tyrosine phosphorylation was blocked by kinase dead Akt "

TNF → Akt: " Conversely, TNF inhibition of IRS-1 tyrosine phosphorylation was blocked by kinase dead Akt "

IRS-1 → Akt: " Conversely, TNF inhibition of IRS-1 tyrosine phosphorylation was blocked by kinase dead Akt "

IRS-1 → mTOR: " mTOR induced the serine phosphorylation of IRS-1 ( Ser-636/639 ), and such phosphorylation was inhibited by rapamycin "

insulin ⊣ TNF: " These results suggest that TNF impairs insulin signaling through IRS-1 by activation of a PI 3-kinase/Akt/mTOR pathway, which is antagonized by PTEN "

Manually curated Databases

  • IRef Biogrid Interaction: IRS1 — MTOR (physical association, affinity chromatography technology)
  • IRef Hprd Interaction: IRS1 — MTOR (in vitro)
  • NCI Pathway Database mTOR signaling pathway: mTORC1 complex (MTOR-MLST8-RPTOR) → IRS1 (IRS1) (modification, activates)
    Evidence: mutant phenotype, assay
  • NCI Pathway Database mTOR signaling pathway: mTORC1 complex (MTOR-MLST8-RPTOR) → p70S6K (RPS6KB1) (modification, activates)
    Evidence: mutant phenotype, assay
  • NCI Pathway Database Insulin Pathway: Insulin Receptor/Insulin/SHC complex (INSR-INS-SHC1) → Insulin Receptor/Insulin/IRS1 complex (INSR-INS-IRS1) (modification, collaborate)
  • NCI Pathway Database Insulin Pathway: Insulin Receptor/Insulin/SHC complex (INSR-INS-SHC1) → IRS1 (IRS1) (modification, collaborate)
  • NCI Pathway Database Insulin Pathway: Insulin Receptor/Insulin/SHC complex (INSR-INS-SHC1) → Insulin Receptor/Insulin complex (INSR-INS) (modification, collaborate)
  • NCI Pathway Database Insulin Pathway: Insulin Receptor/Insulin/SHC complex (INSR-INS-SHC1) → SHC (SHC1) (modification, collaborate)
  • NCI Pathway Database Insulin Pathway: Insulin Receptor/Insulin/IRS1 complex (INSR-INS-IRS1) → IRS1 (IRS1) (modification, collaborate)
  • NCI Pathway Database Insulin Pathway: Insulin Receptor/Insulin/IRS1 complex (INSR-INS-IRS1) → Insulin Receptor/Insulin complex (INSR-INS) (modification, collaborate)
  • NCI Pathway Database Insulin Pathway: Insulin Receptor/Insulin/IRS1 complex (INSR-INS-IRS1) → SHC (SHC1) (modification, collaborate)
  • NCI Pathway Database Insulin Pathway: IRS1 (IRS1) → Insulin Receptor/Insulin complex (INSR-INS) (modification, collaborate)
  • NCI Pathway Database Insulin Pathway: IRS1 (IRS1) → SHC (SHC1) (modification, collaborate)
  • NCI Pathway Database Insulin Pathway: Insulin Receptor/Insulin complex (INSR-INS) → SHC (SHC1) (modification, collaborate)
In total, 19 gene pairs are associated to this article in curated databases