Proc Natl Acad Sci U S A 2001,
PMID: 11287630
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