Gene interactions and pathways from curated databases and text-mining
J Biol Chem 2009, PMID: 19561084

Raptor binds the SAIN (Shc and IRS-1 NPXY binding) domain of insulin receptor substrate-1 (IRS-1) and regulates the phosphorylation of IRS-1 at Ser-636/639 by mTOR.

Tzatsos, Alexandros

In normal physiological states mTOR phosphorylates and activates Akt. However, under diabetic-mimicking conditions mTOR inhibits phosphatidylinositol (PI) 3-kinase/Akt signaling by phosphorylating insulin receptor substrate-1 (IRS-1) at Ser-636/639. The molecular basis for the differential effect of mTOR signaling on Akt is poorly understood. Here, it has been shown that knockdown of mTOR, Raptor, and mLST8, but not Rictor and mSin1, suppresses insulin-stimulated phosphorylation of IRS-1 at Ser-636/639 and stabilizes IRS-1 after long term insulin stimulation. This phosphorylation depends on the PI 3-kinase/PDK1 axis but is Akt-independent. At the molecular level, Raptor binds the SAIN (Shc and IRS-1 NPXY binding) domain of IRS-1 and regulates the phosphorylation of IRS-1 at Ser-636/639 by mTOR. IRS-1 lacking the SAIN domain does not interact with Raptor, is not phosphorylated at Ser-636/639, and favorably interacts with PI 3-kinase. Overall, these data provide new insights in the molecular mechanisms by which mTORC1 inhibits PI 3-kinase/Akt signaling at the level of IRS-1 and suggest that mTOR signaling toward Akt is scaffold-dependent.

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Text Mining Data

IRS-1 → Raptor: " Raptor binds the SAIN ( Shc and IRS-1 NPXY binding ) domain of insulin receptor substrate-1 (IRS-1) and regulates the phosphorylation of IRS-1 at Ser-636/639 by mTOR "

Akt → mTOR: " In normal physiological states mTOR phosphorylates and activates Akt "

3-kinase/Akt ⊣ mTOR: " However, under diabetic mimicking conditions mTOR inhibits phosphatidylinositol (PI) 3-kinase/Akt signaling by phosphorylating insulin receptor substrate-1 (IRS-1) at Ser-636/639 "

3-kinase/Akt ⊣ insulin receptor substrate-1 (IRS-1): " However, under diabetic mimicking conditions mTOR inhibits phosphatidylinositol (PI) 3-kinase/Akt signaling by phosphorylating insulin receptor substrate-1 (IRS-1) at Ser-636/639 "

phosphatidylinositol (PI) 3-kinase/Akt ⊣ mTOR: " However, under diabetic mimicking conditions mTOR inhibits phosphatidylinositol (PI) 3-kinase/Akt signaling by phosphorylating insulin receptor substrate-1 (IRS-1) at Ser-636/639 "

phosphatidylinositol (PI) 3-kinase/Akt ⊣ insulin receptor substrate-1 (IRS-1): " However, under diabetic mimicking conditions mTOR inhibits phosphatidylinositol (PI) 3-kinase/Akt signaling by phosphorylating insulin receptor substrate-1 (IRS-1) at Ser-636/639 "

Akt — mTOR signaling: " The molecular basis for the differential effect of mTOR signaling on Akt is poorly understood "

IRS-1 → insulin: " Here, it has been shown that knockdown of mTOR, Raptor, and mLST8, but not Rictor and mSin1, suppresses insulin stimulated phosphorylation of IRS-1 at Ser-636/639 and stabilizes IRS-1 after long term insulin stimulation "

IRS-1 → Raptor: " At the molecular level, Raptor binds the SAIN ( Shc and IRS-1 NPXY binding ) domain of IRS-1 and regulates the phosphorylation of IRS-1 at Ser-636/639 by mTOR "

3-kinase/Akt ⊣ mTORC1: " Overall, these data provide new insights in the molecular mechanisms by which mTORC1 inhibits PI 3-kinase/Akt signaling at the level of IRS-1 and suggest that mTOR signaling toward Akt is scaffold dependent "

PI 3-kinase/Akt ⊣ mTORC1: " Overall, these data provide new insights in the molecular mechanisms by which mTORC1 inhibits PI 3-kinase/Akt signaling at the level of IRS-1 and suggest that mTOR signaling toward Akt is scaffold dependent "

Manually curated Databases

  • IRef Biogrid Interaction: IRS2 — RPTOR (direct interaction, pull down)
  • IRef Biogrid Interaction: IRS2 — PIK3R1 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: IRS1 — PIK3R1 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: IRS1 — RPTOR (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: IRS1 — RPTOR (direct interaction, pull down)
In total, 4 gene pairs are associated to this article in curated databases