Type I transforming growth factor β receptor binds to and activates phosphatidylinositol 3-kinase

Youn Yi Jae, Incheol Shin, Carlos L. Arteaga

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Abstract

We have examined the interaction of transforming growth factor (TGF) β receptors with phosphatidylinositol 3-(PI3) kinase in epithelial cells. In COS7 cells, treatment with TGFβ increased PI3 kinase activity as measured by the ability of p85-associated immune complexes to phosphorylate inositides in vitro. Both type I and type II TGFβ receptors (TβR) associated with p85, but the association of TβRII appeared to be constitutive. The interaction of TβRI with p85 was induced by treatment with TGFβ. The receptor association with PI3 kinase was not direct as 35S-labeled rabbit reticulocyte p85 did not couple with fusion proteins containing type I and type II receptors. A kinase-dead, dominant-negative mutant of TβRII blocked ligand-induced p85-TβRI association and PI3 kinase activity. In TβRI-null R1B cells, TGFβ did not stimulate PI3 kinase activity. This stimulation was restored upon reconstitution of TβRI by transfection. In R1B and NMuMG epithelial cells, overexpression of a dominant active mutant form of TβRI markedly enhanced ligand-independent PI3 kinase activity, which was blocked by the addition of the TβRI kinase inhibitor LY580278, suggesting a causal link between TβRI function and PI3 kinase. Overexpressed Smad7 also prevented ligand-induced PI3 kinase activity. Taken together, these data suggest that 1) TGFβ receptors can indirectly associate with p85, 2) both receptors are required for ligand-induced PI3 kinase activation, and 3) the activated TβRI serine-threonine kinase can potently induce PI3 kinase activity.

Original languageEnglish (US)
Pages (from-to)10870-10876
Number of pages7
JournalJournal of Biological Chemistry
Volume280
Issue number11
DOIs
StatePublished - Mar 18 2005

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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