Regulation of the p85/p110α phosphatidylinositol 3'-kinase

Distinct roles for the n-terminal and c-terminal sh2 domains

Jinghua Yu, Christina Wjasow, Jonathan M. Backer

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Abstract

Our previous studies on the p85/p110α phosphatidylinositol 3-kinase showed that the p85 regulatory subunit inhibits the p110α catalytic subunit, and that phosphopeptide activation of p85/p110α dimers reflects a disinhibition of p110α (Yu, J., Zhang, Y., McIlroy, J., Rordorf-Nikolic, T., Orr, G. A., and Backer, J. M. (1998) Mol. Cell. Biol. 18, 1379-1387). We now define the domains of p85 required for inhibition of p110α. The iSH2 domain of p85 is sufficient to bind p110α but does not inhibit it. Inhibition of p110α requires the presence of the nSH2 domain linked to the iSH2 domain. Phosphopeptides increase the activity of nSH2/iSH2-p110α dimers, demonstrating that the nSH2 domain mediates both inhibition of p110α and disinhibition by phosphopeptides. In contrast, phosphopeptides did not increase the activity of iSH2/cSH2-p110α, dimers, or dimers composed of p110α and an nSH2/iSH2/cSH2 construct containing a mutant nSH2 domain. Phosphopeptide binding to the cSH2 domain increased p110α activity only in the context of an intact p85 containing both the nSH2 domain and residues 1- 322 (the SH3, proline-rich and breakpoint cluster region-homology domains). These data suggest that the nSH2 domain of p85 is a direct regulator of p110α activity. Regulation of p110α by phosphopeptide binding to the cSH2 domain occurs by a mechanism that requires the additional presence of the nSH2 domain and residues 1-322 of p85.

Original languageEnglish (US)
Pages (from-to)30199-30203
Number of pages5
JournalJournal of Biological Chemistry
Volume273
Issue number46
DOIs
StatePublished - Nov 13 1998

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Phosphatidylinositol 3-Kinase
Phosphopeptides
Dimers
Proline
Catalytic Domain
Chemical activation

ASJC Scopus subject areas

  • Biochemistry

Cite this

Regulation of the p85/p110α phosphatidylinositol 3'-kinase : Distinct roles for the n-terminal and c-terminal sh2 domains. / Yu, Jinghua; Wjasow, Christina; Backer, Jonathan M.

In: Journal of Biological Chemistry, Vol. 273, No. 46, 13.11.1998, p. 30199-30203.

Research output: Contribution to journalArticle

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