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J Biol Chem, Vol. 273, Issue 46, 30199-30203, November 13, 1998
Phosphatidylinositol 3'-Kinase
From the Department of Molecular Pharmacology, Albert Einstein
College of Medicine, Bronx, New York 10461
Our previous studies on the p85/p110
phosphatidylinositol 3-kinase showed that the p85 regulatory subunit
inhibits the p110 catalytic subunit, and that phosphopeptide
activation of p85/p110 dimers reflects a disinhibition of p110
(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 p110. The iSH2 domain of p85 is sufficient to bind p110 but
does not inhibit it. Inhibition of p110 requires the presence of the
nSH2 domain linked to the iSH2 domain. Phosphopeptides increase the
activity of nSH2/iSH2-p110 dimers, demonstrating that the nSH2
domain mediates both inhibition of p110 and disinhibition by
phosphopeptides. In contrast, phosphopeptides did not increase the
activity of iSH2/cSH2-p110 dimers, or dimers composed of p110 and
an nSH2/iSH2/cSH2 construct containing a mutant nSH2 domain.
Phosphopeptide binding to the cSH2 domain increased p110 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-homolgy domains). These data suggest that the nSH2 domain of p85
is a direct regulator of p110 activity. Regulation of p110 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.
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