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Papers In Press, published online ahead of print June 2, 2005
J. Biol. Chem, 10.1074/jbc.M506005200
Submitted on June 2, 2005
Accepted on June 2, 2005

Mechanism of constitutive PI 3-kinase activation by oncogenic mutants of the p85 regulatory subunit

S. C. Shekar, Haiyan Wu, Zheng Fu, Shu-Chin Yip, Sean M. Cahill, Mark E. Girvin, and Jonathan M. Backer

Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461

Corresponding Author: backer{at}aecom.yu.edu

p85/p110 PI 3-kinases regulate multiple cell functions, and are frequently mutated in human cancer. The p85 regulatory subunit stabilizes and inhibits the p110 catalytic subunit. The minimal fragment of p85 capable of regulating p110 is the N-terminal SH2 domain linked to the coiled-coil iSH2 domain (referred to as p85ni). We have previously proposed that the conformationally rigid iSH2 domain tethers p110 to p85, facilitating regulatory interactions between p110 and the p85 nSH2 domain. In an oncogenic mutant of murine p85, truncation at residue 571 leads to constitutively increased PI 3-kinase activity, which has been proposed to result from either loss of an inhibitory Ser608 autophosphorylation site or loss of interactions with cellular regulatory factors. We have examined this mutant (referred to as p65) in vitro, and find that p65 binds but does not inhibit p110, leading to constitutive p110 activity. This activated phenotype is observed with recombinant proteins, in the absence of cellular factors. Importantly, this effect is also produced by truncating p85ni at residue 571. Thus, the phenotype is not due to loss of the Ser608 inhibitory autophosphorylation site, which is not present in p85ni. To determine the structural basis for the phenotype of p65, we used a broadly-applicable spin label/ NMR approach to define the positioning of the nSH2 domain relative to the iSH2 domain. We find that one face of the nSH2 domain packs against the 581-593 region of the iSH2 domain. The loss of this interaction in the truncated p65 would remove the orienting constraints on the nSH2 domain, leading to a loss of p110 regulation by the nSH2. Based on these findings, we propose a general model for oncogenic mutants of p85 and p110, in which disruption of nSH2-p110 regulatory contacts leads to constitutive p110 activity.


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