Cancer-derived mutations in the regulatory subunit p85α of phosphoinositide 3-kinase function through the catalytic subunit p110α

Cancer-specific mutations in the iSH2 (inter-SH2) and nSH2 (N-terminal SH2) domains of p85α, the regulatory subunit of phosphatidylinositide 3-kinase (PI3K), show gain of function. They induce oncogenic cellular transformation, stimulate cellular proliferation, and enhance PI3K signaling. Quantitative determinations of oncogenic activity reveal large differences between individual mutants of p85α. The mutant proteins are still able to bind to the catalytic subunits p110α and p110β. Studies with isoform-specific inhibitors of p110 suggest that expression of p85 mutants in fibroblasts leads exclusively to an activation of p110α, and p110α is the sole mediator of p85 mutant-induced oncogenic transformation. The characteristics of the p85 mutants are in agreement with the hypothesis that the mutations weaken an inhibitory interaction between p85α and p110α while preserving the stabilizing interaction between p85α iSH2 and the adapter-binding domain of p110α.