Characterization of a Tumor-Associated Activating Mutation of the p110β PI 3-Kinase

The PI3-kinase pathway is commonly activated in tumors, most often by loss of PTEN lipid phosphatase activity or the amplification or mutation of p110 alpha. Oncogenic mutants have commonly been found in p110 alpha, but rarely in any of the other catalytic subunits of class I PI3-kinases. We here characterize a p110 beta helical domain mutation, E633K, first identified in a Her2-positive breast cancer. The mutation increases basal p110 beta activity, but does not affect activation of p85/p110 beta dimers by phosphopeptides or G beta gamma. Expression of the mutant causes increases in Akt and S6K1 activation, transformation, chemotaxis, proliferation and survival in low serum. E633 is conserved among class I PI3 Ks, and its mutation in p110 beta is also activating. Interestingly, the E633K mutant occurs near a region that interacts with membranes in activated PI3-kinases, and its mutation abrogates the requirement for an intact Ras-binding domain in p110 beta-mediated transformation. We propose that the E633K mutant activates p110 beta by enhancing its basal association with membranes. This study presents the first analysis of an activating oncogenic mutation of p110 beta.