Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit

Many human cancers involve up-regulation of the phosphoinositide 3-kinase PI3K alpha, with oncogenic mutations identified in both the p110 alpha catalytic and the p85 alpha regulatory subunits. We used crystallographic and biochemical approaches to gain insight into activating mutations in two noncatalytic p110 alpha domains-the adaptor-binding and the helical domains. A structure of the adaptor-binding domain of p110 alpha in a complex with the p85 alpha inter-Src homology 2 (inter-SH2) domain shows that oncogenic mutations in the adaptor-binding domain are not at the inter-SH2 interface but in a polar surface patch that is a plausible docking site for other domains in the holo p110/p85 complex. We also examined helical domain mutations and found that the Glu(545) to Lys(545) (E545K) oncogenic mutant disrupts an inhibitory charge-charge interaction with the p85 N-terminal SH2 domain. These studies extend our understanding of the architecture of PI3Ks and provide insight into how two classes of mutations that cause a gain in function can lead to cancer.