Defining how oncogenic and developmental mutations of PIK3R1 alter the regulation of class IA phosphoinositide 3-kinases

Abstract

The class IA PI3Ks are key signalling enzymes composed of a heterodimer of a p110 catalytic subunit and a p85 regulatory subunit, with PI3K mutations being causative of multiple human diseases including cancer, primary immunodeficiencies, and developmental disorders. Mutations in the p85 regulatory subunit encoded by PIK3R1 can both activate PI3K through oncogenic truncations in the iSH2 domain, or inhibit PI3K through developmental disorder mutations in the cSH2 domain. Using a combined biochemical and hydrogen deuterium exchange mass spectrometry approach we have defined the molecular basis for how these mutations activate both the p110/p110{delta} catalytic subunits. We find that the oncogenic Q572* truncation of PIK3R1 disrupts all inhibitory inputs, with p110 being hyper-activated compared to p110{delta}. In addition, we find that the R649W mutation in the cSH2 of PIK3R1 decreases sensitivity to activation by receptor tyrosine kinases. This work reveals novel insight into isoform specific regulation of p110s by p85.\n\nHighlights- An oncogenic variant of p85, Q572*, leads to hyper-activation of p110 compared to p110{delta}\n- HDX-MS revealed that Q572* leads to disruption of all inhibitory interfaces in p110\n- A SHORT syndrome mutation in p85 leads to decreased sensitivity to RTKs for p110/{delta}