The main regulatory subunits of Class IA phosphatidylinositol 3-kinase (PI3K), p85α and p85β, initiate diverse cellular activities independent of binding to the catalytic subunit p110. Several of these signaling processes directly or indirectly contribute to a regulation of PI3K and could become targets for therapeutic efforts. Areas covered: This review will highlight two general areas of p85 activity: (1) direct interaction with regulatory proteins and with determinants of the cytoskeleton, and (2) a genetic analysis by deletion and domain switches identifying new functions for p85 domains. Expert Opinion: Isoform-specific activities of regulatory subunits have long been at the periphery of the PI3K field. Our understanding of these unique functions of the regulatory subunits is fragmentary and raises many important questions. At this time, there is insufficient information to translate this knowledge into the clinic, but some tempting targets have emerged that could move the field forward with the help of novel technologies in drug design and identification.
Keywords: Catalytic subunit; direct protein–protein interaction; domain switch; fragment-based inhibitor screening; protein truncation; protein–protein interactions as therapeutic targets; regulatory subunit.