The constitutive oncogenic and signaling activities of phosphatidylinositol 3-kinase (PI3K) isoforms p110β and p110δ

The p110β and p110δ isoforms of the catalytic subunit of phosphatidylinositol 3-kinase (PI3K) show enhanced oncogenic and signaling activities as compared with the p110α protein. The adapter binding domains (ABDs) of p110β and p110δ contain an isoform-specific PXXP mo- tif. Mutations of this PXXP to AXXA diminish the oncogenic and signaling activities. This loss of function can be compensated by placing a gain-of-function mutation in the helical domain of the P/A mutants. The P/A mutants still associate with the regulatory p85 subunit, but the affinity of this interaction is decreased. p110α with the ABD of either p110β or p110δ shows an increase of oncogenic and signaling activities, whereas p110β or p110δ with the ABD of p110α have greatly reduced oncogenic and signaling activities. Introducing the PXXP motif in the ABD of p110α re- sults in a significant gain of function. We conclude that the PXXP motif in the ABD of p110β and p110δ is essential for the elevated oncogenic and signaling activities of these isoforms. We pro- pose that the PXXP motif in the ABD of p110β and p110δ affects the interaction with the iSH2 domain of p85, shifting the regulatory SH2 domains into less effective inhibitory conformations.