PKC? phosphorylates PI3K? to activate it and release it from GPCR control.

ABSTRACT: All class I phosphoinositide 3-kinases (PI3Ks) associate tightly with regulatory subunits through interactions that have been thought to be constitutive. PI3K? is key to the regulation of immune cell responses activated by G protein-coupled receptors (GPCRs). Remarkably we find that PKC? phosphorylates Ser582 in the helical domain of the PI3K? catalytic subunit p110? in response to clustering of the high-affinity IgE receptor (Fc?RI) and/or store-operated Ca²?- influx in mast cells. Phosphorylation of p110? correlates with the release of the p84 PI3K? adapter subunit from the p84-p110? complex. Ser582 phospho-mimicking mutants show increased p110? activity and a reduced binding to the p84 adapter subunit. As functional p84-p110? is key to GPCR-mediated p110? signaling, this suggests that PKC?-mediated p110? phosphorylation disconnects PI3K? from its canonical inputs from trimeric G proteins, and enables p110? to operate downstream of Ca²? and PKC?. Hydrogen deuterium exchange mass spectrometry shows that the p84 adaptor subunit interacts with the p110? helical domain, and reveals an unexpected mechanism of PI3K? regulation. Our data show that the interaction of p110? with its adapter subunit is vulnerable to phosphorylation, and outline a novel level of PI3K control.

SUBMITTER: Walser R 

PROVIDER: S-EPMC3692425 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature