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PKCβ phosphorylates PI3Kγ to activate it and release it from GPCR control

Walser, R. and Burke, J. E. and Gogvadze, E. and Bohnacker, T. and Zhang, X. and Hess, D. and Kuenzi, P. and Leitges, M. and Hirsch, E. and Williams, R. L. and Laffargue, M. and Wymann, M. P.. (2013) PKCβ phosphorylates PI3Kγ to activate it and release it from GPCR control. PLoS Biology, Vol. 11, H. 6 , e1001587.

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Official URL: http://edoc.unibas.ch/dok/A6338021

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Abstract

All class I phosphoinositide 3-kinases (PI3Ks) associate tightly with regulatory subunits through interactions that have been thought to be constitutive. PI3Kgamma is key to the regulation of immune cell responses activated by G protein-coupled receptors (GPCRs). Remarkably we find that PKCbeta phosphorylates Ser582 in the helical domain of the PI3Kgamma catalytic subunit p110gamma in response to clustering of the high-affinity IgE receptor (FcepsilonRI) and/or store-operated Ca(2)(+)- influx in mast cells. Phosphorylation of p110gamma correlates with the release of the p84 PI3Kgamma adapter subunit from the p84-p110gamma complex. Ser582 phospho-mimicking mutants show increased p110gamma activity and a reduced binding to the p84 adapter subunit. As functional p84-p110gamma is key to GPCR-mediated p110gamma signaling, this suggests that PKCbeta-mediated p110gamma phosphorylation disconnects PI3Kgamma from its canonical inputs from trimeric G proteins, and enables p110gamma to operate downstream of Ca(2)(+) and PKCbeta. Hydrogen deuterium exchange mass spectrometry shows that the p84 adaptor subunit interacts with the p110gamma helical domain, and reveals an unexpected mechanism of PI3Kgamma regulation. Our data show that the interaction of p110gamma with its adapter subunit is vulnerable to phosphorylation, and outline a novel level of PI3K control.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Division of Biochemistry and Genetics > Cancer- and Immunobiology (Wymann)
UniBasel Contributors:Wymann, Matthias P.
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Public Library of Science
ISSN:1545-7885
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:06 Mar 2015 07:44
Deposited On:06 Mar 2015 07:44

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