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Kurig, B, Shymanets, A, Bohnacker, T, Prajwal, , Brock, C, Ahmadian, MR, Schaefer, M, Gohla, A, Harteneck, C, Wymann, MP, Jeanclos, E and Nürnberg, B (2009) Ras is an indispensable coregulator of the class IB phosphoinositide 3-kinase p87/p110gamma. Proc. Natl. Acad. Sci. U.S.A. 106:20312-7
Class I(B) phosphoinositide 3-kinase gamma (PI3Kgamma) elicits various immunologic and cardiovascular responses; however, the molecular basis for this signal heterogeneity is unclear. PI3Kgamma consists of a catalytic p110gamma and a regulatory p87(PIKAP) (p87, also p84) or p101 subunit. Hitherto p87 and p101 are generally assumed to exhibit redundant functions in receptor-induced and G protein betagamma (Gbetagamma)-mediated PI3Kgamma regulation. Here we investigated the molecular mechanism for receptor-dependent p87/p110gamma activation. By analyzing GFP-tagged proteins expressed in HEK293 cells, PI3Kgamma-complemented bone marrow-derived mast cells (BMMCs) from p110gamma(-/-) mice, and purified recombinant proteins reconstituted to lipid vesicles, we elucidated a novel pathway of p87-dependent, G protein-coupled receptor (GPCR)-induced PI3Kgamma activation. Although p101 strongly interacted with Gbetagamma, thereby mediating PI3Kgamma membrane recruitment and stimulation, p87 exhibited only a weak interaction, resulting in modest kinase activation and lack of membrane recruitment. Surprisingly, Ras-GTP substituted the missing Gbetagamma-dependent membrane recruitment of p87/p110gamma by direct interaction with p110gamma, suggesting the indispensability of Ras for activation of p87/p110gamma. Consequently, interference with Ras signaling indeed selectively blocked p87/p110gamma, but not p101/p110gamma, kinase activity in HEK293 and BMMC cells, revealing an important crosstalk between monomeric and trimeric G proteins for p87/p110gamma activation. Our data display distinct signaling requirements of p87 and p101, conferring signaling specificity to PI3Kgamma that could open up new possibilities for therapeutic intervention.
Animals; Cell Line; Enzyme Activation/physiology; Fluorescent Antibody Technique; Green Fluorescent Proteins; Humans; Mast Cells/metabolism; Mice; Microscopy, Confocal; Models, Molecular; Phosphatidylinositol 3-Kinases/metabolism; Receptors, G-Protein-Coupled/metabolism; Signal Transduction/physiology; ras Proteins/metabolism