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PMID:19906996

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Citation

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

Abstract

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.

Links

PubMed PMC2787109 Online version:10.1073/pnas.0905506106

Keywords

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

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:PI3R6

located_in

GO:0016020: membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:PI3R6

involved_in

GO:0007186: G protein-coupled receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PI3R6

part_of

GO:0016020: membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:PI3R6

involved_in

GO:0043406: positive regulation of MAP kinase activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PI3R6

contributes_to

GO:0046934: phosphatidylinositol-4,5-bisphosphate 3-kinase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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