Ras is an indispensable coregulator of the class IB phosphoinositide 3-kinase p87/p110gamma

Kurig, Barbara and Shymanets, Aliaksei and Bohnacker, Thomas and Prajwal, and Brock, Carsten and Ahmadian, Mohammad Reza and Schaefer, Michael and Gohla, Antje and Harteneck, Christian and Wymann, Matthias P. and Jeanclos, Elisabeth and Nürnberg, Bernd. (2009) Ras is an indispensable coregulator of the class IB phosphoinositide 3-kinase p87/p110gamma. Proceedings of the National Academy of Sciences of the United States of America, Vol. 106. pp. 20312-20317.

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Official URL: http://edoc.unibas.ch/dok/A6004350

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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.
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
Publisher:National Academy of Sciences
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:01 Mar 2013 11:14
Deposited On:01 Mar 2013 11:12

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