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Sci. Signal., 9 June 2009
Vol. 2, Issue 74, p. ra27
[DOI: 10.1126/scisignal.2000259]

RESEARCH ARTICLES

PI3K{gamma} Adaptor Subunits Define Coupling to Degranulation and Cell Motility by Distinct PtdIns(3,4,5)P3 Pools in Mast Cells

Thomas Bohnacker1, Romina Marone1*, Emilie Collmann1*, Ronan Calvez1{dagger}, Emilio Hirsch2, and Matthias P. Wymann1{ddagger}

1 Institute of Biochemistry and Genetics, Department of Biomedicine, University of Basel, Mattenstrasse 28, CH-4058 Basel, Switzerland.
2 Dipartimento di Genetica, Biologia e Biochimica, Università di Torino, Via Nizza 52, I-10126 Turin, Italy.

* These authors contributed equally to this work.

{dagger} Present address: Marie Curie Excellence Team, INSERM U563, CHU Purpan, BP 3028, 31024 Toulouse Cedex 3, France.

Abstract: Phosphoinositide 3-kinase {gamma} (PI3K{gamma}) plays a major role in chronic inflammation and allergy. It is a heterodimer of a catalytic p110{gamma} subunit and an adaptor protein, either p101 or the p101 homolog p84 (p87PIKAP). It is unclear whether both PI3K{gamma} complexes specifically modulate responses such as chemotaxis and degranulation. In mast cells, the p84:p110{gamma} complex synergizes with immunoglobulin E (IgE)– and antigen-clustered Fc{varepsilon}RI receptor signaling and is required to achieve maximal degranulation. During this process, PI3K{gamma} is activated by ligands of heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptors (GPCRs), in particular adenosine receptors, through autocrine and paracrine pathways. Here, we show that p110{gamma} needs p84 to relay signals from GPCRs to formation of phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3], phosphorylation of Akt, migration of cells, and synergistic adenosine-enforced degranulation. Furthermore, the absence of adaptor subunits could not be compensated for by increased p110{gamma} abundance. Differentiated, p110{gamma} null cells also lost adaptor proteins. Complementation of p110{gamma} null mast cells with p101 and p110{gamma} restored the activation of Akt and cell migration, but failed to support degranulation. Lack of degranulation was attributed to a change in the spatiotemporal localization of PI3K{gamma}-derived PtdIns(3,4,5)P3; although both p84:p110{gamma} and p101:p110{gamma} complexes initially deposited PtdIns(3,4,5)P3 at the plasma membrane, p101:p110{gamma}–derived PtdIns(3,4,5)P3 was rapidly endocytosed to motile, microtubule-associated vesicles. In addition, p84:p110{gamma}, but not p101:p110{gamma} signaling was sensitive to disruption of lipid rafts. Our results demonstrate a nonredundant function for the p101 and p84 PI3K{gamma} adaptor proteins and show that distinct pools of PtdIns(3,4,5)P3 at the plasma membrane can elicit specific cell responses.

{ddagger} To whom correspondence should be addressed. E-mail: Matthias.Wymann{at}UniBas.ch

Citation: T. Bohnacker, R. Marone, E. Collmann, R. Calvez, E. Hirsch, M. P. Wymann, PI3K{gamma} Adaptor Subunits Define Coupling to Degranulation and Cell Motility by Distinct PtdIns(3,4,5)P3 Pools in Mast Cells. Sci. Signal. 2, ra27 (2009).

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