Research ArticleCell Biology

PI3Kγ Adaptor Subunits Define Coupling to Degranulation and Cell Motility by Distinct PtdIns(3,4,5)P3 Pools in Mast Cells

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Sci. Signal.  09 Jun 2009:
Vol. 2, Issue 74, pp. ra27
DOI: 10.1126/scisignal.2000259

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Phosphoinositide 3-kinase γ (PI3Kγ) plays a major role in chronic inflammation and allergy. It is a heterodimer of a catalytic p110γ subunit and an adaptor protein, either p101 or the p101 homolog p84 (p87PIKAP). It is unclear whether both PI3Kγ complexes specifically modulate responses such as chemotaxis and degranulation. In mast cells, the p84:p110γ complex synergizes with immunoglobulin E (IgE)– and antigen-clustered FcɛRI receptor signaling and is required to achieve maximal degranulation. During this process, PI3Kγ 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 p110γ 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 p110γ abundance. Differentiated, p110γ null cells also lost adaptor proteins. Complementation of p110γ null mast cells with p101 and p110γ 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 PI3Kγ-derived PtdIns(3,4,5)P3; although both p84:p110γ and p101:p110γ complexes initially deposited PtdIns(3,4,5)P3 at the plasma membrane, p101:p110γ–derived PtdIns(3,4,5)P3 was rapidly endocytosed to motile, microtubule-associated vesicles. In addition, p84:p110γ, but not p101:p110γ signaling was sensitive to disruption of lipid rafts. Our results demonstrate a nonredundant function for the p101 and p84 PI3Kγ adaptor proteins and show that distinct pools of PtdIns(3,4,5)P3 at the plasma membrane can elicit specific cell responses.

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