Research ArticleCell Biology

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

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

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Adaptors Define the Response

Members of the phosphoinositide 3-kinase (PI3K) family phosphorylate phosphatidylinositol 4,5-bisphosphate to generate phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3], which recruits specific proteins, such as the serine-threonine kinase Akt, to the plasma membrane. These proteins activate signaling pathways that lead to such processes as migration and proliferation; aberrant PI3K signaling is associated with cancer and inflammation. The class 1B PI3K member PI3Kγ mediates signals from G protein–coupled receptors (GPCRs) as a consequence of its activation by Gβγ subunits (see the Perspective by Balla). PI3Kγ consists of a heterodimer of the p110γ catalytic domain and either a p84 or a p101 adaptor subunit. Noting that mast cells from mice deficient in p110γ also lacked p84, the predominant adaptor protein in mast cells, Bohnacker et al. reconstituted these cells with p110γ and either of the adaptor subunits and assessed the relative abilities of the different heterodimers to mediate responses to the GPCR ligand adenosine. Although both heterodimers mediated activation of Akt and cell migration, only p84-containing PI3Kγ mediated degranulation. Differences in the identity of the adaptor subunit also led to differences in the localization of PtdIns(3,4,5)P3. These results suggest that therapeutic targeting of specific PI3Kγ adaptor subunits, and perhaps those of other class I PI3Ks, might provide a means for selectively modulating PI3K-dependent responses.