Phosphorylation of Ser582—loss of GPCR coupling of p110γ.

<p>In a resting mast cell, the PI3Kγ complex is responsive to GPCR-mediated dissociation of trimeric G proteins. An adapter protein (here p84) is required for a productive relay of the GPCR signal to PI3Kγ. When FcεRI receptors are clustered via IgE/antigen complexes, a signaling cascade is initiated, which triggers the depletion of intracellular Ca²⁺ stores and the opening of store-operated Ca²⁺ channels. The resulting increase in [Ca²⁺]_i and PLCγ-derived diacylglycerol activate PKCβ, which binds to p110γ and subsequently phosphorylates Ser582 (→pp110γ). Phosphorylated p110γ cannot interact with p84, and is therefore unresponsive to GPCR inputs. GPCR input to PI3Kγ coincides with migration and adhesion, while Ca²⁺/PKCβ activation of p110γ occurs when mast cells degranulate. The phosphorylation of PKB/Akt occurs downstream of PtdIns(3,4,5)<i>P</i>₃, which originates from G protein-activated p84-p110γ complex or PKCβ-activated pp110γ. The phosphorylated residues Thr308 and Ser473 of PKB/Akt are used to monitor PI3K activation. More detailed effector signaling event schemes can be found in <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1001587#pbio.1001587-Wymann1" target="_blank">[52]</a>.