Phospholipase C-β3 Regulates FcεRI-Mediated Mast Cell Activation by Recruiting the Protein Phosphatase SHP-1

Mast cells are major effectors in high-affinity IgE receptor (Fc epsilon RI)-dependent allergic reactions. Here we show that phospholipase C (PLC)-beta 3 is crucial for Fc epsilon RI-mediated mast cell activation. Plcb3(-/-) mice showed blunted Fc epsilon RI-dependent late-phase, but not acute, anaphylactic responses and airway inflammation. Accordingly, Fc epsilon RI stimulation of Plcb3(-/-) mast cells exhibited reduced cytokine production but normal degranulation. Reduced cytokine production in Plcb3(-/-) cells could be accounted for by increased activity of the negative regulatory Src family kinase Lyn and reduced activities of the positive regulatory protein kinases MAPKs. Mechanistically, PLC-beta 3 constitutively interacts with Fc epsilon RI, Lyn, and SHP-1 (protein phosphatase). SHP-1 probably recognizes its substrates Lyn and MAPKs via the recently described kinase tyrosine-based inhibitory motif, KTIM. Consistent with PLC-beta 3- and SHP-1-mediated repression of Lyn activity by dephosphorylation at Tyr396, Fc epsilon RI-mediated phenotypes were similar in Plcb3(-/-) and SHP-1 mutant mast cells. Thus, we have defined a PLC-beta 3- and SHP-1-mediated signaling pathway for Fc epsilon RI-mediated cytokine production.