Btk-dependent regulation of phosphoinositide synthesis

Abstract

Activation of the BCR (B cell antigen receptor) stimulates the production of both PtdIns(3,4,5)P3 and Ins(1,4,5)P3. PtdIns(3,4,5)P3 and Ins(1,4,5)P3 are generated from a common substrate, PtdIns(4,5)P2. In some systems, continuous PtdIns(4,5)P2 synthesis is necessary for maximal Ins(1,4,5)P3 production, but whether this is true for the BCR, and whether PtdIns(4,5)P2 synthesis is regulated following BCR activation, are not known. We found that Btk (Bruton's tyrosine kinase), a member of the Tec family of cytoplasmic protein tyrosine kinases, is constitutively associated with PIP5Ks (phosphatidylinositol 4-phosphate 5-kinases), the enzymes that synthesize PtdIns(4,5)P2. Btk functions as a shuttle to bring PIP5K to the plasma membrane as a means of stimulating PtdIns(4,5)P2 synthesis. The Btk–PIP5K complex appears to localize to lipid rafts. This complex provides a novel shuttling mechanism that allows Btk to regulate the production of the substrate required by both its upstream activator phosphoinositide 3-kinase and its downstream target phospholipase Cγ2.