Btk-dependent regulation of phosphoinositide synthesis

Activation of the BCR (B cell antigen receptor) stimulates the production of both PtdIns(3,4,5)P-3 and Ins(1,4,5)P-3. PtdIns(3,4,5)P-3 and Ins(1,4,5)P-3 are generated from a common substrate, PtdIns(4,5)P2In some systems, continuous Ptdins(4,5)P-2 synthesis is necessary for maximal Ins(1,4,5)P-3 production, but whether this is true for the BCR, and whether PtdIns(4,5)P-2 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 (phosphaticlylinositol 4-phosphate 5-kinases), the enzymes that synthesize PtdIns(4.5)P-2. Btk functions as a shuttle to bring PIP5K to the plasma membrane as a means of stimulating PtdIns(4,5)P-2 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 Cgamma2.