Btk-dependent regulation of phosphoinositide synthesis

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.