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 Cgamma2.
Carpenter
C L
CL
Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, HIM Building, Room 1026, 330 Brookline Avenue, Boston, MA 02215, U.S.A. ccarpent@bidmc.harvard.edu
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000737:chemistry* / Q000378:metabolism; D010716:Phosphatidylinositols / Q000737:chemistry*; D051966:Phospholipase C gamma; D011505:Protein-Tyrosine Kinases / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000378:metabolism
D018129:Phosphatidylinositol Phosphates; D010716:Phosphatidylinositols; C060974:phosphatidylinositol 3,4,5-triphosphate; D019869:Phosphatidylinositol 3-Kinases; C089848:Tec protein-tyrosine kinase; C116930:Pikfyve protein, mouse; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse; D010738:Type C Phospholipases; D051966:Phospholipase C gamma