BTK regulates PtdIns-4,5-P2 synthesis: importance for calcium signaling and PI3K activity.
Intracellular signaling by most cell surface receptors requires the generation of two major second messengers, phosphatidylinositol-3,4,5-trisphosphate (PtdIns-3,4,5-P3) and inositol-1,4,5-trisphosphate (IP3). The enzymes that produce these second messengers, phosphoinositide 3-kinase (PI3K) and phospholipase C (PLC), utilize a common substrate, phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2). Until now, it has not been clear whether de novo PtdIns-4,5-P2 synthesis is necessary for PtdIns-3,4,5-P3 and IP3 production. Here we show that BTK, a member of the Tec family of cytoplasmic protein tyrosine kinases, associates with phosphatidylinositol-4-phosphate 5-kinases (PIP5Ks), the enzymes that synthesize PtdIns-4,5-P2. Upon B cell receptor activation, BTK brings PIP5K to the plasma membrane as a means of generating local PtdIns-4,5-P2 synthesis. This enzyme-enzyme interaction provides a shuttling mechanism that allows BTK to stimulate the production of the substrate required by both its upstream activator, PI3K, and its downstream target, PLC-gamma2.
Saito
Kan
K
Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Tolias
Kimberley F
KF
Saci
Abdelhafid
A
Koon
Henry B
HB
Humphries
Lisa A
LA
Scharenberg
Andrew
A
Rawlings
David J
DJ
Kinet
Jean-Pierre
JP
Carpenter
Christopher L
CL
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000096:biosynthesis*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism
D019269:Phosphatidylinositol 4,5-Diphosphate; D011947:Receptors, Antigen, B-Cell; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D002118:Calcium