BTK regulates PtdIns-4,5-P2 synthesis: importance for calcium signaling and PI3K activity

Immunity. 2003 Nov;19(5):669-78. doi: 10.1016/s1074-7613(03)00297-8.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Agammaglobulinaemia Tyrosine Kinase
  • Animals
  • Calcium / metabolism
  • Calcium Signaling / physiology*
  • Enzyme Activation / physiology
  • Humans
  • Membrane Microdomains / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphatidylinositol 4,5-Diphosphate / biosynthesis*
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Protein-Tyrosine Kinases / metabolism*
  • Receptors, Antigen, B-Cell / metabolism


  • Phosphatidylinositol 4,5-Diphosphate
  • Receptors, Antigen, B-Cell
  • Phosphatidylinositol 3-Kinases
  • Phosphotransferases (Alcohol Group Acceptor)
  • 1-phosphatidylinositol-4-phosphate 5-kinase
  • Protein-Tyrosine Kinases
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human
  • Calcium