PMID- 10201980 OWN - NLM STAT- MEDLINE DCOM- 19990506 LR - 20181201 IS - 0022-1767 (Print) IS - 0022-1767 (Linking) VI - 162 IP - 8 DP - 1999 Apr 15 TI - Phosphorylation of CD19 Y484 and Y515, and linked activation of phosphatidylinositol 3-kinase, are required for B cell antigen receptor-mediated activation of Bruton's tyrosine kinase. PG - 4438-46 AB - Bruton's tyrosine kinase (Btk) plays a critical role in B cell Ag receptor (BCR) signaling, as indicated by the X-linked immunodeficiency and X-linked agammaglobulinemia phenotypes of mice and men that express mutant forms of the kinase. Although Btk activity can be regulated by Src-family and Syk tyrosine kinases, and perhaps by phosphatidylinositol 3,4,5-trisphosphate, BCR-coupled signaling pathways leading to Btk activation are poorly understood. In view of previous findings that CD19 is involved in BCR-mediated phosphatidylinositol 3-kinase (PI3-K) activation, we assessed its role in Btk activation. Using a CD19 reconstituted myeloma model and CD19 gene-ablated animals we found that BCR-mediated Btk activation and phosphorylation are dependent on the expression of CD19, while BCR-mediated activation of Lyn and Syk is not. Wortmannin preincubation inhibited the BCR-mediated activation and phosphorylation of Btk. Btk activation was not rescued in the myeloma by expression of a CD19 mutant in which tyrosine residues previously shown to mediate CD19 interaction with PI3-K, Y484 and Y515, were changed to phenylalanine. Taken together, the data presented indicate that BCR aggregation-driven CD19 phosphorylation functions to promote Btk activation via recruitment and activation of PI3-K. Resultant phosphatidylinositol 3,4,5-trisphosphate probably functions to localize Btk for subsequent phosphorylation and activation by Src and Syk family kinases. FAU - Buhl, A M AU - Buhl AM AD - Division of Basic Sciences, Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206, USA. FAU - Cambier, J C AU - Cambier JC LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. PL - United States TA - J Immunol JT - Journal of immunology (Baltimore, Md. : 1950) JID - 2985117R RN - 0 (Antigens, CD19) RN - 0 (Enzyme Precursors) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (Isoenzymes) RN - 0 (Receptors, Antigen, B-Cell) RN - 42HK56048U (Tyrosine) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - EC 2.7.10.1 (Protein-Tyrosine Kinases) RN - EC 2.7.10.2 (Agammaglobulinaemia Tyrosine Kinase) RN - EC 2.7.10.2 (BTK protein, human) RN - EC 2.7.10.2 (Btk protein, mouse) RN - EC 2.7.10.2 (SYK protein, human) RN - EC 2.7.10.2 (Syk Kinase) RN - EC 2.7.10.2 (Syk protein, mouse) RN - EC 2.7.10.2 (lyn protein-tyrosine kinase) RN - EC 2.7.10.2 (src-Family Kinases) RN - EC 3.1.4.- (Type C Phospholipases) RN - EC 3.1.4.3 (Phospholipase C gamma) SB - AIM SB - IM MH - Agammaglobulinaemia Tyrosine Kinase MH - Animals MH - Antigens, CD19/*metabolism/physiology MH - B-Lymphocytes/enzymology/metabolism/pathology MH - Calcium Signaling/immunology MH - Enzyme Activation/genetics/immunology MH - Enzyme Precursors/metabolism/physiology MH - Humans MH - Immunologic Deficiency Syndromes/*enzymology/genetics/immunology MH - Intracellular Signaling Peptides and Proteins MH - Isoenzymes/metabolism MH - Mice MH - Mice, Inbred CBA MH - Mice, Knockout MH - Phosphatidylinositol 3-Kinases/*metabolism/physiology MH - Phospholipase C gamma MH - Phosphorylation MH - Protein-Tyrosine Kinases/genetics/*metabolism/physiology MH - Receptors, Antigen, B-Cell/*physiology MH - Spleen/cytology/enzymology MH - Syk Kinase MH - Tumor Cells, Cultured MH - Type C Phospholipases/metabolism MH - Tyrosine/*metabolism/physiology MH - X Chromosome/immunology MH - src-Family Kinases/metabolism/physiology EDAT- 1999/04/14 00:00 MHDA- 1999/04/14 00:01 CRDT- 1999/04/14 00:00 PHST- 1999/04/14 00:00 [pubmed] PHST- 1999/04/14 00:01 [medline] PHST- 1999/04/14 00:00 [entrez] PST - ppublish SO - J Immunol. 1999 Apr 15;162(8):4438-46.