Role of the Syk autophosphorylation site and SH2 domains in B cell antigen receptor signaling.

To explore the mechanism(s) by which the Syk protein tyrosine kinase participates in B cell antigen receptor (BCR) signaling, we have studied the function of various Syk mutants in B cells made Syk deficient by homologous recombination knockout. Both Syk SH2 domains were required for BCR-mediated Syk and phospholipase C ...
(PLC)-gamma 2 phosphorylation, inositol 1,4,5-triphosphate release, and Ca2+ mobilization. A possible explanation for this requirement was provided by findings that recruitment of Syk to tyrosine-phosphorylated immunoglobulin (Ig) alpha and Ig beta requires both Syk SH2 domains. A Syk mutant in which the putative autophosphorylation site (Y518/Y519) of Syk was changed to phenylalanine was also defective in signal transduction; however, this mutation did not affect recruitment to the phosphorylated immunoreceptor family tyrosine-based activation motifs (ITAMs). These findings not only confirm that both SH2 domains are necessary for Syk binding to tyrosine-phosphorylated Ig alpha and Ig beta but indicate that this binding is necessary for Syk (Y518/519) phosphorylation after BCR ligation. This sequence of events is apparently required for coupling the BCR to most cellular protein tyrosine phosphorylation, to the phosphorylation and activation of PLC-gamma 2, and to Ca2+ mobilization.
Mesh Terms:
Amino Acid Sequence, B-Lymphocytes, Calcium, Cells, Cultured, Enzyme Precursors, Inositol 1,4,5-Trisphosphate, Intracellular Signaling Peptides and Proteins, Molecular Sequence Data, Mutagenesis, Site-Directed, Peptides, Phosphorylation, Protein-Tyrosine Kinases, Receptors, Antigen, B-Cell, Signal Transduction, Structure-Activity Relationship, src Homology Domains
J. Exp. Med.
Date: Dec. 01, 1995
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