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Abstract
Syk (p72syk) is a 72-kDa, nonreceptor, protein-tyrosine kinase that becomes tyrosine-phosphorylated and activated in B lymphocytes following aggregation of the B-cell antigen receptor. To explore the subcellular location of activated Syk, anti-IgM-activated B-cells were fractionated into soluble and particulate fractions by ultracentrifugation. Activated and tyrosine-phosphorylated Syk was found predominantly in the soluble fraction and was not associated with components of the antigen receptor. Similarly, the activated forms of Syk and its homolog, ZAP-70, were found in soluble fractions prepared from pervanadate-treated Jurkat T-cells. A 54-kDa protein that co-immunoprecipitated with Syk from the soluble fraction of activated B-cells was identified by peptide mapping as alpha-tubulin. alpha-Tubulin was an excellent in vitro substrate for Syk and was phosphorylated on a single tyrosine present within an acidic stretch of amino acids located near the carboxyl terminus. alpha-Tubulin was phosphorylated on tyrosine in intact cells following aggregation of the B-cell antigen receptor in a reaction that was inhibited by the Syk-selective inhibitor, piceatannol. Thus, once activated, Syk releases from the aggregated antigen receptor complex and is free to associate with and phosphorylate soluble proteins including alpha-tubulin.
Highlights
Syk (p72syk) is a 72-kDa cytoplasmic protein-tyrosine kinase that is expressed in a variety of hematopoietic cells where it participates in signal transduction cascades initiated by the engagement of the cell surface receptors with which it associates
That Syk is an important mediator of receptor signaling is indicated by an absence of signaling in SykϪ DT40 chicken B-cells [17], an inhibition of Fc⑀RI-mediated signaling in mast cells by a Syk-selective inhibitor [18], and a blockage in B-cell development in SykϪ “knockout” mice at stages that normally require signals to be sent through the B-cell antigen receptor (BCR) or pre-BCR [19]
Syk Activity in the Cytosol Increases with BCR Stimulation— Aggregation of the BCR leads to an increase in the intrinsic activity of Syk, which can be detected as an increase in the rate of Syk autophosphorylation in anti-Syk immune complexes [1, 30]
Summary
Syk (p72syk) is a 72-kDa cytoplasmic protein-tyrosine kinase that is expressed in a variety of hematopoietic cells where it participates in signal transduction cascades initiated by the engagement of the cell surface receptors with which it associates. Syk is activated in B lymphocytes by aggregation of the B-cell antigen receptor (BCR)1 [1]; in platelets by thrombin [2] or by integrin ligation [3]; in mast cells by aggregation of Fc⑀RI. The activation of Syk in response to the engagement of multichain immune recognition receptors [12] has been studied in the greatest detail. The aggregation of these receptors leads to the phosphorylation of multiple cellular proteins on tyrosine, initiating signaling cascades resulting in increased inositol 1,4,5-trisphosphate production and calcium mobilization This occupancy allows the kinase to catalyze an autophosphorylation reaction, which leads to an increase in its intrinsic activity [21]
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