Inhibition of signaling through the B cell antigen receptor by the protooncogene product, c-Cbl, requires Syk tyrosine 317 and the c-Cbl phosphotyrosine-binding domain.
The Syk protein-tyrosine kinase couples the B cell Ag receptor (BCR) to intracellular biochemical pathways. Syk becomes phosphorylated on multiple tyrosine residues upon receptor cross-linking. Tyrosine 317 is a site of phosphorylation located within the linker region of Syk that separates the amino-terminal, tandem pair of SH2 domains from the ... carboxyl-terminal catalytic domain. The amino acid sequence surrounding phosphotyrosine 317 matches the consensus sequence for recognition by the phosphotyrosine-binding (PTB) domain of the protooncogene product, c-Cbl. The overexpression of c-Cbl in DT40 B cells inhibits Ag receptor-mediated activation of the NF-AT transcription factor. The ability of overexpressed c-Cbl to inhibit signaling requires both Syk tyrosine 317 and a functional c-Cbl PTB domain. Mutant forms of Syk lacking tyrosine 317 exhibit an enhanced ability to couple the BCR to pathways leading to the activation of both NF-AT and Elk-1. Coimmunoprecipitation experiments indicate that Syk phosphotyrosine 317 and the c-Cbl PTB domain enhance, but are not required for, all interactions between these two proteins. In unstimulated cells, c-Cbl and Syk can be isolated in a complex that also contains tubulin. A mutant form of Syk lacking tyrosine at position 317 exhibits an enhanced ability to interact with a diphosphopeptide modeled on the immunoreceptor tyrosine-based activation motif of the CD79a component of the Ag receptor. These studies indicate that c-Cbl may contribute to the regulation of BCR signaling by modulating the ability of Syk to associate with the BCR and couple the receptor to intracellular signaling pathways.
Mesh Terms:
Animals, Binding Sites, Chickens, DNA-Binding Proteins, Enzyme Precursors, Intracellular Signaling Peptides and Proteins, NFATC Transcription Factors, Nuclear Proteins, Phosphotyrosine, Protein Binding, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-cbl, Receptors, Antigen, B-Cell, Signal Transduction, Transcription Factors, Tyrosine, Ubiquitin-Protein Ligases, ets-Domain Protein Elk-1
Animals, Binding Sites, Chickens, DNA-Binding Proteins, Enzyme Precursors, Intracellular Signaling Peptides and Proteins, NFATC Transcription Factors, Nuclear Proteins, Phosphotyrosine, Protein Binding, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-cbl, Receptors, Antigen, B-Cell, Signal Transduction, Transcription Factors, Tyrosine, Ubiquitin-Protein Ligases, ets-Domain Protein Elk-1
J. Immunol.
Date: Dec. 01, 1999
PubMed ID: 10570266
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