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Regulation of downstream signaling pathways by tyrosine phosphorylation in the linker region of Syk

Purdue University
Publication Date
  • Biology
  • Cell|Biology
  • Microbiology
  • Biology


Cross-linking the B cell antigen receptor (BCR) initiates signaling pathways leading to both positive and negative cellular outcomes. The protein-tyrosine kinase Syk is critical for both of these general responses. The mechanism explaining how a single protein can coordinate seemingly opposite cellular outcomes has been the focus of much research recently. This research provides the first evidence that differential phosphorylation of Syk contributes to the regulation of key signaling events which dictate the fate of a cell based on the stimulus. Factors such as the concentration of the antigen, the avidity of the binding, the timing of the stimulation, and the presence of co-stimuli determine whether a lymphocyte will undergo positive or negative signaling. That is, these factors determine whether a lymphocyte will mount an immune response or proceed toward anergy. Phosphorylation in the linker region of Syk negatively regulates signaling down all pathways and selectively regulates signaling down either P13-K-dependent or -independent pathways. The interaction between Tyr-317 of Syk and the SH2 domain of the proto-oncogene product c-Cbl leads to the down-regulation of Syk-dependent signaling by contributing to the dissociation of Syk from the receptor complex. Tyr-342 and Tyr-346, the other two in vivo linker region tyrosine phosphorylation sites, potentially bind several downstream signaling molecules. Both of these are required for detectable in vitro binding to phospholipase C-γ, Vav, and the Src-family kinase Lck. Despite binding these positive effector molecules, mutation of these sites leads to enhanced signaling through the BCR, particularly through P13-K-dependent pathways. Mutation of Tyr-317 also leads to enhanced signaling. However, this increase is due to activation of P13-K-independent pathways. Kinase activity of a Src-family kinase is necessary to induce the effects mediated by the differential phosphorylation of Syk, indicating that a Src-family kinase is primarily responsible for phosphorylation of these residues. These results represent the initial observations suggesting how phosphorylation of a single protein might influence regulation of specific signaling pathways. Regulation of signals down all pathways or the selective regulation of specific pathways may dictate the fate of a cell based on a given stimulus. ^

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