Syk signaling and trafficking during B cell activation

The protein tyrosine kinase Syk couples the B-cell receptor (BCR) for antigen to multiple intracellular signaling pathways and also modulates cellular responses to inducers of oxidative stress in a receptor-independent fashion. The ability of Syk to regulate receptor signaling is influenced by its phosphorylation on tyrosine residues within the linker B region. The phosphorylation of both Y342 and Y346 is necessary for optimal PLCγ and NFAT activation from the BCR. The NMR structure of the C-terminal SH2 domain of PLCgamma (PLCC) bound to a doubly phosphorylated Syk peptide revealed a novel mode of phosphotyrosine recognition. Studies revealed that the SH2 domains of multiple signaling proteins share the ability to bind this doubly phosphorylated site, while others prefer singly phosphorylated site. The dependence of signaling on simultaneous phosphorylation of these two tyrosine residues offers a new mechanism to fine-tune the cellular response to external stimulation. In B cells, Syk is found in both the nuclear and cytoplasmic compartments. The localization is altered following prolonged engagement of the BCR or PMA treatment, which causes Syk to be excluded from the nucleus. Nuclear exclusion requires the activation of protein kinase C and new protein synthesis. Both of these processes also potentiate the activation of caspase 3 in cells in response to oxidative stress in a manner that is dependent on the localization of Syk outside of the nucleus. Our studies suggested that this process is depended on caspase 10 as an initiator. In contrast, restriction of Syk to the nucleus greatly diminishes the stress-induced activation of caspase 3. Thus, it is evident that Syk modulates intracellular signaling not only through its phosphorylation on tyrosine residues, but its subcellular distribution. This suggests Syk as an important player in B cells that is highly regulated at multiple levels