A Mouse Model for the Study of SYK Function through Chemical Genetics Demonstrates SYK-Dependent Signaling through...

The SYK protein-tyrosine kinase is a well-known mediator of signals elicited by the clustering of BCR complexes and other receptors that bear components that contain one or more ITAM sequences. Additional roles for the kinase in signaling through other receptor classes also have been described. To assist in the identification of SYK-regulated processes, we developed mice lacking endogenous Syk genes but containing instead genes coding for an analogue-sensitive form of SYK (SYK-AQL). SYK-AQL supports the development of B cells, and these can be activated with both anti-IgM F(ab')₂ through the BCR and LPS through TLR4. An orthogonal inhibitor that selectively targets SYK-AQL blocks the activation of B cells by anti-IgM F(ab')₂ in SYK-AQL-expressing but not wild-type cells. The SYK-AQL-specific inhibitor, however, does not block B cell activation in response to LPS in either wild-type or SYK-AQL-expressing cells. Thus, SYK is essential for coupling the BCR but not TLR4 to the activation of B cells.