Unperturbed Immune Function despite Mutation of C-Terminal Tyrosines in Syk Previously Implicated in Signaling and Activity Regulation

ABSTRACT

The nonreceptor tyrosine kinase Syk, a central regulator of immune cell differentiation and activation, is a promising drug target for treatment of leukemia and allergic and inflammatory diseases. The clinical failure of Syk inhibitors underscores the importance of understanding the regulation of Syk function and activity. A series of previous studies emphasized the importance of three C-terminal tyrosines in Syk for kinase activity regulation, as docking sites for downstream effector molecules, and for Ca²⁺ mobilization. Here, we investigated the roles of these C-terminal tyrosines in the mouse. Surprisingly, expression of a triple tyrosine-to-phenylalanine human Syk mutant, SYK(Y3F), was not associated with discernible signaling defects either in reconstituted DT40 cells or in B or mast cells from mice expressing SYK(Y3F) instead of wild-type Syk. Remarkably, lymphocyte differentiation, calcium mobilization, and 2,4,6-trinitrophenyl (TNP)-specific immune responses were unperturbed in SYK(Y3F) mice. These results emphasize the capacity of immune cells to compensate for specific molecular defects, likely using redundant intermolecular interactions, and highlight the importance of in vivo analyses for understanding cellular signaling mechanisms.

KEYWORDS:

• BCR signaling
• immunoreceptors
• mast cells
• Syk
• signal transduction

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at https://doi.org/10.1128/MCB.00216-17.

ACKNOWLEDGMENTS

We thank Ludmila Kremer and Nannette Kümpel-Rink for expert technical support. We are indebted to former laboratory members Brit Neuhaus, Ruben Böhmer, and Claudia Beckmann, who contributed to the generation of the SYK(Y3F) mouse model. We are grateful to Michael J. H. Ratcliffe for sharing unpublished sequence data on the chicken Igα locus. We thank Niklas Engels and Michael Engelke for valuable reagents and contributions.

This work was supported by a Bridging Fellowship to V.W. and grants from the Deutsche Forschungsgemeinschaft (SFB 629 and SFB656) and the Max Planck Society to F.K.

V.W. and S.K. performed experiments, analyzed data and wrote the manuscript; S.A. performed the statistical analysis; J.W. contributed vital new reagents and data; F.K. conceived the study, designed research, analyzed data, and wrote the manuscript.

We declare no competing financial interests.