The ERM family protein Ezrin associates with the JNK signaling complex to regulate its activation and antigen-dependent B cell survival. (109.7)

Abstract

Abstract Antigen binding to the B cell antigen receptor (BCR) results in initiation of a highly orchestrated series of enzymatic reactions and protein-protein interactions that transmit the signals for B cell survival and proliferation. The highly conserved Ezrin-Radixin-Moesin (ERM) family members are thought to regulate lymphocyte activation via their membrane-actin crosslinking property, which is in turn regulated by phosphorylation of a conserved threonine residue at their C-terminus. Here, we report a novel signal transduction axis that links antigen-dependent tyrosine phosphorylation of ezrin with activation of the c-Jun N-terminal kinase (JNK). BCR ligation induces phosphorylation of Y353 in ezrin, a residue that is not conserved in other ERM proteins. Phosphorylation of Y353 is dependent on Src and Syk family kinase activity, occurs preferentially on the open conformer of ezrin, and correlates with the strength of BCR signaling in mature B cell subsets. Tyrosine phosphorylated ezrin associates with components of the JNK signaling complex in response to BCR stimulation. A non-phosphorylatable (Y353F) mutant of ezrin acts in a dominant negative manner to specifically impair antigen-induced JNK activation, and reduces B cell survival. Our results demonstrate a unique and novel signaling role for ezrin in regulating antigen-dependent JNK activation and B cell survival.