Expression of the Src-family kinase LynA tunes myeloid-cell signaling and function

Abstract

Abstract The activity of Src-family kinases (SFKs), which phosphorylate immunoreceptor tyrosine-based activation motifs (ITAMs) upon receptor ligation, is a critical factor regulating myeloid cell activation. The SFK Lyn has roles in activating myeloid cells, by phosphorylating ITAMs, and also in inducing suppressive signaling via phosphatase activation. Alternative splicing of lyn mRNA produces two proteins, LynA and LynB, and emerging evidence from our lab and others suggests that LynA and LynB interact with different proteins and preferentially activate different signal cascades. In macrophages LynA is uniquely susceptible to rapid ubiquitin-mediated degradation and functions as a rheostat that regulates ITAM signal strength. Phosphorylation of tyrosine 32 in the unique region of LynA preferentially targets LynA for polyubiquitination by the E3 ligase c-Cbl. In contrast to macrophages, mast cells express little c-Cbl. Upon activation, LynA is not rapidly degraded in mast cells, and SFK-mediated signaling is amplified relative to macrophages. Previous studies of LynA have been hampered by knockout models that lack both LynA and LynB. To understand the role LynA plays in immune development and activation, we used CRISPR-Cas9 gene editing to generate novel mouse strains that express either LynA or LynB. Preliminary studies in these mice have demonstrated novel roles for LynA. Notably, LynA−/− mice have an enrichment in splenic dendritic cells and alveolar macrophages. Thus, LynA is not only an important regulator of myeloid cell activation, tuning cell-specific signaling thresholds, but also helps regulate the function of these cells. Further studies will investigate the impact of LynA deletion in myeloid inflammation sensing.