Unique-region phosphorylation targets LynA for rapid degradation, tuning its expression and signaling in myeloid cells
Abstract
The activity of Src-family kinases (SFKs), which phosphorylate immunoreceptor tyrosine-based activation motifs (ITAMs), is a critical factor regulating myeloid-cell activation. We reported previously that the SFK LynA is uniquely susceptible to rapid ubiquitin-mediated degradation in macrophages, functioning as a rheostat regulating signaling (Freedman et al., 2015). We now report the mechanism by which LynA is preferentially targeted for degradation and how cell specificity is built into the LynA rheostat. Using genetic, biochemical, and quantitative phosphopeptide analyses, we found that the E3 ubiquitin ligase c-Cbl preferentially targets LynA via a phosphorylated tyrosine (Y32) in its unique region. This distinct mode of c-Cbl recognition depresses steady-state expression of LynA in macrophages derived from mice. Mast cells, however, express little c-Cbl and have correspondingly high LynA. Upon activation, mast-cell LynA is not rapidly degraded, and SFK-mediated signaling is amplified relative to macrophages. Cell-specific c-Cbl expression thus builds cell specificity into the LynA checkpoint.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 08, 2019
- Source ID
- 10.7554/elife.46043
Entities
People
- Adrienne S Jolicoeur
- Ben F Brian Iv
- Candace R Guerrero
- Justin M Drake
- Kathryn L Schwertfeger
- Myra G Nunez
- Nagy A Habib
- Pål Sætrom
- Siv A Hegre
- Tanya S Freedman
- Zoi E Sychev
Organizations
- American Cancer Society
- Imperial College London
- Norwegian University of Science and Technology
- Office of the Director
- Prostate Cancer Foundation
- Research Council of Norway
- United States Department of Defense
- University of Minnesota