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Unique-region phosphorylation targets LynA for rapid degradation, tuning its expression and signaling in myeloid cells.
- Source :
-
ELife [Elife] 2019 Jul 08; Vol. 8. Date of Electronic Publication: 2019 Jul 08. - Publication Year :
- 2019
-
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.<br />Competing Interests: BB, AJ, CG, MN, ZS, SH, PS, NH, JD, KS, TF No competing interests declared<br /> (© 2019, Brian et al.)
- Subjects :
- Animals
Humans
Jurkat Cells
Mice, Knockout
Phosphorylation
Proteolysis
Proto-Oncogene Proteins c-cbl genetics
Ubiquitin metabolism
src-Family Kinases genetics
Macrophages metabolism
Mast Cells metabolism
Myeloid Cells metabolism
Proto-Oncogene Proteins c-cbl metabolism
src-Family Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2050-084X
- Volume :
- 8
- Database :
- MEDLINE
- Journal :
- ELife
- Publication Type :
- Academic Journal
- Accession number :
- 31282857
- Full Text :
- https://doi.org/10.7554/eLife.46043