Unique-region phosphorylation targets LynA for rapid degradation, tuning its expression and signaling in myeloid cells

Ben F. Brian, Adrienne S. Jolicoeur, Candace R. Guerrero, Myra G. Nunez, Zoi E. Sychev, Siv A. Hegre, P. Sætrom, Nagy Habib, Justin M. Drake, Kathryn L. Schwertfeger, Tanya S. Freedman

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Article numbere46043
JournaleLife
Volume8
DOIs
StatePublished - Jul 8 2019

Bibliographical note

Funding Information:
NIH Office of the Director R01AR073966 NIH Office of the Director R03AI130978 American Cancer Society UMN IRG-58-001-55 University of Minnesota Grant-in-Aid #92286 University of Minnesota New Faculty Research Award NF-0315-02 University of Minnesota Equipment Award E-0918-01 NIH Office of the Director T32DA007097 Norwegian Research Council 230338 Prostate Cancer Foundation Young Investigator Award U.S. Department of Defense Prostate Cancer Research Program W81XWH-18-1-0542 NIH Office of the Director R01CA215052 NIH Office of the Director R01HD095858

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