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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. In a previous paper (Freedman et al., 2015) we showed that the SFK LynA is uniquely susceptible to rapid ubiquitin-mediated degradation in macrophages, functioning as a rheostat regulating signaling. 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. 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 therefore builds cell specificity into the LynA checkpoint.

ORGANISM(S): Mus Musculus

SUBMITTER: Tanya Freedman

PROVIDER: PXD014621 | panorama | Mon Jul 15 00:00:00 BST 2019

REPOSITORIES: PanoramaPublic

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

Brian Ben F BF Jolicoeur Adrienne S AS Guerrero Candace R CR Nunez Myra G MG Sychev Zoi E ZE Hegre Siv A SA Sætrom Pål P Habib Nagy N Drake Justin M JM Schwertfeger Kathryn L KL Freedman Tanya S TS

eLife 20190708

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 Ly ...[more]

PMID: 31282857

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

Publications

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

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