TY - JOUR
T1 - Unique-region phosphorylation targets LynA for rapid degradation, tuning its expression and signaling in myeloid cells
AU - Brian, Ben F.
AU - Jolicoeur, Adrienne S.
AU - Guerrero, Candace R.
AU - Nunez, Myra G.
AU - Sychev, Zoi E.
AU - Hegre, Siv A.
AU - Sætrom, P.
AU - Habib, Nagy
AU - Drake, Justin M.
AU - Schwertfeger, Kathryn L.
AU - Freedman, Tanya S.
N1 - Publisher Copyright:
© Brian et al.
PY - 2019/7
Y1 - 2019/7
N2 - 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.
AB - 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.
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U2 - 10.7554/eLife.46043
DO - 10.7554/eLife.46043
M3 - Article
C2 - 31282857
AN - SCOPUS:85070661009
SN - 2050-084X
VL - 8
JO - eLife
JF - eLife
M1 - e46043
ER -