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, Kaylee Schwertfeger, Tanya S Freedman

Research output: Contribution to journalArticle

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 1 2019

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Phosphorylation
src-Family Kinases
Macrophages
Myeloid Cells
Tuning
Chemical activation
Mast Cells
Degradation
Tyrosine
Immunoreceptor Tyrosine-Based Activation Motif
Phosphopeptides
Ubiquitin-Protein Ligases
Ubiquitin
Molecular Biology

PubMed: MeSH publication types

  • Journal Article
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

Cite this

Unique-region phosphorylation targets LynA for rapid degradation, tuning its expression and signaling in myeloid cells. / Brian, Ben F.; Jolicoeur, Adrienne S.; Guerrero, Candace R; Nunez, Myra G.; Sychev, Zoi E.; Hegre, Siv A.; Sætrom, P.; Habib, Nagy; Drake, Justin M; Schwertfeger, Kaylee; Freedman, Tanya S.

In: eLife, Vol. 8, e46043, 01.07.2019.

Research output: Contribution to journalArticle

Brian, Ben F. ; Jolicoeur, Adrienne S. ; Guerrero, Candace R ; Nunez, Myra G. ; Sychev, Zoi E. ; Hegre, Siv A. ; Sætrom, P. ; Habib, Nagy ; Drake, Justin M ; Schwertfeger, Kaylee ; Freedman, Tanya S. / Unique-region phosphorylation targets LynA for rapid degradation, tuning its expression and signaling in myeloid cells. In: eLife. 2019 ; Vol. 8.
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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.",
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AU - Nunez, Myra G.

AU - Sychev, Zoi E.

AU - Hegre, Siv A.

AU - Sætrom, P.

AU - Habib, Nagy

AU - Drake, Justin M

AU - Schwertfeger, Kaylee

AU - Freedman, Tanya S

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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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