Unique-region phosphorylation targets LynA for rapid degradation, tuning its expression and signaling in myeloid cells
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, fu...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2019-07-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/46043 |
| _version_ | 1811181160592572416 |
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| author | Ben F Brian IV Adrienne S Jolicoeur Candace R Guerrero Myra G Nunez Zoi E Sychev Siv A Hegre Pål Sætrom Nagy Habib Justin M Drake Kathryn L Schwertfeger Tanya S Freedman |
| author_facet | Ben F Brian IV Adrienne S Jolicoeur Candace R Guerrero Myra G Nunez Zoi E Sychev Siv A Hegre Pål Sætrom Nagy Habib Justin M Drake Kathryn L Schwertfeger Tanya S Freedman |
| author_sort | Ben F Brian IV |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T09:13:46Z |
| format | Article |
| id | doaj.art-4d165d0cea844d01860a31a07e4fe327 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:13:46Z |
| publishDate | 2019-07-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-4d165d0cea844d01860a31a07e4fe3272022-12-22T04:32:25ZengeLife Sciences Publications LtdeLife2050-084X2019-07-01810.7554/eLife.46043Unique-region phosphorylation targets LynA for rapid degradation, tuning its expression and signaling in myeloid cellsBen F Brian IV0Adrienne S Jolicoeur1Candace R Guerrero2Myra G Nunez3Zoi E Sychev4Siv A Hegre5Pål Sætrom6https://orcid.org/0000-0001-8142-7441Nagy Habib7https://orcid.org/0000-0003-4920-4154Justin M Drake8Kathryn L Schwertfeger9Tanya S Freedman10https://orcid.org/0000-0001-5168-5829Department of Pharmacology, University of Minnesota, Minneapolis, United StatesDepartment of Pharmacology, University of Minnesota, Minneapolis, United StatesCollege of Biological Sciences Center for Mass Spectrometry and Proteomics, University of Minnesota, Minneapolis, United StatesDepartment of Pharmacology, University of Minnesota, Minneapolis, United StatesDepartment of Pharmacology, University of Minnesota, Minneapolis, United StatesDepartment of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, NorwayDepartment of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway; Department of Computer Science, Norwegian University of Science and Technology, Trondheim, NorwayDepartment of Surgery and Cancer, Hammersmith Hospital, Imperial College London, London, United KingdomDepartment of Pharmacology, University of Minnesota, Minneapolis, United States; Masonic Cancer Center, University of Minnesota, Minneapolis, United States; Department of Urology, University of Minnesota, Minneapolis, United StatesDepartment of Pharmacology, University of Minnesota, Minneapolis, United States; Masonic Cancer Center, University of Minnesota, Minneapolis, United States; Center for Immunology, University of Minnesota, Minneapolis, United States; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, United StatesDepartment of Pharmacology, University of Minnesota, Minneapolis, United States; Masonic Cancer Center, University of Minnesota, Minneapolis, United States; Center for Immunology, University of Minnesota, Minneapolis, United States; Center for Autoimmune Diseases Research, University of Minnesota, Minneapolis, United StatesThe 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.https://elifesciences.org/articles/46043SFKs/Src-family kinasesCbl E3 ubiquitin ligasemyeloid cell signalingmacrophagemast cellLynA |
| spellingShingle | Ben F Brian IV Adrienne S Jolicoeur Candace R Guerrero Myra G Nunez Zoi E Sychev Siv A Hegre Pål Sætrom Nagy Habib Justin M Drake Kathryn L Schwertfeger Tanya S Freedman Unique-region phosphorylation targets LynA for rapid degradation, tuning its expression and signaling in myeloid cells eLife SFKs/Src-family kinases Cbl E3 ubiquitin ligase myeloid cell signaling macrophage mast cell LynA |
| title | Unique-region phosphorylation targets LynA for rapid degradation, tuning its expression and signaling in myeloid cells |
| title_full | Unique-region phosphorylation targets LynA for rapid degradation, tuning its expression and signaling in myeloid cells |
| title_fullStr | Unique-region phosphorylation targets LynA for rapid degradation, tuning its expression and signaling in myeloid cells |
| title_full_unstemmed | Unique-region phosphorylation targets LynA for rapid degradation, tuning its expression and signaling in myeloid cells |
| title_short | Unique-region phosphorylation targets LynA for rapid degradation, tuning its expression and signaling in myeloid cells |
| title_sort | unique region phosphorylation targets lyna for rapid degradation tuning its expression and signaling in myeloid cells |
| topic | SFKs/Src-family kinases Cbl E3 ubiquitin ligase myeloid cell signaling macrophage mast cell LynA |
| url | https://elifesciences.org/articles/46043 |
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