The Binding of CSL Proteins to Either Co-Activators or Co-Repressors Protects from Proteasomal Degradation Induced by MAPK-Dependent Phosphorylation
| Autor: | Johannes Fechner, Manuela Ketelhut, Dieter Maier, Anette Preiss, Anja C. Nagel |
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| Rok vydání: | 2022 |
| Předmět: |
Receptors
Notch Organic Chemistry General Medicine activator complex CSL degron MAPK Notch signalling dynamics suppressor of hairless proteasomal degradation protein stability repressor complex Catalysis Computer Science Applications Inorganic Chemistry Repressor Proteins Mice Drosophila melanogaster Humans Animals Drosophila Proteins Physical and Theoretical Chemistry Phosphorylation Molecular Biology Co-Repressor Proteins Spectroscopy Protein Binding |
| Zdroj: | International Journal of Molecular Sciences; Volume 23; Issue 20; Pages: 12336 |
| ISSN: | 1422-0067 |
| Popis: | The primary role of Notch is to specify cellular identities, whereby the cells respond to amazingly small changes in Notch signalling activity. Hence, dosage of Notch components is crucial to regulation. Central to Notch signal transduction are CSL proteins: together with respective cofactors, they mediate the activation or the silencing of Notch target genes. CSL proteins are extremely similar amongst species regarding sequence and structure. We noticed that the fly homologue suppressor of hairless (Su(H)) is stabilised in transcription complexes. Using specific transgenic fly lines and HeLa RBPJKO cells we provide evidence that Su(H) is subjected to proteasomal degradation with a half-life of about two hours if not protected by binding to co-repressor hairless or co-activator Notch. Moreover, Su(H) stability is controlled by MAPK-dependent phosphorylation, matching earlier data for RBPJ in human cells. The homologous murine and human RBPJ proteins, however, are largely resistant to degradation in our system. Mutating presumptive protein contact sites, however, sensitised RBPJ for proteolysis. Overall, our data highlight the similarities in the regulation of CSL protein stability across species and imply that turnover of CSL proteins may be a conserved means of regulating Notch signalling output directly at the level of transcription. |
| Databáze: | OpenAIRE |
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