Clearly, Notch signalling activity has been associated with cellular proliferation in a cell-autonomous as well as a non-cell-autonomous fashion. In fact, Notch signalling can be both oncogenic but also tumour suppressive, strongly depending on cell type and context. Moreover, Notch has a central role in oncogenesis that has been extensively studied. In accordance with a pivotal role in accurate cellular differentiation, Notch dysregulation has been associated with several congenital human diseases (reviewed in: ). The Notch receptor as well as all known Notch ligands are membrane tethered proteins, restricting ligand–receptor interactions to neighbouring cells or even within the same cell. In contrast to other pathways acting at a longer range via secreted morphogens or ligands, Notch signalling is restricted to intercellular contacts, thereby allowing for a direct cell–cell communication. The Notch signalling pathway belongs to a handful of highly conserved signalling pathways that govern cellular differentiation and homeostasis throughout development in eumetazoans. 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. Mutating presumptive protein contact sites, however, sensitised RBPJ for proteolysis. The homologous murine and human RBPJ proteins, however, are largely resistant to degradation in our system. Moreover, Su(H) stability is controlled by MAPK-dependent phosphorylation, matching earlier data for RBPJ in human cells. Using specific transgenic fly lines and HeLa RBPJ KO 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.
We noticed that the fly homologue suppressor of hairless (Su(H)) is stabilised in transcription complexes. CSL proteins are extremely similar amongst species regarding sequence and structure. Central to Notch signal transduction are CSL proteins: together with respective cofactors, they mediate the activation or the silencing of Notch target genes. Hence, dosage of Notch components is crucial to regulation. The primary role of Notch is to specify cellular identities, whereby the cells respond to amazingly small changes in Notch signalling activity.
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