Journal
EMBO JOURNAL
Volume 25, Issue 20, Pages 4697-4706Publisher
WILEY
DOI: 10.1038/sj.emboj.7601337
Keywords
Drosophila; endocytosis; notch; Serrate; ubiquitination
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Funding
- Medical Research Council [G0200457] Funding Source: Medline
- Medical Research Council [G0200457] Funding Source: researchfish
- MRC [G0200457] Funding Source: UKRI
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Notch is the receptor in a signalling pathway that operates in a diverse spectrum of developmental processes. Its ligands (e.g. Serrate) are transmembrane proteins whose signalling competence is regulated by the endocytosis-promoting E3 ubiquitin ligases, Mindbomb1 and Neuralized. The ligands also inhibit Notch present in the same cell (cis-inhibition). Here, we identify two conserved motifs in the intracellular domain of Serrate that are required for efficient endocytosis. The first, a dileucine motif, is dispensable for trans-activation and cis-inhibition despite the endocytic defect, demonstrating that signalling can be separated from bulk endocytosis. The second, a novel motif, is necessary for interactions with Mindbomb1/Neuralized and is strictly required for Serrate to trans-activate and internalise efficiently but not for it to inhibit Notch signalling. Cis-inhibition is compromised when an ER retention signal is added to Serrate, or when the levels of Neuralized are increased, and together these data indicate that cis-inhibitory interactions occur at the cell surface. The balance of ubiquitinated/ unubiquitinated ligand will thus affect the signalling capacity of the cell at several levels.
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