Characterisation of the co-adapter function of the E3 ligase Neuralized (Neur) during DSL-ligand induced Notch signalling

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Notch signalling plays a crucial role in many developmental processes in all metazoans. Moreover, it is required for homeostasis of several adult tissues, including in humans, through its involvement in maintenance of adult stem cells. Endocytosis is required for the full ligand induced activation of the pathway. It is initiated by the membrane-associated E3 ligases Neuralized (Neur) and Mindbomb1 (Mib1). They bind to the intracellular domains (ICDs) of DSL ligands to mediate the ubiquitylation (ubi) on lysine (K) side chains. The ubiquitylated ligands are recognised by the endocytic adapter Liquid Facets (Lqf)/Epsin via its ubiquitin binding domains and thereby connected to the endocytic core machinery. In Drosophila, the two E3 ligases can functionally substitute for one another during wing development, indicating that they can perform similar functions, even though they share no sequence similarity apart from a RING (Really Interesting New Gene) Finger domain (RF), which is required for ubi. However, Mib1 cannot replace the function of Neur during neurogenesis, suggesting that Neur can initiate Notch signalling in a manner different from Mib1. Our recent work supports this notion by revealing that ligands that cannot be ubiquitylated can be activated by Neur, but not Mib1. Hence, Neur has another so far unknown function despite its E3 ligase activity, which cannot be provided by Mib1. In this application, we will further characterise the function of Neur and follow the hypothesis that Neur is a novel type of endocytic co-adapter that forms a complex with Lqf/Epsin to connect the ligands in an additional way to the core endocytic machinery.