Ubiquitylation-independent activation of Notch signalling by Delta

Elife. 2017 Sep 29:6:e27346. doi: 10.7554/eLife.27346.

Abstract

Ubiquitylation (ubi) by the E3-ligases Mindbomb1 (Mib1) and Neuralized (Neur) is required for activation of the DSL ligands Delta (Dl) and Serrate (Ser) to activate Notch signalling. These ligases transfer ubiquitin to lysines of the ligands' intracellular domains (ICDs), which sends them into an Epsin-dependent endocytic pathway. Here, we have tested the requirement of ubi of Dl for signalling. We found that Dl requires ubi for its full function, but can also signal in two ubi-independent modes, one dependent and one independent of Neur. We identified two neural lateral specification processes where Dl signals in an ubi-independent manner. Neur, which is needed for these processes, was shown to be able to activate Dl in an ubi-independent manner. Our analysis suggests that one important role of DSL protein ubi by Mib1 is their release from cis-inhibitory interactions with Notch, enabling them to trans-activate Notch on adjacent cells.

Keywords: D. melanogaster; Delta; E3-ligase; Mindbomb1; Notch signalling; cell biology; cis-inhibition; neuralized.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Drosophila / physiology*
  • Drosophila Proteins / metabolism*
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Ki-67 Antigen / metabolism*
  • Membrane Proteins / metabolism*
  • Receptors, Notch / metabolism*
  • Signal Transduction*
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination

Substances

  • Drosophila Proteins
  • Intracellular Signaling Peptides and Proteins
  • Ki-67 Antigen
  • Membrane Proteins
  • Receptors, Notch
  • delta protein
  • Ubiquitin-Protein Ligases
  • neur protein, Drosophila

Grants and funding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.