Notch Ligand Ubiquitylation: What Is It Good For?

Abstract

Summary In the first volume of Developmental Cell, it was reported that the classic Drosophila neurogenic gene neuralized encodes a ubiquitin ligase that monoubiquitylates the Notch ligand Delta, thus promoting Delta endocytosis. A requirement for ligand internalization by the signal-sending cell, although counterintuitive, remains to date a feature unique to Notch signaling. Ten years and many ubiquitin ligases later, we discuss sequels to these three papers with an eye towards reviewing the development of ideas for how ligand ubiquitylation and endocytosis propel Notch signaling.

Activation of Notch in lgd mutant cells requires the fusion of late endosomes with the lysosome

“…The Notch pathway is present in all metazoans and plays a major role in many developmental and homeostatic processes as well as in disease (Weinmaster and Fischer, 2011). In Drosophila the Notch receptor is activated by two ligands, Delta (Dl) and Serrate (Ser).…”

Genetic identification of intracellular trafficking regulators involved in notch dependent binary cell fate acquisition following asymmetric cell division

“…Several lines of evidence suggest that endocytic trafficking of DSL ligands enhances their signalling activity while receptor trafficking insures their steady state level at the cell surface thereby regulating their availability for ligand binding (reviewed by Bray, 2006;Fürthauer and González-Gaitán, 2009;Kopan and Ilagan, 2009;Le Borgne, 2006;Weinmaster and Fischer, 2011;Yamamoto et al, 2010). Although recycling of DSL ligands is necessary to produce an active DSL ligand, the nature of this maturation is still poorly characterised and two models are actually favoured: endocytosis and pulling forces (Klueg and Muskavitch, 1999;Nichols et al, 2007;Windler and Bilder, 2010) versus endocytosis and recycling (Benhra et al, 2010;Emery et al, 2005;Jafar-Nejad et al, 2005;Le Borgne and Schweisguth, 2003;Rajan et al, 2009;Wang and Struhl, 2004).…”

Ral inhibits ligand-independent Notch signaling in Drosophila

“…28,31 Neuralized ubiquitylates Delta, a prerequisite for Delta endocytosis by pre-R3 and activation of Notch in pre-R4. 27 Alternatively or in addition, activated Frizzled relocalizes in a complex with a cortical protein called Disheveled to the R3/R4 interface where the complex prevents Notch receptor activation directly in pre-R3. 30,32 We found that Ral defines a distinct pathway by which R3 is biased to become the Delta signaling cell.…”

“…25 Most evidence suggests that Epsin is required after ligand/ receptor binding to internalize ligand into the signal-sending cells thereby exerting mechanical force on the receptor that leads to its activation. 26,27 We determined that we identified Ral mutants in our screen because Ral is a negative regulator of Notch signaling. 19 We do not understand the mechanism by which Epsin overexpression disrupts eye development and so we cannot say precisely why loss of Ral activity enhances the eye defects.…”