β-Arrestin, well known for its role in G protein-coupled receptor regulation, is also being recognized for its roles in regulating other types of receptors. Now Mukherjee et al. report that Drosophila β-arrestin, Kurtz (Krz), is involved in controlling the abundance of the receptor Notch, which is a single transmembrane receptor that is cleaved in response to ligand binding, releasing a fragment that translocates to the nucleus to regulate transcription. Krz was found in two different screens for proteins that interacted with the Notch regulator and putative E3 ubiquitin ligase Deltex (Dx). Coimmunoprecipitation experiments and colocalization experiments confirmed the interaction of Krz and Dx and further showed that Notch and these two proteins form a ternary complex. When Krz and Dx were transfected into Drosophila S2 cells, the two proteins colocalized in intracellular vesicles and, in fly wings, overexpression of the two proteins led to depletion of Notch from Dx-positive vesicles. In flies, loss of Krz function led to increased Notch abundance and, in a context-dependent manner, this produced increased Notch signaling. Overexpression of both Krz and Dx produced Notch loss-of-function phenotypes and reduced Notch protein abundance. In transfected Drosophila S2 cells, Krz and Dx together promoted ubiquitination of Notch, which was detectable in the presence of proteasome inhibitors. Notch signaling is highly sensitive to gene dosage effects, and β-arrestin appears to be one component that contributes to this sensitivity. Questions that remain include whether Krz recruits additional E3 ubiquitin ligases to the internalized receptor or whether Krz alters the E3 ligase activity of Dx to promote Notch ubiquitination (see Shenoy and Lefkowitz for commentary).
A. Mukherjee, A. Veraksa, A. Bauer, C. Rosse, J. Camonis, S. Artavanis-Tsakonas, Regulation of Notch signalling by non-visual β-arrestin. Nat. Cell Biol. 7, 1191-1201 (2005). [PubMed]
S. K. Shenoy, R. J. Lefkowitz, Receptor regulation: β-arrestin moves up a notch. Nat. Cell Biol. 7, 1159-1161 (2005). [PubMed]