| First Author | Puca L | Year | 2013 |
| Journal | J Cell Sci | Volume | 126 |
| Issue | Pt 19 | Pages | 4457-68 |
| PubMed ID | 23886940 | Mgi Jnum | J:245299 |
| Mgi Id | MGI:5916812 | Doi | 10.1242/jcs.130500 |
| Citation | Puca L, et al. (2013) Alpha-arrestin 1 (ARRDC1) and beta-arrestins cooperate to mediate Notch degradation in mammals. J Cell Sci 126(Pt 19):4457-68 |
| abstractText | Notch signaling is a conserved signaling pathway implicated in embryogenesis and adult tissue maintenance. Notch signaling strength is strictly regulated, notably by maintaining a controlled pool of functional receptor at the cell surface. Mammalian non-activated Notch receptor is internalized, ubiquitylated by the Itch E3 ubiquitin ligase and degraded in the lysosomes. Here, we show that beta-arrestins are necessary for Itch-Notch interaction and for Itch-driven ubiquitylation and degradation of Notch. Interestingly, beta-arrestins do not directly bind Itch but heterodimerize with a member of another subfamily of arrestins called ARRDC1 or alpha-arrestin 1, which harbors PPxY motifs that allow direct interaction with Itch. Cells transfected with ARRDC1 mutated in PPxY motifs show reduced Itch-mediated Notch ubiquitylation and impaired lysosomal degradation of Notch, as observed in beta-arrestin(-/-) or Itch(-/-) cells. Our data show for the first time that ARRDC1 and beta-arrestins heterodimerize and cooperate in the same complex to promote non-activated Notch receptor degradation, thus acting as negative regulators of Notch signaling. |
