期刊
JOURNAL OF CELL SCIENCE
卷 126, 期 19, 页码 4457-4468出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.130500
关键词
Arrestin; Endocytosis; Itch; Notch; Ubiquitin
类别
资金
- Institut Pasteur
- Centre national de la recherche scientifique (CNRS)
- Association pour la Recherche sur le Cancer [SFI20101201664]
- Ligue Nationale Contre le Cancer [LNCC RS11/75-21]
- Pasteur-Paris University (PPU) International PhD program
- SFD (Societe Francaise de Dermatologie)
- FRM (Fondation pour la Recherche Medicale)
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.
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