title: Α-arrestin 1 (ARRDC1) and β-arrestins cooperate to mediate Notch degradation in mammals.
abstract: 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 β-arrestins are necessary for Itch-Notch interaction and for Itch-driven ubiquitylation and degradation of Notch. Interestingly, β-arrestins do not directly bind Itch but heterodimerize with a member of another subfamily of arrestins called ARRDC1 or α-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 β-arrestin(-/-) or Itch(-/-) cells. Our data show for the first time that ARRDC1 and β-arrestins heterodimerize and cooperate in the same complex to promote non-activated Notch receptor degradation, thus acting as negative regulators of Notch signaling.
authors.affiliation: Institut Pasteur and CNRS URA 2582, Signalisation Moléculaire et Activation Cellulaire, 25 Rue du Docteur Roux, 75724 Paris Cedex 15, France.
authors.forename: Loredana
authors.initials: L
authors.lastname: Puca
authors.forename: Patricia
authors.initials: P
authors.lastname: Chastagner
authors.forename: Vannary
authors.initials: V
authors.lastname: Meas-Yedid
authors.forename: Alain
authors.initials: A
authors.lastname: Israël
authors.forename: Christel
authors.initials: C
authors.lastname: Brou
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D045744:Cell Line, Tumor; D004705:Endocytosis / Q000502:physiology; D005347:Fibroblasts / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D054875:Ubiquitination; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D051880:Receptors, Notch; D000071557:beta-Arrestins
keywords: Arrestin; Endocytosis; Itch; Notch; Ubiquitin