Puca L, Chastagner P, Meas-Yedid V, Israel A, Brou C

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, ubiquitinated by the Itch E3 ubiquitin ligase and degraded in the ...

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lysosomes. Here we demonstrate that β-arrestins are necessary for Itch-Notch interaction and for the Itch-driven Notch ubiquitination and degradation. Interestingly, β-arrestins do not directly bind Itch but heterodimerize with a member of another subfamily of arrestins called ARRDC1/α-arrestin 1, which harbors PPXY motifs accounting for direct interaction with Itch. Cells transfected with ARRDC1 mutated in PPXY motifs show reduced Itch-mediated Notch ubiquitination and impaired Notch lysosomal degradation, as observed in β-arrestins-/- 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 acting as negative regulators of Notch signaling.

Date: Jul. 25, 2013

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