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PLoS One. 2008 Jul 16;3(7):e2735. doi: 10.1371/journal.pone.0002735.

AIP4/Itch regulates Notch receptor degradation in the absence of ligand.

Author information

1
Unité de Signalisation Moléculaire et Activation Cellulaire, URA 2582, CNRS, Institut Pasteur, Paris, France.

Abstract

BACKGROUND:

The regulation of Notch signaling heavily relies on ubiquitination events. Drosophila Su(dx), a member of the HECT family of ubiquitin-ligases, has been described as a negative regulator of Notch signaling, acting on the post-endocytic sorting of Notch. The mammalian ortholog of Su(dx), Itch/AIP4, has been shown to have multiple substrates, including Notch, but the precise events regulated by Itch/AIP4 in the Notch pathway have not been identified yet.

METHODOLOGY/PRINCIPAL FINDINGS:

Using Itch-/- fibroblasts expressing the Notch1 receptor, we show that Itch is not necessary for Notch activation, but rather for controlling the degradation of Notch in the absence of ligand. Itch is indeed required after the early steps of Notch endocytosis to target it to the lysosomes where it is degraded. Furthermore Itch/AIP4 catalyzes Notch polyubiquitination through unusual K29-linked chains. We also demonstrate that although Notch is associated with Itch/AIP4 in cells, their interaction is not detectable in vitro and thus requires either a post-translational modification, or a bridging factor that remains to be identified.

CONCLUSIONS/SIGNIFICANCE:

Taken together our results identify a specific step of Notch regulation in the absence of any activation and underline differences between mammalian and Drosophila Notch pathways.

PMID:
18628966
PMCID:
PMC2444042
DOI:
10.1371/journal.pone.0002735
[Indexed for MEDLINE]
Free PMC Article

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