Reference Report

Reference
Citation	Sakata, T., Sakaguchi, H., Tsuda, L., Higashitani, A., Aigaki, T., Matsuno, K., Hayashi, S. (2004). Drosophila Nedd4 regulates endocytosis of Notch and suppresses its ligand-independent activation. Curr. Biol. 14(24): 2228--2236. (Export to RIS)
FlyBase ID	FBrf0183817
Publication Type	Research paper
PubMed ID	15620649
PubMed Abstract	Ligand-induced proteolytic cleavage and internalization of the plasma membrane receptor Notch leads to its activation. Ligand-independent, steady-state internalization of Notch, however, does not lead to activation. The mechanism by which downstream effectors discriminate between these bipartite modes of Notch internalization is not understood. Nedd4 is a HECT domain-containing E3 ubiquitin ligase that targets transmembrane receptors containing the PPSY motif for endocytosis. Deltex is a positive Notch signaling regulator that encodes a putative ubiquitin ligase of the ring finger type.We used the Drosophila system to show that Notch is ubiquitinated and destabilized by Nedd4 in a manner requiring the PPSY motif in the Notch intracellular domain. Loss of Nedd4 function dominantly suppresses the Notch and Deltex mutant phenotypes, and its hyperactivation attenuates Notch activity. In tissue culture cells, the dominant-negative form of Nedd4 blocks steady-state Notch internalization and activates Notch signaling independently of ligand binding. This effect was further potentiated by Deltex. Nedd4 destines Deltex for degradation in a Notch-dependent manner.Nedd4 antagonizes Notch signaling by promoting degradation of Notch and Deltex. This Nedd4 function may be important for protecting unstimulated cells from sporadic activation of Notch signaling.
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Supplementary material	Supplemental Data. [FBrf0188485]
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Language of Publication	English
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Publication Type	Journal
Abbreviation	Curr. Biol.
Title	Current Biology
Publication Year	1991-
ISBN/ISSN	0960-9822
Data from Reference
Alleles (32)
	Dl::N^{ΔECN.Scer\UAS} dx^{Scer\UAS.T:Avic\GFP-YFP} N^264-39 N^MGIIa.MtnA N^{Scer\UAS.T:Zzzz\FLAG} N^{Y2328F.Scer\UAS.T:Zzzz\FLAG} Nedd4^{C974FS.Scer\UAS.T:Ivir\HA1} Nedd4^C974FS Nedd4^D730FS Nedd4^dsRNA.cSa Nedd4^G693E Nedd4^G746S Nedd4^GS13178 Nedd4^L613FS Nedd4^L695F Nedd4^L725FS Nedd4^M884I Nedd4^N121FS Nedd4^N602FS Nedd4^N728S Nedd4^Q855stop Nedd4^{Scer\UAS.T:Ivir\HA1} Nedd4^T119FS Nedd4^unspecified Nedd4^{V831D+del832-837} Nedd4^W699stop Nedd4^Y741H Ppyr\LUC^HLHmγ.PA Scer\GAL4^en-e16E Scer\GAL4^ptc-559.1 T:Avic\GFP^YFP Ubi-p63E^{hs.T:Ivir\HA1}
Genes (10)
	Dl::N dx N Nedd4 Ppyr\LUC Scer\GAL4 T:Ivir\HA1 T:Zzzz\FLAG Ubi-p63E wg
Insertions (2)
	P{en2.4-GAL4}e16E P{GawB}ptc^559.1