Functional Interaction between SEL-10, an F-box Protein, and the Nuclear Form of Activated Notch1 Receptor

The Notch signaling pathway is essential in many cell fate decisions in invertebrates as well as in vertebrates. After ligand binding, a two-step proteolytic cleavage releases the intracellular part of the receptor which translocates to the nucleus and acts as a transcriptional activator. Although N...

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Bibliographic Details
Published in:The Journal of biological chemistry 2001-09, Vol.276 (37), p.34371-34378
Main Authors: Gupta-Rossi, Neetu, Le Bail, Odile, Gonen, Hedva, Brou, Christel, Logeat, Frédérique, Six, Emmanuelle, Ciechanover, Aaron, Israël, Alain
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Caenorhabditis elegans
Caenorhabditis elegans Proteins
Cell Cycle Proteins
Cell Cycle Proteins - genetics
Cell Cycle Proteins - physiology
Cell Line
Cell Nucleus
Cell Nucleus - metabolism
Cellular Biology
Cysteine Endopeptidases
Cysteine Endopeptidases - physiology
F-box protein
Helminth Proteins
Helminth Proteins - genetics
Helminth Proteins - physiology
Humans
Life Sciences
Membrane Proteins
Membrane Proteins - metabolism
Mice
Molecular Sequence Data
Multienzyme Complexes
Multienzyme Complexes - physiology
Notch1 protein
Phosphorylation
Proteasome Endopeptidase Complex
Receptor, Notch1
Receptors, Cell Surface
SEL-10 protein
Transcription Factors
Transcriptional Activation
Ubiquitins
Ubiquitins - metabolism
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Summary:The Notch signaling pathway is essential in many cell fate decisions in invertebrates as well as in vertebrates. After ligand binding, a two-step proteolytic cleavage releases the intracellular part of the receptor which translocates to the nucleus and acts as a transcriptional activator. Although Notch-induced transcription of genes has been reported extensively, its endogenous nuclear form has been seldom visualized. We report that the nuclear intracellular domain of Notch1 is stabilized by proteasome inhibitors and is a substrate for polyubiquitination in vitro. SEL-10, an F-box protein of the Cdc4 family, was isolated in a genetic screen for Lin12/Notch-negative regulators in Caenorhabditis elegans. We isolated human and murine counterparts of SEL-10 and investigated the role of a dominant-negative form of this protein, deleted of the F-box, on Notch1 stability and activity. This molecule could stabilize intracellular Notch1 and enhance its transcriptional activity but had no effect on inactive membrane-anchored forms of the receptor. We then demonstrated that SEL-10 specifically interacts with nuclear forms of Notch1 and that this interaction requires a phosphorylation event. Taken together, these data suggest that SEL-10 is involved in shutting off Notch signaling by ubiquitin-proteasome-mediated degradation of the active transcriptional factor after a nuclear phosphorylation event.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M101343200