Siah-1 binds and regulates the function of Numb

doi:10.1073/pnas.261571998

Siah-1 binds and regulates the function of Numb

^*Molecular Engines Laboratories, 20 Rue Bouvier, 75011 Paris, France; ^‡Department of Molecular Cell Biology, Weizmann Institute of Science, 76100 Rehovot, Israel; ^§Flow Cytometry Unit, Institut Jacques Monod, 2 Place Jussieu, 75251 Paris Cedex 05, France; and ^¶Unitée de Recherche Associée 1773 Centre National de la Recherche Scientifique, Institut Pasteur, 25 Rue du Dr. Roux, 75724 Paris, France

Communicated by Georges Charpak, European Organization for Nuclear Research, Geneva, Switzerland (received for review August 14, 2001)

Abstract

The Drosophila Seven in absentia (Sina) gene product originally was described as a protein that controls cell fate decisions during eye development. Its mammalian homolog, Siah-1, recently was found to be involved in p53-dependent and -independent pathways of apoptosis and G₁ arrest. We report that Siah-1 interacts directly with and promotes the degradation of the cell fate regulator Numb. Siah-1-mediated Numb degradation leads to redistribution of endogenous cell-surface Notch to the cytoplasm and nucleus and to augmented Notch-regulated transcriptional activity. These data imply that through its ability to target Numb for degradation, Siah-1 can act as a key regulator of Numb-related activities, including Notch signaling.

Footnotes

↵ † L.S., B.J.P., N.A.-E., and T.J.-G. contributed equally to this work.
↵ ‖ To whom reprint requests should be addressed. E-mail: atelerman{at}molecularengines.com.
Abbreviations:

Sina,

Seven in absentia;

Siah-1,

Siah-1a gene product;

SOP,

sensory organ progenitor;

PTB,

phosphotyrosine-binding domain;

GST,

glutathione S-transferase;

β-gal,

β-galactosidase;

HA,

hemagglutinin;

IP,

immunoprecipitation;

NICD,

Notch intracellular domain