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Molecular and Cellular Biology, November 2001, p. 7403-7415, Vol. 21, No. 21
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.21.7403-7415.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

SEL-10 Is an Inhibitor of Notch Signaling That Targets Notch for Ubiquitin-Mediated Protein Degradation

Guangyu Wu,1,2 Svetlana Lyapina,3 Indranil Das,1,2 Jinhe Li,4 Mark Gurney,4 Adele Pauley,4 Inca Chui,1,2 Raymond J. Deshaies,3,5 and Jan Kitajewski1,2,*

Departments of Pathology1 and Obstetrics and Gynecology,2 Columbia University, New York, New York 10032; Division of Biology3 and Howard Hughes Medical Institute,5 California Institute of Technology, Pasadena, California 91125; and Department of Neurobiology, Pharmacia & Upjohn, Kalamazoo, Michigan 490014

Received 25 January 2001/Returned for modification 23 March 2001/Accepted 19 July 2001

Notch receptors and their ligands play important roles in both normal animal development and pathogenesis. We show here that the F-box/WD40 repeat protein SEL-10 negatively regulates Notch receptor activity by targeting the intracellular domain of Notch receptors for ubiquitin-mediated protein degradation. Blocking of endogenous SEL-10 activity was done by expression of a dominant-negative form containing only the WD40 repeats. In the case of Notch1, this block leads to an increase in Notch signaling stimulated by either an activated form of the Notch1 receptor or Jagged1-induced signaling through Notch1. Expression of dominant-negative SEL-10 leads to stabilization of the intracellular domain of Notch1. The Notch4 intracellular domain bound to SEL-10, but its activity was not increased as a result of dominant-negative SEL-10 expression. SEL-10 bound Notch4 via the WD40 repeats and bound preferentially to a phosphorylated form of Notch4 in cells. We mapped the region of Notch4 essential for SEL-10 binding to the C-terminal region downstream of the ankyrin repeats. When this C-terminal fragment of Notch4 was expressed in cells, it was highly labile but could be stabilized by the expression of dominant-negative SEL-10. Ubiquitination of Notch1 and Notch4 intracellular domains in vitro was dependent on SEL-10. Although SEL-10 interacts with the intracellular domains of both Notch1 and Notch4, these proteins respond differently to interference with SEL-10 function. Thus, SEL-10 functions to promote the ubiquitination of Notch proteins; however, the fates of these proteins may differ.

* Corresponding author. Mailing address: Departments of Pathology and Obstetrics and Gynecology, Columbia University, 630 West 168 St., New York, NY 10032. Phone: (212) 305-3624. Fax: (212) 305-3624. E-mail: jkk9{at}columbia.edu.

Molecular and Cellular Biology, November 2001, p. 7403-7415, Vol. 21, No. 21
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.21.7403-7415.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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