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

Wu, Guangyu and Lyapina, Svetlana and Das, Indranil and Li, Jinhe and Gurney, Mark and Pauley, Adele and Chui, Inca and Deshaies, Raymond J. and Kitajewski, Jan (2001) SEL-10 Is an Inhibitor of Notch Signaling That Targets Notch for Ubiquitin-Mediated Protein Degradation. Molecular and Cellular Biology, 21 (21). pp. 7403-7415. ISSN 0270-7306. PMCID PMC99913.

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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.

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Deshaies, Raymond J.0000-0002-3671-9354
Additional Information:© 2001, American Society for Microbiology. Received 25 January 2001/Returned for modification 23 March 2001/Accepted 19 July 2001 We are grateful to Yuko Takayasu, Liz Munoz, and Khaled Zeitoun for technical assistance. We thank Iva Greenwald, Martin Julius, and Richard Kessin for comments on the manuscript. We also thank G. Weinmaster, R. Kopan, P. Sorger, P. Jackson, and Y. Xiong for generously providing Jagged1 and Notch1 plasmids, Notch1Delta E plasmid, hSKP1 baculovirus, and anti-hSKP1 and anti-HRT1 antibodies, respectively. This work was supported by grants to J.K. from the NIH (RO1 HL62454 and RO1 CA75353) and the Marilyn Bokemeier Sperry Fund, by a grant to R.J.D. from the NIH (GM52466), and by a Burroughs-Wellcome Young Investigator in the Pharmacological Sciences award given to R.J.D. G.W. was supported by a predoctoral fellowship from the Department of Defense Breast Cancer Research program (DAMD17-97-1-7291), and I.D. was supported by an NIH training grant (2T32 DK07328).
Funding AgencyGrant Number
NIHRO1 HL62454
NIHRO1 CA75353
Marilyn Bokemeier Sperry FundUNSPECIFIED
Burroughs Wellcome FundUNSPECIFIED
Department of Defense Breast Cancer Research ProgramDAMD17-97-1-7291
NIH Predoctoral Fellowship2T32 DK07328
Issue or Number:21
PubMed Central ID:PMC99913
Record Number:CaltechAUTHORS:WUGmcb01
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:3047
Deposited By: Archive Administrator
Deposited On:12 May 2006
Last Modified:02 Oct 2019 22:59

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