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Science 338 (6111): 1229-1232

Copyright © 2012 by the American Association for the Advancement of Science

A Mutation in EGF Repeat-8 of Notch Discriminates Between Serrate/Jagged and Delta Family Ligands

Shinya Yamamoto,1 Wu-Lin Charng,1 Nadia A. Rana,2 Shinako Kakuda,2 Manish Jaiswal,3,4 Vafa Bayat,1,5 Bo Xiong,1 Ke Zhang,6 Hector Sandoval,3 Gabriela David,1 Hao Wang,3 Robert S. Haltiwanger,2 Hugo J. Bellen1,3,4,6,7,8,*

Abstract: Notch signaling affects many developmental and cellular processes and has been implicated in congenital disorders, stroke, and numerous cancers. The Notch receptor binds its ligands Delta and Serrate and is able to discriminate between them in different contexts. However, the specific domains in Notch responsible for this selectivity are poorly defined. Through genetic screens in Drosophila, we isolated a mutation, Notchjigsaw, that affects Serrate- but not Delta-dependent signaling. Notchjigsaw carries a missense mutation in epidermal growth factor repeat-8 (EGFr-8) and is defective in Serrate binding. A homologous point mutation in mammalian Notch2 also exhibits defects in signaling of a mammalian Serrate homolog, Jagged1. Hence, an evolutionarily conserved valine in EGFr-8 is essential for ligand selectivity and provides a molecular handle to study numerous Notch-dependent signaling events.

1 Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.
2 Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794, USA.
3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
4 Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA.
5 Medical Scientist Training Program, Baylor College of Medicine, Houston, TX 77030, USA.
6 Program in Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
7 Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
8 Jan and Dan Duncan Neurological Research Institute, Baylor College of Medicine, Houston, TX 77030, USA.

* To whom correspondence should be addressed. E-mail: hbellen{at}bcm.edu


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Intrinsic Selectivity of Notch 1 for Delta-like 4 Over Delta-like 1.
M. B. Andrawes, X. Xu, H. Liu, S. B. Ficarro, J. A. Marto, J. C. Aster, and S. C. Blacklow (2013)
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Understanding the Determinants of Notch Interactions with Its Ligands.
J. F. de Celis (2013)
Science Signaling 6, pe19
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An extracellular region of Serrate is essential for ligand-induced cis-inhibition of Notch signaling.
R. J. Fleming, K. Hori, A. Sen, G. V. Filloramo, J. M. Langer, R. A. Obar, S. Artavanis-Tsakonas, and A. C. Maharaj-Best (2013)
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The C8ORF38 homologue Sicily is a cytosolic chaperone for a mitochondrial complex I subunit.
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