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Published online
doi:10.1083/jcb.200905105
The Journal of Cell Biology, Vol. 187, No. 3, 343-353
The Rockefeller University Press, 0021-9525 $30.00
© Watanabe et al.
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Enhancement of Notch receptor maturation and signaling sensitivity by Cripto-1



Kazuhide Watanabe1, Tadahiro Nagaoka1, Joseph M. Lee1, Caterina Bianco1, Monica Gonzales1, Nadia P. Castro1, Maria Cristina Rangel1, Kei Sakamoto2, Youping Sun3, Robert Callahan1, and David S. Salomon1

1 Mammary Biology and Tumorigenesis Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
2 Oral Pathology, Tokyo Medical and Dental University Graduate School, Bunkyo-ku, Tokyo 113-8549, Japan
3 Department of Cell Biology, Harvard Medical School, Boston, MA 02115

Correspondence to Kazuhide Watanabe: kazuhidew{at}yahoo.com; or David S. Salomon: salomond{at}mail.nih.gov

Nodal and Notch signaling pathways play essential roles in vertebrate development. Through a yeast two-hybrid screening, we identified Notch3 as a candidate binding partner of the Nodal coreceptor Cripto-1. Coimmunoprecipitation analysis confirmed the binding of Cripto-1 with all four mammalian Notch receptors. Deletion analyses revealed that the binding of Cripto-1 and Notch1 is mediated by the Cripto-1/FRL-1/Cryptic domain of Cripto-1 and the C-terminal region of epidermal growth factor–like repeats of Notch1. Binding of Cripto-1 to Notch1 occurred mainly in the endoplasmic reticulum–Golgi network. Cripto-1 expression resulted in the recruitment of Notch1 protein into lipid raft microdomains and enhancement of the furin-like protein convertase-mediated proteolytic maturation of Notch1 (S1 cleavage). Enhanced S1 cleavage resulted in the sensitization to ligand-induced activation of Notch signaling. In addition, knockdown of Cripto-1 expression in human and mouse embryonal carcinoma cells desensitized the ligand-induced Notch signaling activation. These results suggest a novel role of Cripto-1 in facilitating the posttranslational maturation of Notch receptors.

Abbreviations used in this paper: BFA, brefeldin A; CFC, Cripto-1/FRL-1/Cryptic; EC, embryonal carcinoma; ECD, extracellular domain; FL, full length; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; ICD, intracellular domain; IP, immunoprecipitation; PE, phycoerythrin; SA, streptavidin; WT, wild type; Y2H, yeast two-hybrid.

© 2009 The Rockefeller University Press
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