Enhancement of Notch receptor maturation and signaling sensitivity by Cripto-1

Kazuhide Watanabe, Tadahiro Nagaoka, Joseph M. Lee, Caterina Bianco, Monica Gonzales, Nadia P. Castro, Maria Cristina Rangel, Kei Sakamoto, Youping Sun, Robert Callahan, David S. Salomon

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32 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)343-353
Number of pages11
JournalJournal of Cell Biology
Issue number3
Publication statusPublished - 02-11-2009

All Science Journal Classification (ASJC) codes

  • Cell Biology

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    Watanabe, K., Nagaoka, T., Lee, J. M., Bianco, C., Gonzales, M., Castro, N. P., Rangel, M. C., Sakamoto, K., Sun, Y., Callahan, R., & Salomon, D. S. (2009). Enhancement of Notch receptor maturation and signaling sensitivity by Cripto-1. Journal of Cell Biology, 187(3), 343-353. https://doi.org/10.1083/jcb.200905105