Inhibition of Delta-induced Notch signaling using fucose analogs

Michael Schneider, Vivek Kumar, Lars Ulrik Nordstrøm, Lei Feng, Hideyuki Takeuchi, Huilin Hao, Vincent C. Luca, K. Christopher Garcia, Pamela Stanley, Peng Wu, Robert S. Haltiwanger

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Notch is a cell-surface receptor that controls cell-fate decisions and is regulated by O-glycans attached to epidermal growth factor-like (EGF) repeats in its extracellular domain. Protein O-fucosyltransferase 1 (Pofut1) modifies EGF repeats with O-fucose and is essential for Notch signaling. Constitutive activation of Notch signaling has been associated with a variety of human malignancies. Therefore, tools that inhibit Notch activity are being developed as cancer therapeutics. To this end, we screened L-fucose analogs for their effects on Notch signaling. Two analogs, 6-alkynyl and 6-alkenyl fucose, were substrates of Pofut1 and were incorporated directly into Notch EGF repeats in cells. Both analogs were potent inhibitors of binding to and activation of Notch1 by Notch ligands Dll1 and Dll4, but not by Jag1. Mutagenesis and modeling studies suggest that incorporation of the analogs into EGF8 of Notch1 markedly reduces the ability of Delta ligands to bind and activate Notch1.

Original languageEnglish (US)
Pages (from-to)65-71
Number of pages7
JournalNature Chemical Biology
Volume14
Issue number1
DOIs
StatePublished - Jan 1 2018

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Schneider, M., Kumar, V., Nordstrøm, L. U., Feng, L., Takeuchi, H., Hao, H., Luca, V. C., Garcia, K. C., Stanley, P., Wu, P., & Haltiwanger, R. S. (2018). Inhibition of Delta-induced Notch signaling using fucose analogs. Nature Chemical Biology, 14(1), 65-71. https://doi.org/10.1038/nchembio.2520