Processing of the Notch Ligand Delta by the Metalloprotease Kuzbanian

Huilin Qi, Matthew D. Rand, Xiaohui Wu, Nenad Sestan, Weiyi Wang, Pasko Rakic, Tain Xu, Spyros Artavanis-Tsakonas

Science 283, 91-94 (1999)



    Delta (Dl) functions as a cell nonautonomous membrane-bound ligand that binds to Notch (N), a cell-autonomous receptor, during cell fate specification. Interaction between Delta and Notch leads to signal transduction and elicitation of cellular response. The metalloprotease-disintegrin Kuzbanian (Kuz) is involved in the interaction between Delta and Notch. To examine the role of Kuz in this interaction, the authors performed a dominant negative transgene of Kuz (KuzDN) in flies. The KuzDN phenotypes can be rescued by a higher copy number of Dl molecules. The interaction between Delta and Kuz was further explored. In this work, the authors found that Dl can be cleaved at the cell surface to release a soluble fragment, designated as DlEC (Delta excellular domain). The generation of DlEC can be influenced by Kuz. It demonstrated that the proteolytic processing of the Dl protein is mediated by Kuz. This additional cleavage of Dl, the mode of activity of full-length Dl, is biologically active with an apparent agonistic function in the Notch pathway.


1. Rook, J., Pan, D., Xu, T., and Rubin G. M. KUZ, a conserved metalloprotease-disintegrin protein with two roles in drosophila neurogenesis. Science 273, 1227-1231 (1996)
2. Sotillos, S., Roch, F., and Campuzano, S. The metalloprotease-disintegrin Kuzbanian participates in Notch activation during growth and patterning of drosophila imaginal discs. Development 124, 4769-4779 (1997)
3. Artavanis-Taasaknos, S., Rand, M. D., and Lake, R. J. Notch signaling: cell fate control and signal interaction in development. Science284, 770-776 (1999)