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
Abstract
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.
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