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J. Biol. Chem., Vol. 278, Issue 16, 13607-13610, April 18, 2003
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From the Department of Anatomy and Neurobiology, College of
Medicine, University of Vermont, Burlington, Vermont 05405
The Delta protein is a single-pass transmembrane
ligand for the Notch family of receptors. Delta binding to Notch
invokes regulated intramembrane proteolysis and nuclear translocation of the Notch intracellular domain. Delta is proteolytically processed at two sites, Ala581 and Ala593 in the
juxtamembrane and transmembrane domains, respectively (Mishra-Gorur,
K., Rand, M. D., Perez-Villamil, B., and Artavanis-Tsakonas, S. (2002) J. Cell Biol. 159, 313-324). Controversy over
the role of Delta processing in propagating Notch signals has stemmed
from conflicting reports on the activity or inactivity of soluble
extracellular domain products of Delta. We have examined Delta
proteolysis in greater detail and report that Delta undergoes three
proteolytic cleavages in the region of the juxtamembrane and
transmembrane domains. Only one of these cleavages, analogous to
cleavage at Ala581, is dependent on the Kuzbanian ADAM
metalloprotease. The two additional cleavages correspond to the
previously described cleavage at Ala593 and a novel
unidentified site within or close to the transmembrane domain. Delta
processing is up-regulated in co-cultures with Notch-expressing cells
and is similarly induced by p-aminophenylmercuric
acetate, a well documented activator of metalloproteases.
Furthermore, expression of a truncated intracellular isoform of Delta
shows prominent nuclear localization. Altogether, these data
demonstrate a role for Notch in inducing Delta proteolysis and
implicate a nuclear function for Delta, consistent with a model of
bi-directional signaling through Notch-Delta interactions.
ACCELERATED PUBLICATION
Notch-induced Proteolysis and Nuclear Localization of the
Delta Ligand*
*
This work was supported by National Institutes of Health
Grant NCRR P20 RR16435-01 (awarded to M. D. R.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Anatomy and
Neurobiology, HSRF 426C, College of Medicine, University of Vermont,
Burlington, VT 05405. Tel.: 802-656-0405; Fax: 802-656-4674; E-mail:
mdrand@zoo.uvm.edu.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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