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J. Biol. Chem., Vol. 278, Issue 10, 8771-8779, March 7, 2003
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From the Department of Molecular Genetics, Biochemistry, and
Microbiology, University of Cincinnati, College of Medicine,
Cincinnati, Ohio 45267-0524
JAGGED1 is a member of the Delta/Serrate/Lag-2
(DSL) family of proteins that are cell-bound ligands for Notch
receptors. Initiation of Notch signaling occurs through a series of
proteolytic events upon the binding of Notch to a DSL protein presented
on neighboring cells. Whether DSL proteins themselves are capable of
initiating an intrinsic signaling mechanism within the cell they are
expressed is not known. Aberrant misexpression of JAGGED1 and DELTA1
has been documented in several human tumors; however, the mechanism by
which misexpression of JAGGED1 contributes to oncogenesis has not been
elucidated. We report that expression of human JAGGED1 transforms RKE
cells in culture, therefore providing a model system to elucidate the
function of DSL proteins. JAGGED1-mediated transformation occurs in a
dose-dependent manner and requires a PDZ-ligand at the C
terminus. Mutation of the PDZ-ligand did not affect the ability of
JAGGED1 to initiate Notch signaling in neighboring cells. However, the
PDZ-ligand is required for changes in the expression of JAGGED1 target
genes and transcriptional activation of luciferase reporter constructs.
Our data indicate the existence of a novel PDZ-dependent
signaling pathway intrinsic to JAGGED1. We propose a bi-directional
signaling model such that DSL proteins may have two distinct functions:
to initiate Notch signaling in a neighboring cell and to initiate a
PDZ-dependent signaling mechanism in the DSL-expressing
cell. Moreover, we conclude that this intrinsic signaling
mechanism of JAGGED1 may partly provide a link between aberrant
misexpression of JAGGED1 and tumorigenesis.
The C-terminal PDZ-Ligand of JAGGED1 Is Essential
for Cellular Transformation*,
*
This work was funded in part by Grant RPG LBC-99465 from the
American Cancer Society (to A. J. C.) and Grant ROI CA 83736 from the
National Cancer Institute (to A. J. C.) and the NCI National Institutes of Health Training Grant 5T32 CA59268 (to J. M. A.). A. J. C. is a scholar of the Leukemia and Lymphoma Society (Award 1298-02).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.
The on-line version of this article (available at
http://www.jbc.org) contains supplementary data.
To whom correspondence should be addressed: 231 Albert Sabin Way,
Dept. of Molecular Genetics, University of Cincinnati, College of
Medicine, Cincinnati, OH 45267-0524. Tel.: 513-558-3664; Fax: 513-558-8474; E-mail: tony.capobianco@uc.edu.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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