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J. Biol. Chem., Vol. 278, Issue 10, 8661-8668, March 7, 2003
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From the Department of Pathobiology, School of Veterinary Medicine,
University of Pennsylvania, Philadelphia, Pennsylvania 19104
CD44 is a principal cell-surface receptor for
hyaluronan (HA). Up-regulation of CD44 is often associated with
morphogenesis and tumor invasion. On the contrary, reduction of
cell-cell adhesion due to down-regulation of E-cadherin is associated
with the invasive and metastatic phenotype of carcinomas. In our
current study, we investigated the functional relationship between CD44
and E-cadherin. We established an inverse correlation between
CD44 and E-cadherin indicating that the cells expressing higher levels
of E-cadherin display weaker binding affinity between CD44 and HA. By
using TA3 murine mammary carcinoma (TA3) cells, which display
CD44-dependent HA binding, branching morphogenesis, and
invasion, we demonstrated an inverse functional relationship between
CD44 and E-cadherin by transfecting exogenous E-cadherin into the
cells. Our results showed that increased expression of E-cadherin in
TA3 cells, but not ICAM-1, weakens the binding between CD44 and HA and
blocks spreading of the cells on HA substratum and CD44-mediated
branching morphogenesis and tumor cell invasion. The results reported
here demonstrated for the first time that E-cadherin negatively
regulated CD44-HA interaction and CD44 function and suggested that
balanced function of CD44 and E-cadherin may be essential for normal
epithelial cell functions, and imbalanced up-regulation of CD44
function and/or down-regulation of E-cadherin function likely
contributes to tumor progression.
E-cadherin Negatively Regulates CD44-Hyaluronan
Interaction and CD44-mediated Tumor Invasion and Branching
Morphogenesis*
*
This work was supported in part by a Start-up fund from
University of Pennsylvania, School of Veterinary Medicine.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.
Supported in part by United States Department of Defense Grant
DAMD 17-02-1-0650. To whom correspondence should be addressed: 372E
(old vet), 3800 Spruce St., Dept. of Pathobiology, School of Veterinary
Medicine, University of Pennsylvania, Philadelphia, PA 19104. Tel.:
215-898-2967; Fax: 215-898-0719; E-mail: qyu@vet.upenn.edu.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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