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J. Biol. Chem., Vol. 277, Issue 10, 8022-8032, March 8, 2002
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From the We previously found that bikunin (bik), a
Kunitz-type protease inhibitor, suppresses phorbol ester
(PMA)-stimulated expression of urokinase-type plasminogen activator
(uPA). In the present study, we tried to answer this mechanism using
human chondrosarcoma HCS-2/8 cells. Our results showed the following
novel findings: (a) the standard form of CD44 (CD44s; 85 kDa) is expressed in both unstimulated and PMA-stimulated cells, while
CD44v isoforms containing epitope v9 (110 kDa) are strongly
up-regulated in response to treatment with PMA; (b) CD44v
isoforms containing epitope v9 present on the same cell exclusively
form aggregates in stimulated cells; (c) induction of
uPA mRNA expression could be achieved by using a second
cross-linker antibody to cross-link Fab monomers of anti-CD44;
(d) co-treatment of stimulated cells with anti-CD44 mAb
alone or anti-CD44v9 mAb alone suppresses PMA-induced clustering of
CD44, which results in inhibition of uPA overexpression;
(e) bikunin efficiently disrupts PMA-induced clustering of
CD44, but does not prevent PMA-induced up-regulation of CD44v isoforms
containing epitope v9; and (f) after exposure to bik,
~150-kDa band is mainly detected with immunoprecipitation and this
band is shown to be a heterodimer composed of the 110-kDa v9-containing
CD44v isoforms and a 45-kDa bik receptor (bik-R). In conclusion, we
provide, for the first time, evidence that the bik-R can
physically interact with the CD44v isoforms containing
epitope v9 and function as a repressor to down-regulate PMA-stimulated
uPA expression, at least in part, by preventing clustering of CD44v
isoforms containing epitope v9.
Kunitz-type Protease Inhibitor Bikunin Disrupts Phorbol
Ester-induced Oligomerization of CD44 Variant Isoforms Containing
Epitope v9 and Subsequently Suppresses Expression of Urokinase-type
Plasminogen Activator in Human Chondrosarcoma Cells*
,,, and
Department of Obstetrics and Gynecology,
§ Equipment Center, Hamamatsu University School of Medicine,
Handacho 3600, Hamamatsu, Shizuoka, 431-3192, Japan and the
¶ Department of Biochemistry and Molecular Dentistry, Okayama
University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama, 700-8525, Japan
*
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.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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