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J. Biol. Chem., Vol. 275, Issue 22, 16450-16458, June 2, 2000
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From the Institute of Experimental Cardiology, Cardiology Research
Center, Moscow 121552, Russia
Urokinase plasminogen activator (uPA) is thought
to exert its effects on cell growth, adhesion, and migration by
mechanisms involving proteolysis and interaction with its cell surface
receptor (uPAR). The functional properties of uPA and the significance of its various domains for chemotactic activity were analyzed using
human airway smooth muscle cells (hAWSMC). The wild-type uPA (r-uPAwt),
inactive urokinase with single mutation (His204 to Gln)
(r-uPAH/Q), urokinase with mutation of His204
to Gln together with a deletion of growth factor-like domain (r-uPAH/Q-GFD), the catalytic domain of urokinase
(r-uPALMW), and its kringle domain (r-KD) were expressed in
Escherichia coli. We demonstrate that glycosylated uPA,
r-uPAwt, r-uPAH/Q, and r-uPAH/Q-GFD elicited
similar chemotactic effects. Half-maximal chemotaxis (EC50)
were apparent at approximately 2 nM with all the uPA
variants. The kringle domain induced cell migration with an
EC50 of about 6 nM, whereas the denaturated
r-KD and r-uPALMW were without effect. R-uPAwt-induced
chemotaxis was dependent on an association with uPAR and a uPA-kringle
domain-binding site, determined using a monoclonal uPAR antibody to
prevent the uPA-uPAR interaction, and a monoclonal antibody to the
uPA-kringle domain. The binding of iodinated r-uPAwt with hAWSMC was
due to interaction with a high affinity binding site on the uPAR, and a
lower affinity binding site on an unidentified cell surface
target, which was mediated exclusively through the kringle domain of
urokinase. Specific binding of r-uPAH/Q-GFD to hAWSMC
involved an interaction with a single site whose characteristics were
similar to those of the low affinity site of r-uPAwt binding to hAWSMC.
uPAR-deficient HEK 293 cells specifically bound r-uPAwt and
r-uPAH/Q-GFD via a single, similar type of binding site.
These cells migrated when stimulated by r-uPAH/Q-GFD and
uPAwt, but not r-uPALMW. HEK 293 cells transfected with the
uPAR cDNA expressed two classes of sites that bound r-uPAwt;
however, only a single site was responsible for the binding of
r-uPAH/Q-GFD. Together, these findings indicate that
uPA-induced chemotaxis is dependent on the binding of the
uPA-kringle to the membrane surface of cells and the association of uPA
with uPAR.
The Chemotactic Action of Urokinase on Smooth Muscle Cells Is
Dependent on Its Kringle Domain
CHARACTERIZATION OF INTERACTIONS AND CONTRIBUTION TO
CHEMOTAXIS*
,
*
This work was supported by Russian Fundamental Research
Foundation Grants 96-04-50714 and 00-04-48699.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.
Partial fulfilment of a PhD degree.
§
To whom correspondence should be addressed: Molecular Endocrinology
Laboratory, Inst. of Experimental Cardiology, Cardiology Research
Center, Cherepkovskaya St., 15, Moscow 121552, Russia. Tel.:
7-095-414-67-13; Fax: 7-095-414-67-12; E-mail:
V.Stepanova@cardio.ru.
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