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J. Biol. Chem., Vol. 280, Issue 15, 14811-14818, April 15, 2005

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Regulation of Urokinase Receptor Proteolytic Function by the Tetraspanin CD82^*

Rosemary Bass, Finn Werner, Elena Odintsova¶, Tsuyoshi Sugiura¶, Fedor Berditchevski¶, and Vincent Ellis||

From the School of Biological Science, University of East Anglia, Norwich NR4 7TJ, United Kingdom and the ^¶Cancer Research UK Institute for Cancer Studies, University of Birmingham, Birmingham B15 2TT, United Kingdom

The high affinity interaction between the urokinase-type plasminogen activator (uPA) and its glycolipid-anchored cellular receptor (uPAR) promotes plasminogen activation and the efficient generation of pericellular proteolytic activity. We demonstrate here that expression of the tetraspanin CD82/KAI1 (a tumor metastasis suppressor) leads to a profound effect on uPAR function. Pericellular plasminogen activation was reduced by 50-fold in the presence of CD82, although levels of components of the plasminogen activation system were unchanged. uPAR was present on the cell surface and molecularly intact, but radioligand binding analysis with uPA and anti-uPAR antibodies revealed that it was in a previously undetected cryptic form unable to bind uPA. This was not due to direct interactions between uPAR and CD82, as they neither co-localized on the cell surface nor could be co-immunoprecipitated. However, expression of CD82 led to a redistribution of uPAR to focal adhesions, where it was shown by double immunofluorescence labeling to co-localize with the integrin ₅₁, which was also redistributed in the presence of CD82. Co-immunoprecipitation experiments showed that, in the presence of CD82, uPAR preferentially formed stable associations with ₅₁, but not with a variety of other integrins, including ₃₁. These data suggest that CD82 inhibits the proteolytic function of uPAR indirectly, directing uPAR and ₅₁ to focal adhesions and promoting their association with a resultant loss of uPA binding. This represents a novel mechanism whereby tetraspanins, integrins, and uPAR, systems involved in cell adhesion and migration, cooperate to regulate pericellular proteolytic activity and may suggest a mechanism for the tumor-suppressive effects of CD82/KAI1

Received for publication, December 17, 2004 , and in revised form, January 12, 2005.

^* This work was supported in part by British Heart Foundation Grants PG/1999079 and PG/02/162/14789. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Dept. of Biological Sciences, Imperial College, London SW7 2AZ, UK.

^|| A British Heart Foundation Senior Research Fellow. To whom correspondence should be addressed. Tel.: 44-1603-592570; Fax: 44-1603-592250; E-mail: v.ellis{at}uea.ac.uk.

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