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J. Biol. Chem., Vol. 280, Issue 26, 24792-24803, July 1, 2005

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Domain 2 of the Urokinase Receptor Contains an Integrin-interacting Epitope with Intrinsic Signaling Activity

GENERATION OF A NEW INTEGRIN INHIBITOR^*

Bernard Degryse, Massimo Resnati, Ralf-Peter Czekay¶, David J. Loskutoff, and Francesco Blasi||

From the Department of Molecular Biology and Functional Genomics, DIBIT, Università Vita Salute San Raffaele, Via Olgettina 58, 20132 Milan, Italy and the Division of Vascular Biology, Department of Cell Biology/VB3, The Scripps Research Institute, La Jolla, California 92037

We investigated the interaction between the urokinase receptor (uPAR) and the integrin v3. Vitronectin (VN) induces cell migration by binding to v3, but expression of the uPAR boosts its efficacy. Thus, uPAR may regulate VN-induced cell migration by interacting laterally with v3. In contrast, cells expressing a uPAR mutant lacking domain 2 do not migrate in response to VN. This effect is overcome by D2A, a synthetic peptide derived from the sequence of domain 2. In addition, D2A has chemotactic activity that requires v3 and activates v3-dependent signaling pathways such as the Janus kinase/Stat pathway. Moreover, D2A disrupts uPAR-v3 and uPAR-51 co-immunoprecipitation, indicating that it can bind both of these integrins. We also identify the chemotactically active epitope harbored by peptide D2A. Mutating two glutamic acids into two alanines generates peptide D2A-Ala, which lacks chemotactic activity but inhibits VN-, FN-, and collagen-dependent cell migration. In fact, the GEEG peptide has potent chemotactic activity, and the GAAG sequence has inhibitory capacities. In summary, we have identified an integrin-interacting sequence located in domain 2 of uPAR, which is also a new chemotactic epitope that can activate v3-dependent signaling pathways and stimulate cell migration. This sequence thus plays a pivotal role in the regulation of uPAR-integrin interactions. Moreover, we describe a novel, very potent inhibitor of integrin-dependent cell migration.

Received for publication, December 13, 2004 , and in revised form, April 18, 2005.

^* The work in the laboratory of F.B. was supported by grants from the Italian Association for Cancer Research and by the European Union Framework program 6 Grants IP 2003-503297 and NoE 2003-502935. The work in the laboratory of D.L. was supported by National Institutes of Health Grant HL 31950. This is TSRI manuscript 16980-CB. 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: Albany Medical Center, CCBCR-165, 43 New Scotland Ave., Albany, NY 12208.

^|| To whom correspondence should be addressed. Tel.: 39-02-2643-4744; Fax: 39-02-2643-4844; E-mail: blasi.francesco{at}hsr.it.

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