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J. Biol. Chem., Vol. 278, Issue 23, 20628-20637, June 6, 2003

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Binding of Urokinase-type Plasminogen Activator Receptor (uPAR) to the Mannose 6-Phosphate/Insulin-like Growth Factor II Receptor

CONTRASTING INTERACTIONS OF FULL-LENGTH AND SOLUBLE FORMS OF uPAR^*

Jodi L. Kreiling , James C. Byrd , Robert J. Deisz , Ikuko F. Mizukami , Robert F. Todd, III  and Richard G. MacDonald  ¶

From the Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198-4525 and the Department of Internal Medicine, Hematology and Oncology Division, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan 48109

Urokinase-type plasminogen activator receptor (uPAR) binding by the mannose 6-phosphate/insulin-like growth factor II receptor (Man-6-P/IGF2R) is considered important to Man-6-P/IGF2R tumor suppressor function via regulation of cell surface proteolytic activity. Our goal was to map the uPAR binding site of the Man-6-P/IGF2R by analyzing the uPAR binding characteristics of a panel of minireceptors containing different regions of the Man-6-P/IGF2R extracytoplasmic domain. Coimmunoprecipitation assays revealed that soluble recombinant uPAR (suPAR) bound the Man-6-P/IGF2R at two distinct sites, one localized to the amino-terminal end of the Man-6-P/IGF2R extracytoplasmic domain (repeats 1–3) and the other to the more carboxyl-terminal end (repeats 7–9). These sites correspond with the positions of the two Man-6-P binding domains of Man-6-P/IGF2R. Indeed, the suPAR-Man-6-P/IGF2R interaction was inhibited by Man-6-P, and binding-competent su-PAR species represented a minor percentage (8–30%) of the suPAR present. In contrast, Man-6-P/IGF2R binding of endogenous, full-length uPAR solubilized from plasma membranes of the prostate cancer cell line, PC-3, was not inhibited by Man-6-P. Further studies showed that very little (<5%) endogenous uPAR was Man-6-P/IGF2R binding-competent. We conclude that, contrary to previous reports, the interaction between uPAR and Man-6-P/IGF2R is a low percentage binding event and that suPAR and full-length uPAR bind the Man-6-P/IGF2R by different mechanisms.

Received for publication, March 4, 2003

^* This work was supported by University of Nebraska Medical Center Seed Grant 01-13 (to R. G. M.), National Institutes of Health Grant 5R01CA91885 (to R. G. M.), and stipend support from the Graduate Studies, Bukey, McDonald, Emley, and Widaman Fellowships as well as the Dr. Fred W. Upson grant-in-aid award through the University of Nebraska Medical Center. 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.

^¶ To whom all correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-4525. Tel.: 402-559-7824; Fax: 402-559-6650; E-mail: rgmacdon{at}unmc.edu.

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