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J. Biol. Chem., Vol. 281, Issue 49, 37836-37843, December 8, 2006

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CKAP4/p63 Is a Receptor for the Frizzled-8 Protein-related Antiproliferative Factor from Interstitial Cystitis Patients^*

Thomas P. Conrads, Gillian M. Tocci, Brian L. Hood, Chen-Ou Zhang^¶, Li Guo^||**, Kristopher R. Koch^||**, Christopher J. Michejda, Timothy D. Veenstra, and Susan K. Keay^||**1

From the Laboratory of Proteomics and Analytical Technologies, SAIC-Frederick, Inc., NCI, National Institutes of Health, Frederick, Maryland 21702, Molecular Aspects of Drug Design Section, Structural Biophysics Laboratory, NCI, National Institutes of Health, Frederick, Maryland 21702, the ^¶Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland 21201, the ^||Research Service, Veterans Affairs Maryland Health Care System, Baltimore, Maryland 21201, and the ^**Division of Infectious Diseases, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201

Antiproliferative factor (APF) is a low molecular weight sialoglycopeptide that is secreted by bladder cells from interstitial cystitis patients and is a potent inhibitor of both normal bladder epithelial and bladder carcinoma cell proliferation. We hypothesized that APF may produce its antiproliferative effects by binding to a transmembrane receptor. This study demonstrates that cytoskeleton-associated protein 4/p63 (CKAP4/p63), a type II transmembrane receptor, binds with high affinity to APF. The antiproliferative activity of APF is effectively inhibited by preincubation with anti-CKAP4/p63-specific antibodies, as well as by short interfering RNA knockdown of CKAP4/p63. Immunofluorescent confocal microscopy showed co-localization of anti-CKAP4/p63 and rhodamine-labeled synthetic APF binding in both cell membrane and perinuclear areas. APF also inhibits the proliferation of HeLa cervical carcinoma cells that are known to express CKAP4/p63. These data indicate that CKAP4/p63 is an important epithelial cell receptor for APF.

Received for publication, May 12, 2006 , and in revised form, September 21, 2006.

^* This work was supported by National Institutes of Health Grant NIDDK R01 DK52596, the Merit Review Funding from Veterans Affairs, and in part by the Intramural Research Program of the NCI, National Institutes of Health, under Contract N01-CO-12400. 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.

¹ To whom correspondence should be addressed: Veterans Affairs Medical Center, Rm. 3B-184, 10 N. Greene St., Baltimore, MD 21201. Tel.: 410-605-7000 (ext. 6450); Fax: 410-605-7837; E-mail: skeay{at}medicine.umaryland.edu.

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