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J. Biol. Chem., Vol. 283, Issue 24, 16928-16939, June 13, 2008

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PATE Gene Clusters Code for Multiple, Secreted TFP/Ly-6/uPAR Proteins That Are Expressed in Reproductive and Neuron-rich Tissues and Possess Neuromodulatory Activity^*

Fiana Levitin, Mordechai Weiss, Yoonsoo Hahn^¶1, Omer Stern, Roger L. Papke^||, Robert Matusik^**, Srinivas R. Nandana^**, Ravit Ziv, Edward Pichinuk, Sharbel Salame, Tapan Bera^¶, James Vincent^¶, Byungkook Lee^¶, Ira Pastan^¶, and Daniel H. Wreschner^¶2

From the Department of Cell Research and Immunology, Tel Aviv University, Ramat Aviv, 69978 Israel, the Department of Endocrinology, Assaf Harofe Medical Center, Tzrifin 70300, Israel, the ^||Department of Pharmacology and Therapeutics, University of Florida, Gainesville, Florida 32610-0267, ^¶NCI, National Institutes of Health, Bethesda, Maryland 20892, the ^**Vanderbilt University Medical Center, Nashville, Tennessee 37232-2765, and Geneswitch Technology LLC, Waban, Massachusetts 02468

We report here syntenic loci in humans and mice incorporating gene clusters coding for secreted proteins each comprising 10 cysteine residues. These conform to three-fingered protein/Ly-6/urokinase-type plasminogen activator receptor (uPAR) domains that shape three-fingered proteins (TFPs). The founding gene is PATE, expressed primarily in prostate and less in testis. We have identified additional human PATE-like genes (PATE-M, PATE-DJ, and PATE-B) that co-localize with the PATE locus, code for novel secreted PATE-like proteins, and show selective expression in prostate and/or testis. Anti-PATE-B-specific antibodies demonstrated the presence of PATE-B in the region of the sperm acrosome and at high levels on malignant prostatic epithelial cells. The syntenic mouse Pate-like locus encompasses 14 active genes coding for secreted proteins, which are all, except for Pate-P and Pate-Q, expressed primarily in prostate and/or testis. Pate-P and Pate-Q are expressed solely in placental tissue. Castration up-regulates prostate expression of mouse Pate-B and Pate-E, whereas testosterone ablates this induced expression. The sequence similarity between TFP/Ly-6/uPAR proteins that modulate activity of nicotinic acetylcholine receptors and the PATE (Pate)-like proteins stimulated us to see whether these proteins possess analogous activity. Pharmacological studies showed significant modulation of the nicotinic acetylcholines by the PATE-B, Pate-C, and Pate-P proteins. In concert with these findings, certain PATE (Pate)-like genes were extensively expressed in neuron-rich tissues. Taken together, our findings indicate that in addition to participation of the PATE (Pate)-like genes in functions related to fertility and reproduction, some of them likely act as important modulators of neural transmission.

Received for publication, February 22, 2008 , and in revised form, April 1, 2008.

The nucleotide sequence(s) reported in this paper has been submitted to the Gen-Bank^TM/EBI Data Bank with accession number(s) EU703625 [GenBank] , EU703626 [GenBank] , EU703627 [GenBank] , EU703628 [GenBank] , and EU703629.

^* This work was supported, in whole or in part, by a National Institutes of Health grant (Intramural Research Program, NCI, Center for Cancer Research). This work was also supported by a Union Internationale Contre Cancer translational research fellowship (to D. H. W.) and Frances Williams Preston Laboratories of the T. J. Martell Foundation (to R. M.). 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 Present address: Dept. of Life Science, Chung-Ang University, Seoul 156-756, South Korea.

² To whom correspondence should be addressed: Dept. of Cell Research and Immunology, Tel Aviv University, Ramat Aviv, Israel 69978. Tel.: 972-3-6407425; Fax: 972-3-6422046; E-mail: danielhw{at}post.tau.ac.il.

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