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J. Biol. Chem., Vol. 281, Issue 6, 3505-3512, February 10, 2006

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Apical Transport and Folding of Prostate-specific Membrane Antigen Occurs Independent of Glycan Processing^*

Deborah Castelletti, Giulio Fracasso, Marwan Alfalah, Sara Cingarlini, Marco Colombatti, and Hassan Y. Naim¹

From the Department of Physiological Chemistry, University of Veterinary Medicine Hannover, Bünteweg 17, D-30559 Hannover, Germany and the Department of Pathology, University of Verona, I-37100 Verona, Italy

Prostate-specific membrane antigen (PSMA) is an integral cell-surface membrane glycoprotein that is overexpressed in prostate carcinomas rendering it an appropriate target for antibody-based therapeutic strategies. The biosynthesis of PSMA in transfected COS-1 cells reveals a slow conversion of mannose-rich to complex glycosylated PSMA compatible with slow transport kinetics from the endoplasmic reticulum to the Golgi. Importantly, mannose-rich PSMA persists as a trypsin-sensitive protein throughout its entire life cycle, and only Golgi-located PSMA glycoforms acquire trypsin resistance. This resistance, used here as a tool to examine correct folding, does not depend on the type of glycosylation, because different PSMA glycoforms generated in the presence of inhibitors of carbohydrate processing in the Golgi are also trypsin resistant. The conformational transition of PSMA to a correctly folded molecule is likely to occur in the Golgi and does not implicate ER molecular chaperones, such as BiP. We show here that PSMA is not only heavily N-but also O-glycosylated. The question arising is whether glycans, which do not play a role in folding of PSMA, are implicated in its transport to the cell surface. Neither the cell-surface expression of PSMA nor its efficient apical sorting in polarized Madin-Darby canine kidney cells are influenced by modulators of N- and O-glycosylation. The acquisition of folding determinants in the Golgi, therefore, is an essential prerequisite for protein trafficking and sorting of PSMA and suggests that altered or aberrant glycosylation often occurring during tumorigenesis has no regulatory effect on the cell-surface expression of PSMA.

Received for publication, August 26, 2005 , and in revised form, October 7, 2005.

^* This work was supported by the Deutsche Forschungsgemeinschaft (Bonn, Germany, Grant Na 331/1-4 to H. Y. N.) and by MIUR (PRIN 2003) and from Fondazione Cassa di Risparmio di Verona, Vicenza, Belluno e Ancona, Bando 2004 Integrazione Tra Tecnologia e Sviluppo di Settore (to M. C.). 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. Tel.: 49-511-953-8780; Fax: 49-511-953-8585; E-mail: hassan.naim{at}tiho-hannover.de.

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