HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 283, Issue 4, 2373-2384, January 25, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/4/2373    most recent M708763200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mayer, G. Articles by Seidah, N. G. Search for Related Content PubMed PubMed Citation Articles by Mayer, G. Articles by Seidah, N. G. Social Bookmarking                      What's this?

The Regulated Cell Surface Zymogen Activation of the Proprotein Convertase PC5A Directs the Processing of Its Secretory Substrates^*

Gaétan Mayer¹, Josée Hamelin, Marie-Claude Asselin, Antonella Pasquato, Edwidge Marcinkiewicz, Meiyi Tang, Siamak Tabibzadeh, and Nabil G. Seidah²

From the Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montréal, Quebec H2W 1R7, Canada and Stony Brook University, Stony Brook, New York 11794

The proprotein convertases are synthesized as zymogens that acquire activity upon autocatalytic removal of their NH₂-terminal prosegment. Based on the convertase furin, to fold properly and gain activity, the convertases PC5A, PACE4, and PC7 are presumed to undergo two sequential prosegment cleavages in the endoplasmic reticulum and then in the trans-Golgi network. However, biochemical and immunocytochemical experiments revealed that mouse PC5A is complexed to its prosegment at the plasma membrane. This labeling is lost upon treatment with heparin and is increased by overexpressing members of the syndecan family and CD44, suggesting attachment of secreted PC5A-prosegment complex to heparan sulfate proteoglycans. Following stimulation of Y1 cells with adrenocorticotropic hormone or 8-bromo-cyclic AMP, the cell surface labeling of the prosegment of PC5A is greatly diminished, whereas the signal for mature PC5A is increased. Moreover, after stimulation, the protease activity of PC5A is enhanced, as evidenced by the cleavage of the PC5A substrates Lefty, ADAMTS-4, endothelial lipase, and PCSK9. Our data suggest a novel mechanism for PC5A activation and substrate cleavage at the cell surface, through a regulated removal of its prosegment. A similar mechanism may also apply to the convertase PACE4, thereby extending our knowledge of the molecular details of the zymogen activation and functions of these heparan sulfate proteoglycan-bound convertases.

Received for publication, October 23, 2007 , and in revised form, November 14, 2007.

^* This research was supported by Canadian Institute of Health Research Grant MGP-44363 and Canada Chair 201652. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S7.

¹ Supported by postdoctoral fellowships from the Conscil de recherches en sciences naturelles et en géníe du Canada/Natural Sciences and Engineering Research Council of Canada and Institut de recherches cliniques de Montréal-Pizzagalli.

² To whom correspondence should be addressed: Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, 110 Pine Ave. W., Montreal, Quebec H2W 1R7, Canada. Tel.: 514-987-5609; Fax: 514-987-5542; E-mail: seidahn{at}ircm.qc.ca.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				A. Cedzich, F. Huttenlocher, B. M. Kuhn, J. Pfannstiel, L. Gabler, A. Stintzi, and A. Schaller The Protease-associated Domain and C-terminal Extension Are Required for Zymogen Processing, Sorting within the Secretory Pathway, and Activity of Tomato Subtilase 3 (SlSBT3) J. Biol. Chem., May 22, 2009; 284(21): 14068 - 14078. [Abstract] [Full Text] [PDF]

				C. Gyamera-Acheampong and M. Mbikay Proprotein convertase subtilisin/kexin type 4 in mammalian fertility: a review Hum. Reprod. Update, March 1, 2009; 15(2): 237 - 247. [Abstract] [Full Text] [PDF]

				V. Nikolova, C.-Y. Koo, S. A. Ibrahim, Z. Wang, D. Spillmann, R. Dreier, R. Kelsch, J. Fischgrabe, M. Smollich, L. H. Rossi, et al. Differential roles for membrane-bound and soluble syndecan-1 (CD138) in breast cancer progression Carcinogenesis, March 1, 2009; 30(3): 397 - 407. [Abstract] [Full Text] [PDF]

				G. Mayer, S. Poirier, and N. G. Seidah Annexin A2 Is a C-terminal PCSK9-binding Protein That Regulates Endogenous Low Density Lipoprotein Receptor Levels J. Biol. Chem., November 14, 2008; 283(46): 31791 - 31801. [Abstract] [Full Text] [PDF]