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J. Biol. Chem., Vol. 283, Issue 7, 4014-4021, February 15, 2008

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Distinct Linkage between Post-translational Processing and Differential Secretion of Progastrin Derivatives in Endocrine Cells^*

From the Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, KB 3014, Copenhagen University Hospital, Blegdamsvej 9, Copenhagen DK-2100, Denmark

Prohormones often undergo extensive cellular processing prior to secretion. These post-translational processing events occur in organelles of the constitutive or regulated secretory pathway. The aim of this study was to examine the relationship between post-translational modifications and the secretory pathways taken by peptides derived from progastrin, the prohormone of gastrin, which in vivo is secreted by cells of the pyloric glands and stimulates the release of gastric acid. Targeting progastrin to compartments of the early secretory pathway shows that endoproteolytic processing is initiated in a pre-trans-Golgi network compartment of endocrine but not non-endocrine cells. The resulting N-terminal fragments of progastrin are secreted via the constitutive pathway, whereas endoproteolytically processed C-terminal fragments are secreted via the regulated or constitutive-like pathways. C-terminal fragments derived from progastrin differ in characteristic manners in levels and patterns of carboxyamidation and tyrosine sulfation in accordance with the secretory pathway taken. Point mutations introduced into a sorting motif disrupt these patterns, suggesting that differences in post-translational modifications are attributable to differential intracellular sorting of precursors. The results suggest a two-step sorting mechanism for progastrin leading to differential secretion of processed fragments via different secretory pathways.

Received for publication, September 20, 2007 , and in revised form, November 15, 2007.

^* This work was supported by the Danish Medical Research Council and the NOVO Nordic Foundation. 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.: 45-354-53-215; Fax: 45-354-54-640; E-mail: jrb{at}rh.dk.

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