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J. Biol. Chem., Vol. 281, Issue 16, 11050-11057, April 21, 2006

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Prohormone Convertase 1/3 Is Essential for Processing of the Glucose-dependent Insulinotropic Polypeptide Precursor^*

Randi Ugleholdt, Marie-Louise H. Poulsen, Peter J. Holst^¶, Jean-Claude Irminger^||, Cathrine Orskov, Jens Pedersen, Mette M. Rosenkilde^**, Xiaorong Zhu, Donald F. Steiner, and Jens J. Holst¹

From the Departments of Medical Physiology, Medical Anatomy, ^¶Medical Microbiology and Immunology, and ^**Pharmacology, the Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark, ^||Louis-Jeantet Research Laboratories, University Medical Center, 1211 Geneva 4, Switzerland, and Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois 60637

The physiology of the incretin hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), and their role in type 2 diabetes currently attract great interest. Recently we reported an essential role for prohormone convertase (PC) 1/3 in the cleavage of intestinal proglucagon, resulting in formation of GLP-1, as demonstrated in PC1/3-deficient mice. However, little is known about the endoproteolytic processing of the GIP precursor. This study investigates the processing of proGIP in PC1/3 and PC2 null mice and in cell lines using adenovirus-mediated overexpression. Supporting a role for PC1/3 in proGIP processing, we found co-localization of GIP and PC1/3 but not PC2 in intestinal sections by immunohistochemistry, and analysis of intestinal extracts from PC1/3-deficient animals demonstrated severely impaired processing to GIP, whereas processing to GIP was unaltered in PC2-deficient mice. Accordingly, overexpression of preproGIP in the neuroendocrine AtT-20 cell line that expresses high levels of endogenous PC1/3 and negligible levels of PC2 resulted in production of GIP. Similar results were obtained after co-expression of preproGIP and PC1/3 in GH₄ cells that express no PC2 and only low levels of PC1/3. In addition, studies in GH₄ cells and the -TC1.9 cell line, expressing PC2 but not PC1/3, indicate that PC2 can mediate processing to GIP but also to other fragments not found in intestinal extracts. Taken together, our data indicate that PC1/3 is essential and sufficient for the production of the intestinal incretin hormone GIP, whereas PC2, although capable of cleaving proGIP, does not participate in intestinal proGIP processing and is not found in intestinal GIP-expressing cells.

Received for publication, February 7, 2006

^* This work was supported by the Danish Medical Research Council, Novo Nordisk Foundation, and the European Federation for the Study of Diabetes. 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.: 45-3532-7518; Fax: 45-3532-7537; E-mail: holst{at}mfi.ku.dk.

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