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J. Biol. Chem., Vol. 279, Issue 51, 53442-53450, December 17, 2004

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Limited Redundancy of the Proprotein Convertase Furin in Mouse Liver^*

Anton J. M. Roebroek, Neil A. Taylor, Els Louagie, Ilse Pauli, Liesbeth Smeijers, An Snellinx¶, Annick Lauwers, Wim J. M. Van de Ven||, Dieter Hartmann¶, and John W. M. Creemers**

From the Experimental Mouse Genetics, Laboratory for Molecular Cell Biology, ^¶Laboratory for Neuronal Cell Biology, ^||Laboratory for Molecular Oncology, Department for Human Genetics, University of Leuven and Flanders Interuniversity Institute for Biotechnology, B-3000 Leuven, Belgium

Furin is an endoprotease of the family of mammalian proprotein convertases and is involved in the activation of a large variety of regulatory proteins by cleavage at basic motifs. A large number of substrates have been attributed to furin on the basis of in vitro and ex vivo data. However, no physiological substrates have been confirmed directly in a mammalian model system, and early embryonic lethality of a furin knock-out mouse model has precluded in vivo verification of most candidate substrates. Here, we report the generation and characterization of an interferon inducible Mx-Cre/loxP furin knock-out mouse model. Induction resulted in near-complete ablation of the floxed fur exon in liver.

In sharp contrast with the general furin knock-out mouse model, no obvious adverse effects were observed in the transgenic mice after induction. Histological analysis of the liver did not reveal any overt deviations from normal morphology. Analysis of candidate substrates in liver revealed complete redundancy for the processing of the insulin receptor. Variable degrees of redundancy were observed for the processing of albumin, ₅ integrin, lipoprotein receptor-related protein, vitronectin and ₁-microglobulin/bikunin. None of the tested substrates displayed a complete block of processing. The absence of a severe phenotype raises the possibility of using furin as a local therapeutic target in the treatment of pathologies like cancer and viral infections, although the observed redundancy may require combination therapy or the development of a more broad spectrum convertase inhibitor.

Received for publication, June 25, 2004 , and in revised form, October 6, 2004.

^* This work was supported by grants and scholarships from the "Fonds voor Wetenschappelijk Onderzoek Vlaanderen" and the "Geconcerteerde Onderzoeksacties 2002-2006." 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.

^** To whom correspondence should be addressed: Laboratory for Molecular Cell Biology, Dept. for Human Genetics, K.U. Leuven/V.I.B., Gasthuisberg O/N 6, Box 602, Herestraat 49, B-3000 Leuven, Belgium. Tel.: 32-16-346080; Fax: 32-16-346073; E-mail: john.creemers{at}med.kuleuven.ac.be.

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