Limited redundancy of the proprotein convertase furin in mouse liver.
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, alpha(5) integrin, lipoprotein receptor-related protein, vitronectin and alpha(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.
Experimental Mouse Genetics, University of Leuven and Flanders Interuniversity Institute for Biotechnology, B-3000 Leuven, Belgium.
Anton J M
AJ
Roebroek
Neil A
NA
Taylor
Els
E
Louagie
Ilse
I
Pauli
Liesbeth
L
Smeijers
An
A
Snellinx
Annick
A
Lauwers
Wim J M
WJ
Van de Ven
Dieter
D
Hartmann
John W M
JW
Creemers
D000418:Albumins / Q000378:metabolism; D000483:Alleles; D000510:Alpha-Globulins / Q000378:metabolism; D020816:Amino Acid Motifs; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D017931:DNA Primers / Q000737:chemistry; D004591:Electrophoresis, Polyacrylamide Gel; D045683:Furin / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D005838:Genotype; D007150:Immunohistochemistry; D039482:Integrin alpha5 / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008957:Models, Genetic; D009369:Neoplasms / Q000378:metabolism; D010641:Phenotype; D043484:Proprotein Convertases / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D011995:Recombination, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013379:Substrate Specificity; D019076:Transgenes; D014360:Trypsin Inhibitor, Kunitz Soybean / Q000378:metabolism; D019096:Vitronectin / Q000378:metabolism
D000418:Albumins; D000510:Alpha-Globulins; D017931:DNA Primers; D039482:Integrin alpha5; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011973:Receptors, LDL; D011994:Recombinant Proteins; C109148:SPINT2 protein, human; D019096:Vitronectin; C016001:alpha-1-microglobulin; D014360:Trypsin Inhibitor, Kunitz Soybean; D043484:Proprotein Convertases; D045683:Furin