Endoproteolytic processing of integrin pro-α subunits involves the redundant function of furin and proprotein convertase (PC) 5A, but not paired basic amino acid converting enzyme (PACE) 4, PC5B or PC7

Author:

LISSITZKY Jean-Claude1,LUIS José1,MUNZER Jon Scott2,BENJANNET Suzanne3,PARAT Francis1,CHRÉTIEN Michel3,MARVALDI Jacques1,SEIDAH Nabil Georges2

Affiliation:

1. CNRS UPRESA 6032, Faculté de Pharmacie, 27 Boulevard J. Moulin, 13385 Marseille 5 Cedex, France

2. J. A. DeSève Laboratory of Biochemical Neuroendocrinology, and the Protein Engineering Network of Centres of Excellence, Clinical Research Institute of Montreal, University of Montreal, 110 Pine Avenue West, Montreal, QC H2W 1R7, Canada

3. J. A. DeSève Laboratory of Molecular Neuroendocrinology, and the Protein Engineering Network of Centres of Excellence, Clinical Research Institute of Montreal, University of Montreal, 110 Pine Avenue West, Montreal, QC H2W 1R7, Canada

Abstract

Several integrin α subunits undergo post-translational endoproteolytic processing at pairs of basic amino acids that is mediated by the proprotein convertase furin. Here we ask whether other convertase family members can participate in these processing events. We therefore examined the endoproteolysis rate of the integrin subunits pro-α5, α6 and αv by recombinant furin, proprotein convertase (PC)5A, paired basic amino acid converting enzyme (PACE)4, PC1, PC2 and PC7 in vitro and/or ex vivo after overexpression in LoVo cells that were deficient in furin activity. We found that 60-fold more PC1 than furin was needed to produce 50% cleavage of pro-α subunit substrates in vitro; the defective pro-α chain endoproteolysis in LoVo cells was not rescued by overexpression of PC1 or PC2. No endoproteolysis occurred with PC7 either in vitro or ex vivo, although similar primary sequences of the cleavage site are found in integrins and in proteins efficiently processed by PC7, which suggests that a particular conformation of the cleavage site is required for optimal convertase-substrate interactions. In vitro, 50% cleavage of pro-α subunits was obtained with one-third of the amount of PC5A and PACE4 than of furin. In LoVo cells, PC5A remained more active than furin, PACE4 activity was quite low, and PC5B, which differs from PC5A by a C-terminal extension containing a transmembrane domain, was very inefficient in processing integrin α-subunit precursors. In conclusion, these results indicate that integrin α-subunit endoproteolytic processing involves the redundant function of furin and PC5A and to a smaller extent PACE4, but not of PC1, PC2, PC5B or PC7.

Publisher

Portland Press Ltd.

Subject

Cell Biology,Molecular Biology,Biochemistry

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