Endoproteolytic processing of integrin pro-alpha 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

Several integrin alpha 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 endoprote olysis rate of the integrin subunits pro-alpha 5, alpha 6 and alpha v by re combinant furin, proprotein convertase (PC)5A, paired basic amino acid conv erting enzyme (PACE)4, PC1, PC2 and PC7 in vitro and/or ex vivo after overe xpression in LoVo cells that were deficient in furin activity. We found tha t 60-fold more PC1 than furin was needed to produce 50 % cleavage of pro-al pha subunit substrates in vitro; the defective pro-alpha chain endoproteoly sis in LoVo cells was not rescued by overexpression of PC1 or PC2. No endop roteolysis occurred with PC7 either in vitro or ex vivo, although similar p rimary sequences of the cleavage site are found in integrins and in protein s efficiently processed by PC7, which suggests that a particular conformati on of the cleavage site is required for optimal convertase-substrate intera ctions. In vitro, 50 % cleavage of pro-alpha subunits was obtained with one -third of the amount of PC5A and PACE4 than of furin. In LoVo cells, PC5A r emained mon active than furin, PACE4 activity was quite low, and PC5B, whic h differs from PC5A by a C-terminal extension containing a transmembrane do main, was very inefficient in processing integrin alpha-subunit precursors. In conclusion, these results indicate that integrin alpha-subunit endoprot eolytic processing involves the redundant function of furin and PC5A and to a smaller extent PACE4, but not of PC1, PC2, PC5B or PC7.