The proprotein convertases furin and PACE4 play a significant role in tumor progression

Processing of latent precursor proteins by proprotein convertases (PCs) int o their biologically active products is a common mechanism required for man y important biologic functions. This process is tightly regulated, leading to the generation of active peptides and proteins including neuropeptides a nd polypeptide hormones, protein tyrosine phosphatases, growth factors and their receptors, and enzymes including matrix metalloproteases (MMPs). Thes e processing reactions occurs at pairs of basic amino acids. Within the pas t several years, a novel family of Ca2+ dependent serine proteases has been identified, all of which possess homology to the endoproteases subtilisin (bacteria) and kexin (yeast). This family of PCs is currently comprised of fewer than a dozen members, known as furin/ paired basic amino-acid-cleavin g enzyme (PACE), PC1/PC3, PC2, PC4, PACE4, PC5/PC6, and PC7/PC8/lymphoma pr oprotein convertase. They share a high degree of amino-acid identity of 50- 75% within their catalytic domains. Despite the relatively high degree of h omology in the PC family, only PACE4 and furin localize to the same chromos ome: mouse chromosome 7 and human chromosome 15. Recent reports have suppor ted a possible functional role for PCs in tumorigenesis. For instance, conv ertases have been shown to be expressed in various tumor lines and human pr imary tumors. Furin and PACE4 process stromelysin 3 (MMP-11 or Str-3), an M MP involved in tumor invasion, into its mature, active form. Similarly, a g rowing family of MMPs, known as membrane-type metalloproteinases (MT-MMPs), and growth factors and adhesion molecules such as E-cadherin show similar amino-acid motifs and thus could be activated by furin and PACE4. These dat a, taken together with the high expression levels of PACE4 in 50% of murine chemically induced spindle cell tumors, confer to PACE4 and possibly other PCs a possible functional role in the activation of MMPs and consequently in tumor cell invasion and tumor progression. This was further supported by the remarkable enhancement in the invasive ability of the PACE4-transfecte d murine tumor cell lines. Mel. Carcinog. 28:63-69, 2000. (C) 2000 Wiley-Li ss. Inc.