THE FAMILY OF SUBTILISIN/KEXIN LIKE PRO-PROTEIN AND PROHORMONE CONVERTASES - DIVERGENT OR SHARED FUNCTIONS

Six mammalian processing enzymes were recently discovered which exhibit significant similarities to both yeast kexin and bacterial subtilisins. These subtilisin/kexin-like convertases were called furin/PACE, PC1/PC3, PC2, PACE4, PC4 and PC5/PC6. The analysis of the mRNA expression of these convertases in rat tissues and cell lines by Northern blot analysis demonstrated a unique pattern for each enzyme. Thus, although furin and PACE4 mRNA (4.4 kb each) exhibit a widespread tissue distribution only furin is ubiquitously expressed. PACE4 exhibits a major 4.4 kb mRNA form, and in some tissues a 3.9 kb form is detected. PC5 mRNA (3.8 kb major) is more restricted in its distribution than PACE4 and furin, and it exhibits the presence of multiple mRNA forms, resulting in variable lengths of the C-terminal Cys-rich domain. In addition, like furin and PACE4, PC5 is expressed in both regulated and constitutively secreting cells. In contrast, PC1 (3 and 5 kb) and PC2 (2.8 and 5 kb) are primarily expressed in tissues and cells containing secretory granules. Multiple mRNA forms are also detected, but as far as is known none affect their open reading frame and only result in a variable length of the 3' non-coding sequence. Finally, PC4 mRNA (2.8 kb major and 1.9 kb minor) is only expressed in testicular germ cells. Biosynthetic analysis of the zymogen activation of PC1 and PC2 and their cleavage specificity following their cellular co-expression with a number of precursors, demonstrated that although pro-PC 1 is rapidly activated to PC1 in the endoplasmic reticulum, pro-PC2 conversion into PC2 is rather slow. The cleavage of pro-PC2 into PC2 starts in the trans Golgi network and is regulated by an endogenous endocrine and neural precursor called 7B2. Although the genetic organization of the convertase genes is very similar, they exhibit unique promoter sequences and only furin and PACE4 genes are localized on the same chromosome.