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

Six mammalian processing enzymes were recently discovered which exhibi t significant similarities to both yeast kexin and bacterial subtilisi ns. These subtilisin/kexin-like convertases were called furin/PACE, PC 1/PC3, PC2, PACE4, PC4 and PC5/PC6. The analysis of the mRNA expressio n 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 distri bution 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 mRN A (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, l ike furin and PACE4, PC5 is expressed in both regulated and constituti vely 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 kno wn 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. Biosynth etic analysis of the zymogen activation of PC1 and PC2 and their cleav age specificity following their cellular co-expression with a number o f precursors, demonstrated that although pro-PC 1 is rapidly activated to PC1 in the endoplasmic reticulum, pro-PC2 conversion into PC2 is r ather slow. The cleavage of pro-PC2 into PC2 starts in the trans Golgi network and is regulated by an endogenous endocrine and neural precur sor called 7B2. Although the genetic organization of the convertase ge nes is very similar, they exhibit unique promoter sequences and only f urin and PACE4 genes are localized on the same chromosome.