The endoproteolytic maturation of progastrin and procholecystokinin

The homologous brain-gut propeptides, procholecystokinin (proCCK) and progastrin, both undergo extensive posttranslational maturation in specific neuroendocrine cells. The process comprises multiple endoproteolytic cleavages at mono- and dibasic sites, in addition to exoproteolytic trimmings and amino acid derivatizations. Knockout of prohormone convertases (PCs) in mice and studies in cell lines indicate that PC1, PC2 and, to a minor extent, PC5, are responsible for most of the endoproteolytic cleavages of both prohormones. Progastrin in antral G-cells is cleaved by PC1 at two di-Arg sites, R36R37 and R73R74, whereas, PC2 only cleaves at the single di-Lys site, K53K54. Pituitary corticotrophs and intestinal TG-cells, both of which express gastrin, do not cleave K53K54 due to lack of PC2. In proCCK five monobasic (R25, R44, R50, K61 and R75) as well as a single dibasic site (R85R86) can all be cleaved by both PC1 and PC2. But the cleavage differs in a cell-specific manner in that PC1 is responsible for the entire endoproteolytic cleavage in intestinal endocrine I-cells, except for perhaps the K61 site. In contrast PC2 is responsible for most endoproteolysis of proCCK in the cerebral CCK-neurons, which do not express PC1 in significant amounts. Moreover, PC5 appears to contribute to a minor extent to the neuronal proCCK and to the antral progastrin processing. This review emphasizes that prohormone convertases play a decisive but substrate and cell-specific role in the biosynthetic maturation of gastrin and CCK.