Posttranslational processing of progastrin

Gastrin and cholecystokinin (CCK) are homologous hormones with important functions in the brain and the gut. Gastrin is the main regulator of gastric acid secretion and gastric mucosal growth, whereas cholecystokinin regulates gall bladder emptying, pancreatic enzyme secretion and besides acts as a major neurotransmitter in the central and peripheral nervous systems. The tissue-specific expression of the hormones is regulated at the transcriptional level, but the posttranslational phase is also decisive and is highly complex in order to ensure accurate maturation of the prohormones in a cell specific manner. Despite the structural similarities of gastrin and CCK, there are decisive differences in the posttranslational processing and secretion schemes, suggesting that specific features in the processing may have evolved to serve specific purposes. For instance, CCK peptides circulate in low picomolar concentrations, whereas the cellular expression of gastrin is expressed at higher levels, and accordingly gastrin circulates in 10-20-fold higher concentrations. Both common cancers and the less frequent neuroendocrine tumors express the gastrin gene and prohormone. But the posttranslational processing progastrin is often greatly disturbed in neoplastic cells.The posttranslational phase of the biogenesis of gastrin and the various progastrin products in gastrin gene-expressing tissues is now reviewed here. In addition, the individual contributions of the processing enzymes are discussed, as are structural features of progastrin that are involved in the precursor activation process. Thus, the review describes how the processing depends on the cell-specific expression of the processing enzymes and kinetics in the secretory pathway.