Sonic hedgehog (Shh) processing is regulated by gastrin‐induced protease activity

Objective In the mammalian adult stomach sonic hedgehog (Shh) is expressed in parietal cells. Gastrin, a gastric epithelial trophic factor, regulates acid production in the parietal cell. Gastrin‐deficient (G−/−) mice have impaired acid secretion and over time develop parietal cell atrophy that eventually results in gastric cancer. Since loss of Shh correlates with atrophic gastritis, the hypothesis that gastrin regulates Shh production within the parietal cell was tested. Methods Shh expression was analyzed by qRT‐PCR and western blot using RNA and protein extracted from mucosal scrapings of wild type, G−/− and gastrin‐infused G−/− mice. Whole cell extracts (WCE) were prepared from canine parietal cells treated with vehicle, gastrin, omeprazole or omeprazole plus gastrin and incubated with in vitro translated Shh 45kDa peptide. Results Both the 45kDa precursor and 19kDa biologically active Shh proteins were absent in the G−/ − mice. Restoration of acid secretion after gastrin infusion resulted in Shh processing of the precursor to the 19kDa form and increase Shh mRNA abundance. Gastrin‐treated canine parietal cells showed an induction in the 45kDa precursor in WCE and an increase in the secreted 19kDa biologically active peptide. When acid secretion from the parietal cells was blocked with omeprazole, the gastrin effect on Shh processing was abolished. In vitro translated Shh peptide incubated with WCE collected from gastrin treated parietal cells resulted in processing of the 45kDa to 19kDa fragment; this processing was blocked with the protease inhibitor pepstatin. Conclusion Our data is the first to show that processing of Shh is regulated, acid‐dependent and facilitated by gastrin‐induced protease activity.