page 1235. The co-opted protein turns on multiple signaling pathways in gastric cells that cause the normally adhesive cells to pull apart from their neighbors.
Roughly half of all people worldwide have H. pylori living in their stomachs. Most people host the infection without consequence but, in some, H. pylori infection triggers peptic ulcers and gastric cancer. H. pylori encodes a set of proteins that allows it to adhere to and thrive in the stomach and to avoid immune attack. One of these proteins—CagA (cytotoxin-associated antigen-A)—helps ward off immune cells but also disrupts the epithelial cells that line the stomach.
Many studies have investigated how CagA, which is injected into gastric epithelial cells through a specialized bacterial secretion system, helps breach the epithelial lining of the stomach. Once inside the cells, CagA binds to a variety of intracellular signaling proteins. But it was not clear which of these proteins is required for CagA-induced cell scattering.
Suzuki and colleagues now identify a new target of CagA: the Crk family of adaptor proteins. CagA–Crk binding in infected epithelial cells triggered the activation of downstream signaling pathways, including the Ras–Raf and Rac1–WAVE pathways, which are normally induced during routine cell turnover. These signals prompted the expulsion of adhesive proteins β-catenin and E-cadherin from the adherens junctions that hold the cells together.
The liberation of β-catenin from adherens junctions not only compromises cell contacts, but likely also induces aberrant proliferation of the cells, as nuclear β-catenin drives the expression of cell cycle–promoting genes such as cyclin D1. Both cell scattering and proliferation compromise the integrity of the stomach lining, thus contributing to the development of H. pylori–induced gastric disease.