Helicobacter pylori (H. pylori) is a bacterium that is present in the gastrointestinal tract of about half the world's human population and is believed to cause gastric cancer. H. pylori strains carrying the cagA gene are known to be particularly virulent, but little is known about CagA function. In the 13 December issue of Science, Japanese researchers describe a protein-fishing expedition that led to the discovery of what might be a transfomation-inducing CagA target.

H. pylori strains that carry the cagA gene are nasty creatures that attach to host gastric epithelial cells and inject CagA protein. Inside the cell, CagA is phosphorylated and triggers morphological changes similar to those induced by growth factors. But how can one bacterial protein activate cell shape change?

To find out how CagA operates, Higashi et al. went fishing for proteins that interact with it. They transfected human gastric epithelial cells with haemagglutinin-tagged CagA, and also with a mutant form that could not be phosphorylated. As predicted, expression of wild-type, but not phosphorylation-resistant, CagA induced cellular elongation and spreading. Immunoprecipitation experiments revealed that the wild type — but not the phosphorylation-resistant — protein bound a protein called SHP-2. SHP-2 is a protein tyrosine phosphatase that is known to positively regulate signal transduction events from a variety of activated receptor tyrosine kinases. SHP-2 has also been shown to activate cell migration and adhesion.

SHP-2's phosphatase activity seems to be required for cell morphological changes. Treatment of CagA-expressing gastric epithelial cells with phosphatase inhibitors prevented induction of cellular spreading and elongation. Higashi et al. also created a phosphatase-defective form of SHP-2 that was still able to interact with CagA, and found that co-transfection of cells with this mutant, along with CagA, did not induce cell spreading.

So, if the phosphatase activity of SHP-2 is required to induce cell shape changes, what does CagA do? Because CagA is membrane associated, the authors proposed that the role of CagA might be to recruit SHP-2 to the plasma membrane. Accordingly, expression of a membrane-targeted, constitutively active form of SHP-2 was able to induce cell morphological changes in the absence of CagA. This indicates that SHP-2 acts at the plasma membrane to induce cell shape change, and its activation might be an important component of gastric tumorigenesis. It also provides an explanation for numerous epidemiological studies showing that cagA+ strains are more carcinogenic than cagA− strains.