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Helicobacter pylori  strains carrying the  cagA  gene are associated with severe disease outcomes, most notably gastric cancer. CagA protein is delivered into gastric epithelial cells by a type  IV  secretion system. The translocated CagA undergoes tyrosine phosphorylation at the C‐terminal  EPIYA  motifs by host cell kinases. Tyrosine‐phosphorylated CagA acquires the ability to interact with and activate  SHP 2, thereby activating mitogenic signaling and inducing cell morphological transformation (hummingbird phenotype). CagA also interacts with  PAR 1b via the  CM  sequence, resulting in induction of junctional and polarity defects. Furthermore, CagA‐ PAR 1b interaction stabilizes the CagA‐ SHP 2 complex. Because transgenic mice systemically expressing CagA develop gastrointestinal and hematological malignancies, CagA is recognized as a bacterium‐derived oncoprotein. Interestingly, the C‐terminal region of CagA displays a large diversity among  H. pylori  strains, which influences the ability of CagA to bind to  SHP 2 and  PAR 1b. In the present study, we investigated the biological activity of v225d CagA, an Amerindian CagA of  H. pylori  isolated from a Venezuelan Piaroa Amerindian subject, because the variant CagA does not possess a canonical  CM  sequence. We found that v225d CagA interacts with  SHP 2 but not  PAR 1b. Furthermore,  SHP 2‐binding activity of v225d CagA was much lower than that of CagA of  H. pylori  isolated from Western countries (Western CagA). v225d CagA also displayed a reduced ability to induce the hummingbird phenotype than that of Western CagA. Given that perturbation of  PAR 1b and  SHP 2 by CagA underlies the oncogenic potential of CagA, the v225d strain is considered to be less oncogenic than other well‐studied  cagA ‐positive  H. pylori  strains.

Natural variant of the Helicobacter pylori CagA oncoprotein that lost the ability to interact with PAR 1