Structural and molecular insights into Helicobacter pylori CagA-SHP2 complex: From pathogenic signaling to targeted therapeutic opportunities in gastric cancer.

Gastric cancer (GC) remains a major global health burden, ranking as the fifth most common malignancy worldwide. Helicobacter pylori (H. pylori) is strongly implicated in gastric carcinogenesis and was classified as a Class 1 carcinogen by the World Health Organization (WHO) in 1994. Among H. pylori virulence factors, cytotoxin-associated gene A (CagA) plays a pivotal oncogenic role by modulating host signaling pathways through highly specialized molecular interactions utilizing the CagA multimerization (CM) and EPIYA motifs. Following translocation into gastric epithelial cells (GECs) via the type IV secretion system (T4SS), tyrosine phosphorylation at EPIYA motifs ensures aberrant interaction between CagA and the host Src homology 2 domain-containing phosphatase 2 (SHP2). This interaction represents a unique host-pathogen crosstalk mechanism that functionally mimics oncogenic PTPN11 gain-of-function mutations, resulting in sustained activation of MAPK/ERK and focal adhesion kinase (FAK) pathways, cytoskeletal reorganization, increased cellular motility, and the characteristic hummingbird phenotype. This review aims to summarize current knowledge on the structural and functional interplay between CagA and SHP2 and its role in gastric carcinogenesis, while broadly addressing how geographic diversity in CagA variants shapes the interaction and its consequences. It further discusses the broader oncogenic impact of CagA-driven signaling alterations, including emerging evidence for a hit-and-run oncogenic mechanism, and their relevance to disease progression and prevention strategies. The CagA-SHP2 axis emerges as a central pathogenic hub in H. pylori-associated gastric carcinogenesis and an attractive pharmacological target for the development of mechanism-based therapeutic strategies for the disease.