Structural and functional diversity in the PAR1b/MARK2‐binding region of Helicobacter pylori CagA

Abstract

Helicobacter pylori (H. pylori) cagA-positive strains are associated with gastritis, peptic ulcerations, and gastric adenocarcinoma. Upon delivery into gastric epithelial cells, the cagA-encoded CagA protein specifically binds and aberrantly activates SHP-2 oncoprotein in a manner that is dependent on CagA tyrosine phosphorylation. CagAderegulated SHP-2 then elicits aberrant Erk activation while causing an elongated cell shape known as the hummingbird phenotype. In polarized epithelial cells, CagA also binds to PAR1b/MARK2 and inhibits the PAR1b kinase activity, thereby disrupting tight junctions and epithelial cell polarity independent of CagA tyrosine phosphorylation. We show here that the CagA-multimerization (CM) sequence that mediates interaction of CagA with PAR1b is not only essential for the CagA-triggered junctional defects but also plays an important role in induction of the hummingbird phenotype by potentiating CagA-SHP-2 complex formation. We also show that the CM sequence of CagA isolated from East Asian H. pylori (referred to as the E-CM sequence) binds PAR1b more strongly than that of CagA isolated from Western H. pylori (referred to as the W-CM sequence). Within Western CagA species, the ability to bind PAR1b is proportional to the number of W-CM sequences. Furthermore, the level of PAR1b-binding activity of CagA correlates with the magnitude of junctional defects and the degree of hummingbird phenotype induction. Our findings reveal that structural diversity in the CM sequence is an important determinant for the degree of virulence of CagA, a bacterial oncoprotein that is associated with gastric carcinogenesis. (Cancer Sci

Characterization of Helicobacter pylori cagA andvacAGenotypes among Alaskans and Their Correlation with Clinical Disease

“…It may be important to distinguish between these two types of cagA genes, as the CagA protein coded for by most East Asian strains appears to be more biologically active than most CagA proteins coded for by non-Asian cagA genes (16,26), and this has been associated with an increased risk of PUD and gastric cancer (22). In our study population, 95% of persons infected with a cagA-positive strain of H. pylori that could be subtyped had a non-Asian cagA-positive strain.…”

Helicobacter pyloriand Gastric Cancer: Factors That Modulate Disease Risk

“…The PAR1b-binding region of CagA has been identified as the 16-amino-acid CagA sequence also known as the CagA multimerization (CM) sequence, which is involved in CagA dimerization (256). Interestingly, the CM sequence of CagA proteins isolated from East Asian H. pylori strains binds PAR1b more strongly than the CM sequence of proteins isolated from Western strains of H. pylori (180). Within Western H. pylori strains, the number of CM repeats is directly proportional to the ability of CagA to bind to PAR1b (180).…”

Characterization of the Translocation-competent Complex between the Helicobacter pylori Oncogenic Protein CagA and the Accessory Protein CagF

“…1A. Within the host cell, CagA interacts with several proteins such as CSK, CRK, SHP-2, PAR-1, GRB-2, ASPP-2, and E-cadherin in both phosphorylation-dependent and -independent manners and, thus, parasitizes cytoskeletal organization, proliferation, motility, apoptosis, mitogenic gene expression, and cell-* This work was supported in part by an Alexander von Humboldt Foundation experienced researcher fellowship (to E. J. S.) as well as a Fulbright scholarship and International Sephardic Education Foundation fellowship (to T. H. R. cell contact (12)(13)(14)(15)(16)(17)(18). This perturbation of cellular function facilitates the colonization of H. pylori within the stomach and indirectly promotes cancer by disruption of host cell signaling pathways.…”