Structure and function of <i>Helicobacter pylori</i> CagA, the first-identified bacterial protein involved in human cancer

Abstract

Chronic infection with Helicobacter pylori cagA-positive strains is the strongest risk factor of gastric cancer. The cagA gene-encoded CagA protein is delivered into gastric epithelial cells via bacterial type IV secretion, where it undergoes tyrosine phosphorylation at the Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs. Delivered CagA then acts as a non-physiological scaffold/hub protein by interacting with multiple host signaling molecules, most notably the pro-oncogenic phosphatase SHP2 and the polarity-regulating kinase PAR1/MARK, in both tyrosine phosphorylation-dependent and -independent manners. CagA-mediated manipulation of intracellular signaling promotes neoplastic transformation of gastric epithelial cells. Transgenic expression of CagA in experimental animals has confirmed the oncogenic potential of the bacterial protein. Structural polymorphism of CagA influences its scaffold function, which may underlie the geographic difference in the incidence of gastric cancer. Since CagA is no longer required for the maintenance of established gastric cancer cells, studying the role of CagA during neoplastic transformation will provide an excellent opportunity to understand molecular processes underlying “Hit-and-Run” carcinogenesis.

Conserved SQ and QS motifs in bacterial effectors suggest pathogen interplay with the ATM kinase family during infection

“…For some of these, linear motif mimicry has been reported, and so we have been collecting these motifs to enter into the ELM database. One example is the EPIYA motif which occurs as repeats in CagA, where it was found to mimic an eukaryotic substrate (45). While studying conservation of this motif to prepare the ELM resource entry, we noticed that CagA alignments also had conserved SQs, despite a lack of evidence for ATM phosphorylation ( Figure S1).…”

“…This makes the reliable assessment of the significance of their occurrence challenging. Known functional SQ motifs reside in disordered regions, and considering disordered protein segments in general, Ser and Gln are known to be disorder-promoting (45). A comparison between the disordered regions of the known cellular AADk substrates and the disordered regions of the whole human proteome revealed that Ser, Gln and Thr are the three most over-represented residues in the substrates (Figure 2).…”

Comparative analysis of the Hom family of outer membrane proteins in isolates from two geographically distinct regions: The United States and South Korea

“…[7][8][9] A link between infection with CagA positive strains and increased risk for gastric cancer development is well established. The CagA cytotoxin is injected into host cells and then modulates host cell signal pathways.…”

“…The CagA cytotoxin is injected into host cells and then modulates host cell signal pathways. [7][8][9] A link between infection with CagA positive strains and increased risk for gastric cancer development is well established. 8,9 Additionally, variation within the CagA carboxyl-terminal EPIYA motif is well characterized and known to occur geographically.…”

“…[7][8][9] A link between infection with CagA positive strains and increased risk for gastric cancer development is well established. 8,9 Additionally, variation within the CagA carboxyl-terminal EPIYA motif is well characterized and known to occur geographically. 10,11 The VacA toxin has also been shown to contain variable regions.…”