Influence of Helicobacter pylori oncoprotein CagA in gastric cancer: A critical-reflective analysis

Figure 1 Helicobacter pylori oncoprotein: molecular structure and CagA-mediated carcinogenesis underlying mechanisms. A: Structural domain differences between East Asian and western CagA. CagA tertiary structure is characterized by a structured N-terminal region and an unstructured C-terminal tail. The oncoprotein contains repetitive sequences in its C-terminal polymorphic region, known as the EPIYA motifs and CM motif. EPIYA-A and EPIYA-B motifs were identified in almost all CagA-positive H. pylori strains, followed by one, two, or three EPIYA-C sequences in western strains, or an EPIYA-D segment in East Asian strains. The CM motif, although highly conserved, possesses a 5-amino-acid difference between East Asian and western strains, hence distinguishing East Asian and Western CagA; B: Molecular mechanisms of CagA-mediated carcinogenesis. Upon translocation, CagA EPIYA motifs are tyrosine-phosphorylated by Src family or c-Abl kinases of the host cell. After phosphorylation, CagA localizes to the inner leaflet of the plasmatic membrane and acts as a promiscuous scaffold or hub protein that simultaneously disturbs multiple host signaling pathways, involved in regulation of a large range of cellular processes, including proliferation, differentiation and apoptosis. Ultimately, the disharmonic interaction between CagA and host proteins leads to pro-oncogenic cellular alterations. CM: CagA-multimerization; CM^W: western CagA.