Helicobacter pylori CagA Induces AGS Cell Elongation through a Cell Retraction Defect That Is Independent of Cdc42, Rac1, and Arp2/3

Abstract

Helicobacter pylori, which infects over one-half the world's population, is a significant risk factor in a spectrum of gastric diseases, including peptic ulcers and gastric cancer. Strains of H. pylori that deliver the effector molecule CagA into host cells via a type IV secretion system are associated with more severe disease outcomes. In a tissue culture model of infection, CagA delivery results in a dramatic cellular elongation referred to as the "hummingbird" phenotype, which is characterized by long, thin cellular extensions. These actin-based cytoskeletal rearrangements are reminiscent of structures that are regulated by Rho GTPases and the Arp2/3 complex. We tested whether these signaling pathways were important in the H. pylori-induced cell elongation phenotype. Contrary to our expectations, we found that these molecules are dispensable for cell elongation. Instead, time-lapse video microscopy revealed that cells infected by cagA ؉ H. pylori become elongated because they fail to release their back ends during cell locomotion. Consistent with a model in which CagA causes cell elongation by inhibiting the disassembly of adhesive cell contacts at migrating cells' lagging ends, immunohistochemical analysis revealed that focal adhesion complexes persist at the distal tips of elongated cell projections. Thus, our data implicate a set of signaling molecules in the hummingbird phenotype that are different than the molecules previously suspected.

Role of Partitioning-defective 1/Microtubule Affinity-regulating Kinases in the Morphogenetic Activity of Helicobacter pylori CagA

“…Mechanistically, the hummingbird phenotype is caused by a defect of rear retraction during cell movement (52). This morphological abnormality is reminiscent of that observed in cells lacking non-muscle myosin II (53,54).…”

“…Phenotype Induced by CagA-The thin and long protrusions of the hummingbird phenotype are mechanistically due to retraction failure at the rear end of the moving cell (52). It has been reported that non-muscle myosin II, especially myosin IIB, is responsible for retraction of the rear tail (53)(54)(55).…”

Helicobacter pyloriand Gastric Cancer: Factors That Modulate Disease Risk

“…The interaction between CagA and SHP-2 also dephosphorylates and inactivates focal adhesion kinase (FAK), resulting in cell elongation (316). Phosphorylated CagA also induces cell elongation by inducing a defect in cell retraction; however, the signaling molecules required for this phenotype remain undefined (38). In addition, the catalytic activity of c-Src is inhibited by phosphorylated CagA, which leads to tyrosine dephosphorylation of the actin binding proteins cortactin, ezrin, and vinculin, leading to cell elongation (208,280,281).…”

Evaluation of Cell- Morphological Changes by Helicobacter pylori CagA and Pragmin in AGS Human Gastric Carcinoma Cells

“…Furthermore, it was shown that H. pylori induced a characteristic morphology of host epithelial cells, which has been referred to as the hummingbird phenotype; this was resulting from regulation of both the actin cytoskeleton and focal adhesion and it may be involved in carcinogenesis. Notably, it has been emphasized by many findings indicating that elongation morphology of host cell is strictly dependent on CagA injection (16)(17)(18). Despite the discovery of many target molecules in host cells, which is caused by H. pylori infec-tion, the related processes that lead to hummingbird phenotype are still unclear.…”