The Helicobacter pylori CagA protein induces tyrosine dephosphorylation of ezrin

Abstract

Helicobacter pylori is one of the most wide-spread bacterial pathogens and infects the human stomach to cause diseases, such as gastritis, gastric ulceration, and gastric cancer. A major virulence determinant is the H. pylori CagA protein (encoded by the cytotoxin-associated gene A) which is translocated from the bacteria into the cytoplasm of host cells by a type IV secretion system. In the host cell, CagA is phosphorylated on tyrosine residues and induces rearrangements of the actin cytoskeleton. We have previously shown that tyrosine-phosphorylated CagA inhibits the catalytic activity of Src family kinases and induces tyrosine dephosphorylation of several host cell proteins. Here, we identified one of these proteins as ezrin by a combination of preparative gel electrophoresis, two-dimensional electrophoresis (2-DE) and matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS). Specific pharmacological inhibition of Src family kinases also induces ezrin dephosphorylation. Therefore, ezrin dephosphorylation appears to be induced by CagA-mediated Src inactivation. Ezrin is the founding member of the ezrin-radixin-moesin (ERM) family of proteins which are signalling integrators at the cell cortex. Since ezrin is a component of microvilli and a linker protein between actin filaments and membrane proteins, this observation has important implications for H. pylori pathogenesis and might also help to explain the development of gastric cancer.

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

“…In this regard, it was reported that Src-mediated CagA phosphorylation is followed by a rapid inactivation of Src kinase activity by the binding of CagA to Csk, and then, Src kinase inactivation leads to the dephosphorylation of Src target proteins such as vinculin, ezrin, and cortactin, which are important in the process of regulation of the actin cytoskeleton and focal adhesions. This process contributes to inducing morphological changes of H. pylori-infected cells (18,23,24). Also, it was shown that phosphorylation of cortactin (serine 405) was mediated by ERK1/2 kinases, which might trap activated FAK, leading to a disturbed turnover of focal adhesions and cell elongation morphology (25).…”

Phosphorylation of Helicobacter pylori CagA by c-Abl leads to cell motility

“…The Src-mediated phosphorylation of CagA is followed by an inactivation of the catalytic activity of Src kinases resulting in the dephosphorylation of the actin-binding Src substrates ezrin and cortactin (Selbach et al, 2003;Selbach et al, 2004). As Src kinases are rapidly inactivated, the sustained CagA phosphorylation observed in prolonged H. pylori infections must be accomplished by other molecular means (Selbach et al, 2003).…”

Analysis of Cell Type-Specific Responses Mediated by the Type IV Secretion System of Helicobacter pylori

“…CagA has been reported to interact with several host cell proteins and to stimulate various signaling processes in the host (25). Moreover, tyrosine-phosphorylated CagA inhibits c-Src, which leads to tyrosine dephosphorylation of the cellular Src substrates cortactin and ezrin (33,35).…”