Abstract
Cortactin is a well-known regulatory protein of the host actin cytoskeleton and represents an attractive target of microbial pathogens like Helicobacter pylori. H. pylori manipulates cortactin’s phosphorylation status by type-IV secretion-dependent injection of its virulence protein CagA. Multiple host tyrosine kinases, like FAK, Src, and Abl, are activated during infection, but the pathway(s) involved is (are) not yet fully established. Among them, Src and Abl target CagA and stimulate tyrosine phosphorylation of the latter at its EPIYA-motifs. To investigate the role of cortactin in more detail, we generated a CRISPR/Cas9 knockout of cortactin in AGS gastric epithelial cells. Surprisingly, we found that FAK, Src, and Abl kinase activities were dramatically downregulated associated with widely diminished CagA phosphorylation in cortactin knockout cells compared to the parental control. Together, we report here a yet unrecognized cortactin-dependent signaling pathway involving FAK, Src, and Abl activation, and controlling efficient phosphorylation of injected CagA during infection. Thus, the cortactin status could serve as a potential new biomarker of gastric cancer development.
Highlights
Helicobacter pylori usually infects its human hosts during early childhood and is one of the most successful pathogens in history, with approximately 50% of the global population colonized
The mechanisms by which H. pylori causes gastric cancer have been under investigation ever since the link between disease and pathogen was discovered [4], but can best be described as two major pathways: One comprises the direct impact on host cell signaling via H. pylori’s virulence factors, which leads to altered cell behavior and malignant cellular autonomy
We discovered that cortactin is required for profound activation of the non-receptor tyrosine kinases focal adhesion kinase (FAK), Src, and Abl, followed by efficient phosphorylation of injected CagA upon infection
Summary
Helicobacter pylori usually infects its human hosts during early childhood and is one of the most successful pathogens in history, with approximately 50% of the global population colonized. The pathogen is known as a causative agent of multiple gastric diseases, such as severe gastritis, peptic ulceration, or stomach cancer in a subset of patients [1,2,3]. The mechanisms by which H. pylori causes gastric cancer have been under investigation ever since the link between disease and pathogen was discovered [4], but can best be described as two major pathways: One comprises the direct impact on host cell signaling via H. pylori’s virulence factors, which leads to altered cell behavior and malignant cellular autonomy. Long-term infection is a crucial process for the bacterium, requiring a multitude of steps such as survival in the harsh conditions of the human stomach, reaching the gastric epithelial cell layer and adhering to it, followed by manipulating host cell signaling to the pathogen’s advantage [8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
