• The Helicobacter pylori CagA protein is a multifunctional bacterial effector and a central virulence determinant associated with gastric diseases, including cancer. While the tyrosine-phosphorylated form of CagA has received extensive attention for its role in oncogenic signaling, accumulating evidence highlights the critical biological activity of CagA independent of its phosphorylation status.
• After translocation into gastric epithelial cells via the Type IV Secretion System (T4SS), only a subset of intracellular CagA undergoes tyrosine phosphorylation at specific EPIYA motifs by host kinases such as Src and Abl. The remaining pool—either unphosphorylated or only partially phosphorylated—retains functional significance and actively participates in altering host cell signaling.
• Experimental data from studies employing Western blotting, phospho-specific antibodies, and immunoprecipitation consistently detect both phosphorylated and non-phosphorylated CagA in infected cells (Amieva et al., 2003; Higashi et al., 2002; Bagnoli et al., 2005), supporting the view that phosphorylation is not required for all aspects of CagA-mediated pathogenesis. 
• Non-phosphorylated CagA contributes significantly to Helicobacter pylori pathogenesis through multiple phosphorylation-independent mechanisms. 
  • It binds to and inhibits PAR1b/MARK2, a key regulator of epithelial polarity, leading to tight junction disassembly and barrier disruption (Saadat et al., 2007; Nishikawa et al., 2008). 
  • CagA also interacts with E-cadherin and β-catenin, affecting adherens junctions and promoting aberrant β-catenin signaling (Murata-Kamiya et al., 2007). 
  • Additionally, it activates NF-κB signaling and pro-inflammatory gene expression (Brandt et al., 2005), contributing to chronic inflammation and immune evasion. 
  • Furthermore, non-phosphorylated CagA suppresses apoptosis by activating the PI3K/Akt pathway and other survival signals (Jones et al., 2008; Mimuro et al., 2007), enhancing bacterial persistence within host cells.
• The phosphorylation status of CagA is tightly regulated by multiple factors that shape its functional outcomes in host cells. 
  • The composition of EPIYA motifs plays a central role: Western strains typically carry EPIYA-A, -B, and -C segments, while East Asian strains harbor the more readily phosphorylated EPIYA-D, influencing the proportion of phosphorylated versus unphosphorylated CagA (Hatakeyama, 2004; Azuma et al., 2004). 
  • Host kinase availability—particularly Src and Abl—also affects phosphorylation, with variations depending on cell type and physiological context (Mueller et al., 2012). 
  • Additionally, subcellular localization of CagA determines its access to kinases; molecules sequestered in membrane microdomains or cytoplasmic regions may escape phosphorylation (Tegtmeyer et al., 2017). 
  • Post-translational modifications such as ubiquitination or lipid interactions may further stabilize the unphosphorylated form or target phosphorylated CagA for degradation (Backert et al., 2015). 
  • Finally, the polarization state and inflammatory status of host cells influence kinase signaling pathways, thereby modulating the phosphorylation dynamics and downstream effects of CagA.
• CagA signaling that is independent of its phosphorylation status constitutes a fundamental aspect of H. pylori pathogenesis. Alongside phosphorylated CagA, this non-canonical activity contributes to the breakdown of epithelial homeostasis, immune modulation, and ultimately carcinogenesis. Elucidating the mechanisms that regulate this signaling axis may uncover novel therapeutic opportunities to combat H. pylori-associated diseases.

REFERENCES

• Amieva et al., 2003. Disruption of the epithelial apical-junctional complex by Helicobacter pylori CagA. Science. 300(5624), 1430-4. PMID-12775840; Full Text: Science, PMC
• Bagnoli et al., 2005. Helicobacter pylori CagA induces a transition from polarized to invasive phenotypes in MDCK cells. Proc Natl Acad Sci U S A. 102(45), 16339-44. PMID-16258069; Full Text: PNAS, PMC
• Higashi et al., 2002. SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein. Science. 295(5555), 683-6. PMID-11743164; Full Text: Science