| Criteria | Phosphorylation-Dependent CagA Function | Phosphorylation-Independent CagA Function | Remarks |
| Molecular Basis | Relies on phosphorylation at EPIYA motifs by host Src and Abl kinases | Functions without phosphorylation; depends on direct protein-protein interactions | Both mechanisms contribute to the overall virulence of CagA. |
| Key Motifs Involved | EPIYA motifs (especially EPIYA-C and EPIYA-D) | CM (CagA multimerization) motifs and other structural regions | Different domains of CagA mediate different sets of host interactions. |
| Major Host Targets | SHP2 phosphatase, Crk adaptors, C-terminal Src kinase (Csk) | PAR1/MARK kinases, E-cadherin, ZO-1, β-catenin, Grb2 | Targets differ based on phosphorylation status. |
| Primary Cellular Effects | Activation of SHP2 → ERK pathway, cytoskeletal rearrangements, “hummingbird” phenotype | Disruption of cell polarity, tight junction integrity, and cell adhesion | Phosphorylated CagA alters signaling; unphosphorylated CagA disrupts structural components. |
| Signaling Pathways Activated | MAPK/ERK, JAK/STAT, and Src signaling pathways | Wnt/β-catenin, PI3K/Akt, NF-κB pathways | CagA impacts multiple oncogenic and inflammatory pathways via both mechanisms. |
| Oncogenic Potential | High — through SHP2 activation and proliferation signaling | Also high — through β-catenin stabilization and chronic inflammation | Both contribute to gastric carcinogenesis, synergistically or independently. |
| Experimental Confirmation | Detected using phospho-specific antibodies and site-mutagenesis | Observed in phospho-defective mutants (e.g., CagA with EPIYA motif mutations) | Both approaches help dissect CagA’s mechanism of action. |
| Temporal Dynamics Post-Infection | Phosphorylation occurs shortly after translocation and is transient | Persists even when phosphorylation is blocked | Phosphorylation-independent functions may play a longer-lasting role in host modulation. |
| Relevance in Strain Variation | Strong in East Asian strains (EPIYA-D motif more potent in SHP2 activation) | Found in all strains; more conserved functions | Reflects geographical variation in gastric cancer risk. |
| Inhibitor Sensitivity | Affected by Src/Abl kinase inhibitors | Not sensitive to kinase inhibition | Helps differentiate between the two function types in experimental settings. |
