JAK3-Mediated Structural Remodeling of β-Catenin Suppresses Epithelial–Mesenchymal Transition: Insights from In Silico Modeling
Year: 2026
Type: article
Abstract: INTRODUCTION: Janus kinase 3 (JAK3) is a non-receptor tyrosine kinase that phosphorylates multiple proteins, including β-catenin, a critical component of adherens junctions (AJs). We previously demonstrated that JAK3-mediated phosphorylation of β-catenin regulates its basolateral localization and preserves epithelial barrier integrity. However, the structural basis underlying JAK3-β-catenin interactions and their role in epithelial-mesenchymal transition (EMT) remains unclear. METHODOLOGY: Here, we employed homology modeling, molecular docking, and structural simulations to investigate phosphorylation-dependent interactions between JAK3 and β-catenin. RESULTS: Our analysis revealed that Src-mediated phosphorylation at Y654 induces conformational remodeling of the β-catenin N-terminal domain (NTD), creating a favorable interface for JAK3 binding and shifting its interaction from the armadillo repeat domain to the NTD. Subsequent JAK3-mediated phosphorylation at Y30, Y64, and Y86 restores β-catenin conformation, stabilizes the E-cadherin/β-catenin complex, and limits nuclear translocation. Phosphomimetic analyses identified distinct structural contributions of these residues. CONCLUSIONS: Collectively, these findings reveal a sequential Src-JAK3 phosphorylation mechanism that maintains AJ integrity and suppresses EMT, providing potential therapeutic insights into epithelial cancer progression.
Source: Biology
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,258
OpenAlex ID: W7215090205