JAK3-Mediated Structural Remodeling of β-Catenin Suppresses Epithelial-Mesenchymal Transition: Insights from In Silico Modeling.
- 1Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, Kingsville, TX 78363, USA.
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.
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BibTeX
@article{das2026jak3mediated,
title = {{JAK3-Mediated Structural Remodeling of β-Catenin Suppresses Epithelial-Mesenchymal Transition: Insights from In Silico Modeling.}},
author = {Jugal Kishore Das and Jayshree Mishra and Narendra Kumar},
journal = {Biology},
year = {2026},
month = oct,
doi = {10.3390/biology15191738},
url = {https://europepmc.org/article/MED/42883412},
note = {CC BY},
}
RIS
TY - JOUR
TI - JAK3-Mediated Structural Remodeling of β-Catenin Suppresses Epithelial-Mesenchymal Transition: Insights from In Silico Modeling.
AU - Jugal Kishore Das
AU - Jayshree Mishra
AU - Narendra Kumar
PY - 2026
DA - 2026/10/01
JO - Biology
DO - 10.3390/biology15191738
UR - https://europepmc.org/article/MED/42883412
AB - 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.
SN - 2079-7737
ER -