Janus kinase 3 regulates adherens junctions and epithelial mesenchymal transition through β-catenin

Compromise in adherens junctions (AJs) is associated with several chronic inflammatory diseases. We reported previously that Janus kinase 3, a non-receptor tyrosine kinase, plays a crucial role in AJ formation through its interaction with β-catenin. In this report, we characterize the structural det...

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Bibliographic Details
Published in:The Journal of biological chemistry 2017-10, Vol.292 (40), p.16406-16419
Main Authors: Mishra, Jayshree, Das, Jugal Kishore, Kumar, Narendra
Format: Article
Language:English
Subjects:
adherens junction
Adherens Junctions - genetics
Adherens Junctions - metabolism
alpha Catenin - genetics
alpha Catenin - metabolism
barrier functions
beta Catenin - genetics
beta Catenin - metabolism
Cell Line
Epithelial-Mesenchymal Transition - physiology
epithelial–mesenchymal transition (EMT)
Humans
JAK
Janus Kinase 3 - genetics
Janus Kinase 3 - metabolism
mucosal immunology
Phosphorylation - physiology
Protein Domains
protein structure function
Protein Transport - physiology
Signal Transduction
Tyrosine - genetics
Tyrosine - metabolism
β-catenin
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Summary:Compromise in adherens junctions (AJs) is associated with several chronic inflammatory diseases. We reported previously that Janus kinase 3, a non-receptor tyrosine kinase, plays a crucial role in AJ formation through its interaction with β-catenin. In this report, we characterize the structural determinants responsible for Jak3 interactions with β-catenin and determine the functional implications of previously unknown tyrosine residues on β-catenin phosphorylated by Jak3. We demonstrate that Jak3 autophosphorylation was the rate-limiting step during Jak3 trans-phosphorylation of β-catenin, where Jak3 directly phosphorylated three tyrosine residues, viz. Tyr30, Tyr64, and Tyr86 in the N-terminal domain (NTD) of β-catenin. However, prior phosphorylation of β-catenin at Tyr654 was essential for further phosphorylation of β-catenin by Jak3. Interaction studies indicated that phosphorylated Jak3 bound to phosphorylated β-catenin with a dissociation constant of 0.28 μm, and although both the kinase and FERM (Band 4.1, ezrin, radixin, and moesin) domains of Jak3 interacted with β-catenin, the NTD domain of β-catenin facilitated its interactions with Jak3. Physiologically, Jak3-mediated phosphorylation of β-catenin suppressed EGF-mediated epithelial–mesenchymal transition and facilitated epithelial barrier functions by AJ localization of phosphorylated β-catenin through its interactions with α-catenin. Moreover, loss of Jak3-mediated phosphorylation sites in β-catenin abrogated its AJ localization and compromised epithelial barrier functions. Thus, we not only characterize Jak3 interaction with β-catenin but also demonstrate the mechanism of molecular interplay between AJ dynamics and EMT by Jak3-mediated NTD phosphorylation of β-catenin.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M117.811802