Janus kinase 3 regulates adherens junctions and epithelial mesenchymal transition through -catenin.
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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 -catenin. In this report, we characterize the structural determinants responsible for Jak3 interactions with -catenin and determine the functional implications of previously unknown tyrosine residues on -catenin phosphorylated by Jak3. We demonstrate that Jak3 autophosphorylation was the rate-limiting step during Jak3 trans-phosphorylation of -catenin, where Jak3 directly phosphorylated three tyrosine residues, viz. Tyr30, Tyr64, and Tyr86 in the N-terminal domain (NTD) of -catenin. However, prior phosphorylation of -catenin at Tyr654 was essential for further phosphorylation of -catenin by Jak3. Interaction studies indicated that phosphorylated Jak3 bound to phosphorylated -catenin with a dissociation constant of 0.28 m, and although both the kinase and FERM (Band 41, ezrin, radixin, and moesin) domains of Jak3 interacted with -catenin, the NTD domain of -catenin facilitated its interactions with Jak3. Physiologically, Jak3-mediated phosphorylation of -catenin suppressed EGF-mediated epithelial-mesenchymal transition and facilitated epithelial barrier functions by AJ localization of phosphorylated -catenin through its interactions with -catenin. Moreover, loss of Jak3-mediated phosphorylation sites in -catenin abrogated its AJ localization and compromised epithelial barrier functions. Thus, we not only characterize Jak3 interaction with -catenin but also demonstrate the mechanism of molecular interplay between AJ dynamics and EMT by Jak3-mediated NTD phosphorylation of -catenin.
author list (cited authors)
Mishra, J., Das, J. K., & Kumar, N.
complete list of authors
Mishra, Jayshree||Das, Jugal Kishore||Kumar, Narendra