| First Author | Mishra J | Year | 2017 |
| Journal | J Biol Chem | Volume | 292 |
| Issue | 40 | Pages | 16406-16419 |
| PubMed ID | 28821617 | Mgi Jnum | J:247306 |
| Mgi Id | MGI:5916238 | Doi | 10.1074/jbc.M117.811802 |
| Citation | Mishra J, et al. (2017) Janus kinase 3 regulates adherens junctions and epithelial mesenchymal transition through beta-catenin. J Biol Chem 292(40):16406-16419 |
| abstractText | 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 beta-catenin. In this report, we characterize the structural determinants responsible for Jak3 interactions with beta-catenin and determine the functional implications of previously unknown tyrosine residues on beta-catenin phosphorylated by Jak3. We demonstrate that Jak3 autophosphorylation was the rate-limiting step during Jak3 trans-phosphorylation of beta-catenin, where Jak3 directly phosphorylated three tyrosine residues, viz. Tyr30, Tyr64, and Tyr86 in the N-terminal domain (NTD) of beta-catenin. However, prior phosphorylation of beta-catenin at Tyr654 was essential for further phosphorylation of beta-catenin by Jak3. Interaction studies indicated that phosphorylated Jak3 bound to phosphorylated beta-catenin with a dissociation constant of 0.28 mum, and although both the kinase and FERM (Band 41, ezrin, radixin, and moesin) domains of Jak3 interacted with beta-catenin, the NTD domain of beta-catenin facilitated its interactions with Jak3. Physiologically, Jak3-mediated phosphorylation of beta-catenin suppressed EGF-mediated epithelial-mesenchymal transition and facilitated epithelial barrier functions by AJ localization of phosphorylated beta-catenin through its interactions with alpha-catenin. Moreover, loss of Jak3-mediated phosphorylation sites in beta-catenin abrogated its AJ localization and compromised epithelial barrier functions. Thus, we not only characterize Jak3 interaction with beta-catenin but also demonstrate the mechanism of molecular interplay between AJ dynamics and EMT by Jak3-mediated NTD phosphorylation of beta-catenin. |
