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

ABSTRACT: 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.

SUBMITTER: Mishra J 

PROVIDER: S-EPMC5633104 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature