Cortactin is a scaffolding platform for the E-Cadherin adhesion complex controlled by protein kinase D1 phosphorylation

Abstract

Dynamic regulation of cell-cell adhesion by the coordinated formation and dissolution of E–Cadherin-based adherens junctions (AJs) is critical for tissue homeostasis. The actin-binding protein Cortactin interacts with E-Cadherin and enables F-actin accumulation at AJs. We here were interested to study broader functional interactions of Cortactin in adhesion complexes. In line with literature, we demonstrate that Cortactin binds to E-Cadherin and a posttranslational modification of Cortactin, RhoA–induced phosphorylation by PKD1 at S298, impairs AJ assembly and supports their dissolution. Two novel S298-phosphorylation-dependent interactions were identified: Phosphorylation of Cortactin decreases its interaction with beta-Catenin and the actin-binding protein Vinculin. Secondly, binding of Vinculin to beta-Catenin as well as linkage of Vinculin to F-actin are also significantly compromised. Accordingly, we found that regulation of cell-cell adhesion by phosphorylation of Cortactin downstream of RhoA/PKD1 is vitally dependent on Vinculin–mediated protein interactions. Thus, Cortactin unexpectedly is an important integration node for the dynamic regulation of protein complexes during breakdown and formation of AJs.