DLC1 Interaction with -Catenin Stabilizes Adherens Junctions and Enhances DLC1 Antioncogenic Activity

The DLC1 (for deleted in liver cancer 1) tumor suppressor gene encodes a RhoGAP protein that inactivates Rho GTPases, which are implicated in regulation of the cytoskeleton and adherens junctions (AJs), a cell-cell adhesion protein complex associated with the actin cytoskeleton. Malignant transformation and tumor progression to metastasis are often associated with changes in cytoskeletal organization and cell-cell adhesion. Here we have established in human cells that the AJ-associated protein -catenin is a new binding partner of DLC1. Their binding was mediated by the N-terminal amino acids 340 to 435 of DLC1 and the N-terminal amino acids 117 to 161 of -catenin. These proteins colocalized in the cytosol and in the plasma membrane, where together they associated with E-cadherin and -catenin, constitutive AJ proteins. Binding of DLC1 to -catenin led to their accumulation at the plasma membrane and required DLC1 GAP activity. Knocking down -catenin in DLC1-positive cells diminished DLC1 localization at the membrane. The DLC1–-catenin complex reduced the Rho GTP level at the plasma mem-brane, increased E-cadherin’s mobility, affected actin organization, and stabilized AJs. This process eventually contributed to a robust oncosuppressive effect of DLC1 in metastatic prostate carcinoma cells. Together, these results unravel a new mechanism through which DLC1 exerts its strong oncosuppressive function by positively influencing AJ stability. Cancer initiation and progression constitute a multistep pro-cess, associated with both structural changes in certain genes and alterations in the dynamics and magnitude of their expres-sion.Mutations and various chromosome rearrangements can in