title: DLC1 interaction with α-catenin stabilizes adherens junctions and enhances DLC1 antioncogenic activity.
abstract: 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 α-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 α-catenin. These proteins colocalized in the cytosol and in the plasma membrane, where together they associated with E-cadherin and β-catenin, constitutive AJ proteins. Binding of DLC1 to α-catenin led to their accumulation at the plasma membrane and required DLC1 GAP activity. Knocking down α-catenin in DLC1-positive cells diminished DLC1 localization at the membrane. The DLC1-α-catenin complex reduced the Rho GTP level at the plasma membrane, 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.
authors.affiliation: Laboratory of Experimental Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Veenu
authors.initials: V
authors.lastname: Tripathi
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Popescu
authors.forename: Drazen B
authors.initials: DB
authors.lastname: Zimonjic
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism*; D001665:Binding Sites; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis; D011485:Protein Binding; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D051178:alpha Catenin / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: D015820:Cadherins; C112352:DLC1 protein, human; D020690:GTPase-Activating Proteins; D025521:Tumor Suppressor Proteins; D051178:alpha Catenin; D020741:rho GTP-Binding Proteins