The Role of α-catenin in Mechano-sensing of the Extracellular Matrix

Rigidity of the extracellular matrix (ECM) affects cellular processes like growth, migration and epithelial-to-mesenchymal transition (EMT). Rigidity testing requires the assembly of actomyosin-based contractile units (CUs) attached to integrin-based adhesions which apply forces to the ECM to test its rigidity. Assembly of these units requires α-actinin, but surprisingly, does not require its actin binding domain. Using live-cell imaging, traction force measurements, and high-resolution confocal microscopy, we tested the hypothesis that α-actinin regulates adhesion strength through recruitment of the secondary actin binding protein, α-catenin. Here, we show α-catenin’s role in ECM mechano-sensing as it is recruited to integrin adhesions by α-actinin. In MDA-MB-231 and Pancreatic Ductal Adenocarcinoma cells (PDAC), the presence of α-catenin inhibits the recruitment of the adhesion protein vinculin. In its absence, in MDA-MB-468 cells, vinculin dominates the nascent adhesions thus stating α-catenin’s role in reinforcing matrix adhesions. Furthermore, we observe that α-catenin plays an important role in maintaining protrusion-retraction cycles at the cell edge. This directly correlates to high proliferation, motility and migratory rates in PDAC cells, which is consistent with the observation that α-catenin is overexpressed in highly invasive pancreatic cancers. Moreover, as α-catenin is associated with cell-cell adhesions in epithelial cells, we hypothesized that it has a role in EMT. Knocking down α-catenin in MDCK cells allowed EMT only on stiff matrices, suggesting that on rigid ECM α-catenin is translocated to cell-matrix adhesions to induce EMT. Collectively, these results establish a major role for α-catenin in integrin adhesions, ECM mechano-sensing, EMT, cell proliferation and motility.