Vinculin Y822 phosphorylation regulates cardiomyocyte adhesion dynamics and adherens junction maturation in the heart

Abstract

In the heart, cell-matrix and cell-cell adhesions reorganize in response to increased cardiac demand and growth to promote cardiomyocyte maturation. Vinculin, a mechanosensitive adaptor protein, links filamentous actin to cell-matrix and cell-cell adhesions and is thus positioned to regulate adhesion reorganization. However, how the two adhesion systems are coordinated in the heart, and the role of vinculin in this process is poorly understood. Here, we define the role of vinculin phosphorylation at tyrosine residue 822 (pY822) in cardiomyocyte adhesion and heart function. We found that pY822 correlated with dynamic junction remodeling in the developing heart but was lost as junctions matured postnatally. We then mutated Y822 to phenylalanine (Y822F) in the mouse to determine pY822 function in vivo. Homozygous mutant Vcl Y822F mice were viable and exhibited normal cardiac function at ten weeks of age; however, cardiac dysfunction was observed at 28 weeks. Vinculin and adherens junction proteins were reduced at cardiomyocyte junctions in Y822F hearts. In contrast, 5/{beta}1 integrin and fibronectin increased along the lateral border of Y822F cardiomyocytes. Our results demonstrate that vinculin Y822 phosphorylation regulates the balance between cadherin and integrin adhesion organization, highlighting the importance of post-translational modification in modulating vinculin function in heart physiology.