Vinculin Y822 phosphorylation regulates adhesion remodeling during cardiomyocyte maturation.

In the heart, cardiomyocyte cell-matrix and cell-cell adhesions reorganize in response to increased cardiac demand and growth. Vinculin (VCL), a mechanosensitive adaptor protein, links filamentous actin to cell-matrix and cell-cell adhesions. Yet how VCL regulates remodeling of the two adhesion systems is poorly understood. Here, we investigate the role of phosphorylation at VCL tyrosine residue 822 (pY822) in cardiomyocyte adhesion and heart function. VCL Y822 phosphorylation levels peaked during adhesion remodeling in the developing heart and were reduced as adhesions matured postnatally. VCL pY822 levels also increased in the adult heart following injury. We mutated Vcl Y822 to phenylalanine (Y822F) in the mouse to determine the in vivo function of pY822. Homozygous mutant Vcl Y822F mice were viable but exhibited cardiac dysfunction at 28 weeks. We found that VCL pY822 regulated cardiomyocyte cell-matrix and cell-cell adhesions during postnatal heart development. Defects in cell-cell adhesion organization were also observed in cultured Vcl Y822F cardiomyocytes. Our results demonstrate that VCL Y822 phosphorylation regulates adhesion organization in cardiomyocytes, highlighting the importance of post-translational modification in modulating VCL function in the heart.

Duke Scholars

Author Brenton D. Hoffman Biomedical Engineering