Shear stress-stimulated AMPK couples endothelial cell mechanics, metabolism and vasodilation.

Endothelial cells respond to mechanical force by stimulating cellular signaling, but how these pathways are linked to elevations in cell metabolism and whether metabolism supports the mechanical response remains poorly understood. Here, we show that the application of force to endothelial cells stimulates VE-cadherin to activate liver kinase B1 (LKB1; also known as STK11) and AMP-activated protein kinase (AMPK), a master regulator of energy homeostasis. VE-cadherin-stimulated AMPK increases eNOS (also known as NOS3) activity and localization to the plasma membrane, reinforcement of the actin cytoskeleton and cadherin adhesion complex, and glucose uptake.

Mechanical activation of VE-cadherin stimulates AMPK to increase endothelial cell metabolism and vasodilation.

Endothelia cells respond to mechanical force by stimulating cellular signaling, but how these pathways are linked to elevations in cell metabolism and whether metabolism supports the mechanical response remains poorly understood. Here, we show that application of force to VE-cadherin stimulates liver kinase B1 (LKB1) to activate AMP-activated protein kinase (AMPK), a master regulator of energy homeostasis. VE-cadherin stimulated AMPK increases eNOS activity and localization to the plasma membrane as well as reinforcement of the actin cytoskeleton and cadherin adhesion complex, and glucose uptake.

Mechanotransduction: Forcing a change in metabolism.

Epithelial and endothelial cells experience numerous mechanical cues throughout their lifetimes. Cells resist these forces by fortifying their cytoskeletal networks and adhesions. This reinforcement is energetically costly.

Vinculin Y822 is an important determinant of ligand binding.

Vinculin is an actin-binding protein present at cell-matrix and cell-cell adhesions, which plays a critical role in bearing force experienced by cells and dissipating it onto the cytoskeleton. Recently, we identified a key tyrosine residue, Y822, whose phosphorylation plays a critical role in force transmission at cell-cell adhesions. The role of Y822 in human cancer remains unknown, even though Y822 is mutated to Y822C in uterine cancers.

Gene Therapy With the N-Terminus of Junctophilin-2 Improves Heart Failure in Mice.

Background: Transcriptional remodeling is known to contribute to heart failure (HF). Targeting stress-dependent gene expression mechanisms may represent a clinically relevant gene therapy option. We recently uncovered a salutary mechanism in the heart whereby JP2 (junctophilin-2), an essential component of the excitation-contraction coupling apparatus, is site-specifically cleaved and releases an N-terminal fragment (JP2NT [N-terminal fragment of JP2]) that translocates into the nucleus and functions as a transcriptional repressor of HF-related genes.