An EMMPRIN/γ-catenin/Nm23 complex drives ATP production and actomyosin contractility at endothelial junctions

Abstract

Cell-cell adhesions are important sites through which cells experience and resist forces. In endothelial cells, these forces regulate junction dynamics and determine endothelial barrier strength. We identify the Ig superfamily member EMMPRIN (also known as basigin) as a coordinator of forces at endothelial junctions. EMMPRIN localization at junctions correlates with endothelial junction strength in different mouse vascular beds. Accordingly, EMMPRIN-deficient mice show altered junctions and increased junction permeability. Lack of EMMPRIN alters the localization and function of VE-cadherin (also known as cadherin-5) by decreasing both actomyosin contractility and tugging forces at endothelial cell junctions. EMMPRIN ensures proper actomyosin-driven maturation of competent endothelial junctions by forming a molecular complex with c-catenin (also known as junction plakoglobin) and Nm23 (also known as NME1), a nucleoside diphosphate kinase, thereby locally providing ATP to fuel the actomyosin machinery. These results provide a novel mechanism for the regulation of actomyosin contractility at endothelial junctions and might have broader implications in biological contexts such as angiogenesis, collective migration and tissue morphogenesis by coupling compartmentalized energy production to junction assembly.

Self-propelling vesicles define glycolysis as the minimal energy machinery for neuronal transport

“…Nonetheless, this compartmentalization of ATP-producing enzymes coupled closely to molecular motors on moving organelles provides a highly efficient thermodynamic system, as it ensures a locally high ATP concentration that always remains at the proximity of the molecular motors. Interestingly, this compartmentalization emerges as a general mechanism to maintain high local energy concentration in dynamic systems1130, not only for ATP but also for GTP, as recently reported for the coupling of nucleoside diphosphate kinase NM23 members to the actomyosin machinery for contractility at endothelial junctions41 and for membrane remodelling by acting on dynamin superfamily members42.…”

Cell–cell junctional mechanotransduction in endothelial remodeling

“…These findings implicate the existence of a mechanism, by which tight junctions regulate VE-cadherin-dependent mechanotransduction. Moreover, the presence of another transmembrane adhesion receptor EMMPRIN (extracellular matrix metalloproteinase inducer) at endothelial junctions is important for myosin II activity during the maturation of VE-cadherin-based junctions [62]. …”

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“…The role of NME enzymatic activities has been less certain. Roles for the NME NDPK activity in the provision of certain nucleotides have been reported to contribute to dynamin function [55], oxidative stress [56], and endothelial contractility [57]. The NDPK activity of NME is not the only enzymatic activity emanating from its histidine 118 autophosphorylation, NME can also serve as a HPK.…”