BRAF Modulates the Interplay Between Cell–Cell and Cell–Extracellular Matrix Adhesions in PECAM-1-Mediated Mechanotransduction

Gráczer, Éva Laura and Pászty, Katalin and Harsányi, Laura and Lehoczky, Csilla and Fülöp, Antónia and Varga, Andrea (2024) BRAF Modulates the Interplay Between Cell–Cell and Cell–Extracellular Matrix Adhesions in PECAM-1-Mediated Mechanotransduction. Int. J. Mol. Sci. 2024, 25, 11234. https://doi.org/10.3390/ijms252011234 (25). No.-11234.

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Abstract

Mechanotransduction, the process how cells sense and convert mechanical stimuli into biochemical response, is crucial in the migration of leukocytes or cancer cells through the endothelium during inflammation or metastasis. Migrating cells exert forces on the endothelium through cell surface adhesion molecules, such as platelet endothelial adhesion molecule, PECAM-1 and this is essential for a successful transmigration. To study PECAM-1-mediated mechanotransduction, we applied PECAM-1-antibody coated magnetic beads and exerted about 40 pN force on the endothelial monolayer. We show that force increases cell-ECM adhesion in the cell center and is accompanied with the opening of cell-cell junctions. Upon depletion of the MEK/ERK kinase, BRAF, force in-creases cell-ECM adhesion both at the cell periphery and in the cell center, but this does not result in the opening the cell-cell junctions. Decreasing cell-ECM adhesion in BRAF-depleted cells through FAK inhibition results in the remodeling of cell-cell junctions. Force-induced increase of cell-ECM adhesion in the cell center correlates with the activation of the transcriptional cofactor, Yes-associated protein (YAP). Furthermore, the induced activation of YAP through LATS inhibition prevents junctional remodeling in control cells. Thus, the activation of YAP might determine the strength of cell-cell junctions during PECAM-1 mediated mechanotransduction.

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