p90RSK-MAGI1 Module Controls Endothelial Permeability by Post-translational Modifications of MAGI1 and Hippo Pathway

• Published in: Frontiers in cardiovascular medicine Vol. 7; p. 542485
• Main Authors: Abe, Rei J, Savage, Hannah, Imanishi, Masaki, Banerjee, Priyanka, Kotla, Sivareddy, Paez-Mayorga, Jesus, Taunton, Jack, Fujiwara, Keigi, Won, Jong Hak, Yusuf, Syed Wamique, Palaskas, Nicolas L, Banchs, Jose, Lin, Steven H, Schadler, Keri L, Abe, Jun-Ichi, Le, Nhat-Tu
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 13.11.2020
• Subjects: Cardiovascular Medicine; EC permeability; Hippo pathway; MAGI1; p90RSK; SUMOylation; MAGI1; p90RSK; Hippo pathway; SUMOylation; EC permeability
• ISSN: 2297-055X; 2297-055X
• DOI: 10.3389/fcvm.2020.542485

Previously, we reported that post-translational modifications (PTMs) of MAGI1, including S741 phosphorylation and K931 de-SUMOylation, both of which are regulated by p90RSK activation, lead to endothelial cell (EC) activation. However, roles for p90RSK and MAGI1-PTMs in regulating EC permeability remain unclear despite MAGI1 being a junctional molecule. Here, we show that thrombin (Thb)-induced EC permeability, detected by the electric cell-substrate impedance sensing (ECIS) based system, was decreased by overexpression of dominant negative p90RSK or a MAGI1-S741A phosphorylation mutant, but was accelerated by overexpression of p90RSK, siRNA-mediated knockdown of , or the MAGI1-K931R SUMOylation mutant. MAGI1 depletion also increased the mRNA and protein expression of the large tumor suppressor kinases 1 and 2 (LATS1/2), which inhibited YAP/TAZ activity and increased EC permeability. Because the endothelial barrier is a critical mediator of tumor hypoxia, we also evaluated the role of p90RSK activation in tumor vessel leakiness by using a relatively low dose of the p90RSK specific inhibitor, FMK-MEA. FMK-MEA significantly inhibited tumor vessel leakiness at a dose that does not affect morphology and growth of tumor vessels . These results provide novel insights into crucial roles for p90RSK-mediated MAGI1 PTMs and the Hippo pathway in EC permeability, as well as p90RSK activation in tumor vessel leakiness.