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

Rei J. Abe, Hannah Savage, Masaki Imanishi, Priyanka Banerjee, Sivareddy Kotla, Jesus Paez-Mayorga, Jack Taunton, Keigi Fujiwara, Jong Hak Won, Syed Wamique Yusuf, Nicolas L. Palaskas, Jose Banchs, Steven H. Lin, Keri L. Schadler, Jun Ichi Abe, Nhat Tu Le

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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 magi1, 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 in vivo. 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.

Original languageEnglish (US)
Article number542485
JournalFrontiers in Cardiovascular Medicine
Volume7
DOIs
StatePublished - Nov 13 2020

Keywords

  • EC permeability
  • Hippo pathway
  • MAGI1
  • SUMOylation
  • p90RSK

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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