Inhibition of RhoA and mTORC2/Rictor by Fingolimod (FTY720) induces p21-activated kinase 1, PAK-1 and amplifies podosomes in mouse peritoneal macrophages

Immunobiology
Wei ChenMalgorzata Kloc

Abstract

Macrophage functions in the immune response depend on their ability to infiltrate tissues and organs. The penetration between and within the tissues requires degradation of extracellular matrix (ECM), a function performed by the specialized, endopeptidase- and actin filament- rich organelles located at the ventral surface of macrophage, called the podosomes. Podosome formation requires local inhibition of small GTPase RhoA activity, and depends on Rac 1/Rho guanine nucleotide exchange factor 7, β-PIX and its binding partner the p21-activated kinase (PAK-1). The activity of RhoA and Rac 1 is in turn regulated by mTOR/mTORC2 pathway. Here we showed that a fungus metabolite Fingolimod (FTY720, Gilenya), which is clinically approved for the treatment of multiple sclerosis, down-regulates Rictor, which is a signature molecule of mTORC2 and dictates its substrate (actin cytoskeleton) specificity, down-regulates RhoA, up-regulates PAK-1, and causes amplification of podosomes in mouse peritoneal macrophages.

Citations

Nov 18, 2018·Journal of Tissue Engineering and Regenerative Medicine·Malgorzata KlocJacek Z Kubiak
Jul 20, 2019·Cells·Matthias BrosStephan Grabbe
Jun 4, 2020·Archivum Immunologiae Et Therapiae Experimentalis·Ahmed UosefMalgorzata Kloc
Jan 1, 2021·International Journal of Molecular Sciences·Malgorzata KlocRafik Mark Ghobrial
Nov 7, 2020·Translational Oncology·Tristan RuppVincent Castagné
Apr 3, 2021·Frontiers in Cell and Developmental Biology·Hui LiuZigang Dong
Apr 29, 2021·Journal of Biomedical Science·Lucia Sophie KilianAshraf Yusuf Rangrez
Nov 10, 2021·Journal of Cellular Biochemistry·Tereza KořánováKateřina Kuželová

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