Inhibition of RhoA and mTORC2/Rictor by Fingolimod (FTY720) induces p21-activated kinase 1, PAK-1 and amplifies podosomes in mouse peritoneal macrophages |
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Authors: | Wei Chen Rafik M. Ghobrial Xian C. Li Malgorzata Kloc |
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Affiliation: | 1. Houston Methodist Research Institute, Houston, TX, USA;2. Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha 410011, China;3. Weill Cornell Medical College, 407 E 61st St, New York, USA;4. University of Texas, MD Anderson Cancer Center, Department of Genetics, Houston, TX, USA |
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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. |
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Keywords: | Macrophage Podosome Actin PAK1 mTOR mTORC2 RhoA Rac-1 FTY720 Matrix degradation |
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