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.
Original language | English (US) |
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Pages (from-to) | 634-647 |
Number of pages | 14 |
Journal | Immunobiology |
Volume | 223 |
Issue number | 11 |
DOIs | |
State | Published - Nov 2018 |
Keywords
- Actin
- FTY720
- Macrophage
- Matrix degradation
- PAK1
- Podosome
- Rac-1
- RhoA
- mTOR
- mTORC2
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
- Hematology