Inhibition of RhoA and mTORC2/Rictor by Fingolimod (FTY720) induces p21-activated kinase 1, PAK-1 and amplifies podosomes in mouse peritoneal macrophages.
Immunobiology
; 223(11): 634-647, 2018 11.
Article
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| MEDLINE
| ID: mdl-30005970
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, ß-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.
Palabras clave
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Base de datos:
MEDLINE
Asunto principal:
Macrófagos Peritoneales
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Proteína de Unión al GTP rac1
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Proteína de Unión al GTP rhoA
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Matriz Extracelular
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Quinasas p21 Activadas
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Podosomas
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Esclerosis Múltiple
Idioma:
En
Revista:
Immunobiology
Año:
2018
Tipo del documento:
Article