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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11 Scopus citations

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 languageEnglish (US)
Pages (from-to)634-647
Number of pages14
JournalImmunobiology
Volume223
Issue number11
DOIs
StatePublished - Nov 2018

Keywords

  • Actin
  • FTY720
  • Macrophage
  • Matrix degradation
  • PAK1
  • Podosome
  • Rac-1
  • RhoA
  • mTOR
  • mTORC2

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Hematology

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