Gas6/Axl signaling activates the phosphatidylinositol 3-kinase/Akt1 survival pathway to protect oligodendrocytes from tumor necrosis factorα-induced apoptosis

Sai Latha Shankar, Kathleen O'Guin, Mimi Kim, Brian Varnum, Greg Lemke, Celia F. Brosnan, Bridget Shafit-Zagardo

Research output: Contribution to journalArticle

73 Scopus citations

Abstract

Growth arrest-specific protein 6 (gas6) activity is mediated through the receptor tyrosine kinase family members Axl, Rse, and Mer, all of which are expressed in human oligodendrocytes. In this study, we examined whether recombinant human (rh) gas6 protects oligodendrocytes from growth factor (insulin) withdrawal or tumor necrosis factor-α (TNFα) cytotoxicity. In addition, we examined whether the effect was caspase-dependent, which receptor mediated the protective effect, and whether survival required Akt1 activation. Oligodendrocyte viability was assessed by O4 staining and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling. Addition of rhgas6 to insulin-depleted cultures resulted in a significant increase in oligodendrocyte viability. Rhgas6 and caspase inhibitors also reduced active caspase-3 immunoreactivity relative to TNFα-only-treated cultures. In cultures treated with TNFα (100 ng/ml), the oligodendrocyte survival rate was 18% compared with cultures treated with TNFα and rhgas6 (64%) or the caspase inhibitors IETD-fmk [z-Ile-Glu(OMe)-Thr-Asp(OMe)- fluoromethyl ketone] (65%) and zVAD-fmk (N-benzyloxycarbonyl-Val-Ala-Asp- fluoromethyl ketone) (63%). Increased phosphoAkt (Ser473) immunoreactivity was detected 15 min after administration of gas6 and TNFα to oligodendrocyte cultures but not in TNFα-treated cultures. The gas6 protective effect was abrogated by the Axl decoy receptor Axl-Fc, by the phosphatidylinositol 3 (PI3) kinase inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one], and in Akt1-/- oligodendrocytes. Oligodendrocyte cultures established from wild-type and Rse-/- mice, but not from Axl-/- mice, were also protected from TNFα-induced cell death when maintained in rhgas6. We conclude that gas6 signaling through the Axl receptor and the PI3 kinase/Akt1 survival pathway protects oligodendrocytes from growth factor withdrawal and TNFα-mediated cell death.

Original languageEnglish (US)
Pages (from-to)5638-5648
Number of pages11
JournalJournal of Neuroscience
Volume26
Issue number21
DOIs
StatePublished - Sep 7 2006

Keywords

  • Akt
  • Apoptosis
  • Axl
  • Gas6
  • Oligodendrocytes
  • TNFα

ASJC Scopus subject areas

  • Neuroscience(all)

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