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PMID:16723520

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Citation

Shankar, SL, O'Guin, K, Kim, M, Varnum, B, Lemke, G, Brosnan, CF and Shafit-Zagardo, B (2006) Gas6/Axl signaling activates the phosphatidylinositol 3-kinase/Akt1 survival pathway to protect oligodendrocytes from tumor necrosis factor alpha-induced apoptosis. J. Neurosci. 26:5638-48

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-alpha (TNFalpha) 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 TNFalpha-only-treated cultures. In cultures treated with TNFalpha (100 ng/ml), the oligodendrocyte survival rate was 18% compared with cultures treated with TNFalpha 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 TNFalpha to oligodendrocyte cultures but not in TNFalpha-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 TNFalpha-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 TNFalpha-mediated cell death.

Links

PubMed Online version:10.1523/JNEUROSCI.5063-05.2006

Keywords

Apoptosis/drug effects; Apoptosis/physiology; Cell Survival/drug effects; Cells, Cultured; Cytoprotection/drug effects; Cytoprotection/physiology; Dose-Response Relationship, Drug; Enzyme Activation; Humans; Intercellular Signaling Peptides and Proteins/metabolism; Oligodendroglia/cytology; Oligodendroglia/drug effects; Oligodendroglia/metabolism; Phosphatidylinositol 3-Kinases/metabolism; Signal Transduction/drug effects; Signal Transduction/physiology; Tumor Necrosis Factor-alpha/administration & dosage

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:TNFA

involved_in

GO:0006919: activation of cysteine-type endopeptidase activity involved in apoptotic process

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:P42574)|has_input:(UniProtKB:Q14790)

Seeded From UniProt

complete

MOUSE:UFO

involved_in

GO:0043066: negative regulation of apoptotic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:UFO

involved_in

GO:0051897: positive regulation of protein kinase B signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:GAS6

involved_in

GO:0043491: protein kinase B signaling

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:GAS6

involved_in

GO:0043154: negative regulation of cysteine-type endopeptidase activity involved in apoptotic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:GAS6

involved_in

GO:0033138: positive regulation of peptidyl-serine phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:P31750)

Seeded From UniProt

complete

HUMAN:GAS6

involved_in

GO:1900142: negative regulation of oligodendrocyte apoptotic process

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:0000128)

Seeded From UniProt

complete

HUMAN:GAS6

involved_in

GO:0051897: positive regulation of protein kinase B signaling

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:GAS6

enables

GO:0043027: cysteine-type endopeptidase inhibitor activity involved in apoptotic process

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:GAS6

involved_in

GO:0001934: positive regulation of protein phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:GAS6

involved_in

GO:0043066: negative regulation of apoptotic process

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:0000128)

Seeded From UniProt

complete

HUMAN:TNFA

involved_in

GO:0043065: positive regulation of apoptotic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TNFA

involved_in

GO:0006919: activation of cysteine-type endopeptidase activity involved in apoptotic process

ECO:0000314: direct assay evidence used in manual assertion

P

has_input:(UniProtKB:P42574)|has_input:(UniProtKB:Q14790)

Seeded From UniProt

complete

HUMAN:TNFA

involved_in

GO:0001934: positive regulation of protein phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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