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The Journal of Neuroscience, May 24, 2006, 26(21):5638-5648; doi:10.1523/JNEUROSCI.5063-05.2006

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Development/Plasticity/Repair
Gas6/Axl Signaling Activates the Phosphatidylinositol 3-Kinase/Akt1 Survival Pathway to Protect Oligodendrocytes from Tumor Necrosis Factor-Induced Apoptosis

Sai Latha Shankar,¹ Kathleen O’Guin,¹ Mimi Kim,² Brian Varnum,³ Greg Lemke,⁴ Celia F. Brosnan,¹ and Bridget Shafit-Zagardo¹

Departments of ¹Pathology and ²Epidemiology, Albert Einstein College of Medicine, Bronx, New York 10461, ³Amgen Corporation, Thousand Oaks, California 91320, and ⁴Molecular Neurobiology Laboratory, The Salk Institute, La Jolla, California 92037

Correspondence should be addressed to Dr. Bridget Shafit-Zagardo, Department of Pathology, Forcheimmer 516, 1300 Morris Park Avenue, Albert Einstein College of Medicine, Bronx, NY 10461. Email: zagardo{at}aecom.yu.edu

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

Key words: Gas6; oligodendrocytes; TNF; apoptosis; Axl; Akt

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Received Jan. 12, 2005; revised April 11, 2006; accepted April 13, 2006.

Correspondence should be addressed to Dr. Bridget Shafit-Zagardo, Department of Pathology, Forcheimmer 516, 1300 Morris Park Avenue, Albert Einstein College of Medicine, Bronx, NY 10461. Email: zagardo{at}aecom.yu.edu

This article has been cited by other articles:

				J. G. Weinger, K. M. Omari, K. Marsden, C. S. Raine, and B. Shafit-Zagardo Up-Regulation of Soluble Axl and Mer Receptor Tyrosine Kinases Negatively Correlates with Gas6 in Established Multiple Sclerosis Lesions Am. J. Pathol., July 1, 2009; 175(1): 283 - 293. [Abstract] [Full Text] [PDF]

				M. D. Binder, H. S. Cate, A. L. Prieto, D. Kemper, H. Butzkueven, M. M. Gresle, T. Cipriani, V. G. Jokubaitis, P. Carmeliet, and T. J. Kilpatrick Gas6 Deficiency Increases Oligodendrocyte Loss and Microglial Activation in Response to Cuprizone-Induced Demyelination J. Neurosci., May 14, 2008; 28(20): 5195 - 5206. [Abstract] [Full Text] [PDF]

				N. Tibrewal, Y. Wu, V. D'mello, R. Akakura, T. C. George, B. Varnum, and R. B. Birge Autophosphorylation Docking Site Tyr-867 in Mer Receptor Tyrosine Kinase Allows for Dissociation of Multiple Signaling Pathways for Phagocytosis of Apoptotic Cells and Down-modulation of Lipopolysaccharide-inducible NF-{kappa}B Transcriptional Activation J. Biol. Chem., February 8, 2008; 283(6): 3618 - 3627. [Abstract] [Full Text] [PDF]

				M. Hutterer, P. Knyazev, A. Abate, M. Reschke, H. Maier, N. Stefanova, T. Knyazeva, V. Barbieri, M. Reindl, A. Muigg, et al. Axl and Growth Arrest Specific Gene 6 Are Frequently Overexpressed in Human Gliomas and Predict Poor Prognosis in Patients with Glioblastoma Multiforme Clin. Cancer Res., January 1, 2008; 14(1): 130 - 138. [Abstract] [Full Text] [PDF]

				T. Revil, J. Toutant, L. Shkreta, D. Garneau, P. Cloutier, and B. Chabot Protein Kinase C-Dependent Control of Bcl-x Alternative Splicing Mol. Cell. Biol., December 15, 2007; 27(24): 8431 - 8441. [Abstract] [Full Text] [PDF]

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