Gas6 rescues cortical neurons from amyloid β protein-induced apoptosis

Yagami, Tatsurou; Ueda, Kazuki; Asakura, Kouichi; Sakaeda, Toshiyuki; Nakazato, H.; Kuroda, Takayuki; Hata, Satoshi; Sakaguchi, Gaku; Itoh, Naohiro; Nakano, Toru; Kambayashi, Yoshikazu; Tsuzuki, Hiroshige

doi:10.1016/s0028-3908(02)00333-7

Cited by 83 publications

(59 citation statements)

References 26 publications

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“…Whereas Axl was only detectable in gliomas, Gas6 showed a strong expression in neurons of nontumoral tissue. A comparable neuronal expression of Gas6 mRNA has already been reported in the adult rat brain (26) and in primary cultures of rat hippocampal neurons (28,29). In vitro Gas6/Axl signaling attenuated neuronal cell death caused by serum starvation (26), secretory phospholipase A2 (28), and amyloid h protein (29).…”

Section: Discussionsupporting

confidence: 72%

Axl and Growth Arrest–Specific Gene 6 Are Frequently Overexpressed in Human Gliomas and Predict Poor Prognosis in Patients with Glioblastoma Multiforme

Hutterer

Knyazev

Abate³

et al. 2008

Clinical Cancer Research

245

243

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Purpose: The receptor tyrosine kinase Axl has recently been identified as a critical element in the invasive properties of glioma cell lines. However, the effect of Axl and its ligand growth arrestŝ pecific gene 6 (Gas6) in human gliomas is still unknown. Experimental Design: Axl and Gas6 expression was studied in 42 fresh-frozen and 79 paraffinembedded glioma specimens by means of reverse transcription-PCR and immunohistochemistry. The prognostic value of Axl and Gas6 expression was evaluated using a population-based tissue microarray derived from a cohort of 55 glioblastoma multiforme (GBM) patients.Results: Axl and Gas6 were detectable in gliomas of malignancy gradesWHO 2 to 4. Moderate to high Axl mRNA expression was found in 61%, Axl protein in 55%, Gas6 mRNA in 81%, and Gas6 proteinin 74% of GBMsamples, respectively. GBM patients withhigh Axl expression and Axl/Gas6 coexpression showed a significantly shorter time to tumor progression and an association with poorer overall survival. Comparative immunohistochemical studies showed that Axl staining was most pronounced in glioma cells of pseudopalisades and reactive astrocytes. Additionally, Axl/ Gas6 coexpression was observed in glioma cells and tumor vessels. In contrast, Axl staining was not detectable in nonneoplastic brain tissue and Gas6 was strongly expressed in neurons.Conclusions: In human gliomas, Axl and Gas6 are frequently overexpressed in both glioma and vascular cells and predict poor prognosis in GBM patients. Our results indicate that specific targeting of the Axl/Gas6 signaling pathway may represent a potential new approach for glioma treatment.

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Section: Discussionsupporting

confidence: 72%

Axl and Growth Arrest–Specific Gene 6 Are Frequently Overexpressed in Human Gliomas and Predict Poor Prognosis in Patients with Glioblastoma Multiforme

Hutterer

Knyazev

Abate³

et al. 2008

Clinical Cancer Research

245

243

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“…Gas6 is present at high levels in the brain throughout development and continues to be expressed in the adult (Prieto et al 1999). It has been reported that Gas6 has an anti-apoptotic effect on neurons (Goruppi et al 1996;Hasanbasic et al 2004), especially on protecting neurons from amyloid-beta-induced apoptosis (Yagami et al 2002). Furthermore, Gas6 may act as a neurotrophic factor for hippocampal (Funakoshi et al 2002) and cortical (Yagami et al 2003) neurons.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Microglial Phagocytosis and Inflammatory Gene Expression by Gas6 Acting on the Axl/Mer Family of Tyrosine Kinases

Grommes

Lee

Wilkinson

et al. 2007

J Neuroimmune Pharmacol

132

129

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Removal of apoptotic cells is an essential process for normal development and tissue maintenance. Importantly, apoptotic cells stimulate their phagocytosis by macrophages while actively suppressing inflammatory responses. Growth arrest specific gene 6 (Gas6) is involved in this process, bridging phosphatidylserine residues on the surface of apoptotic cells to the Axl/Mer family of tyrosine kinases which stimulate phagocytosis. Animals with mutations or loss of these receptors exhibit phenotypes reflective of impaired phagocytosis and a hyperactive immune response. We report that Gas6 induces phagocytosis in microglia through a novel non-classical phagocytic mechanism. Gas6 stimulates a type-II-related phagocytic response, but requires Vav phosphorylation and Rac activation, distinguishing it from the classical type II mechanism. Importantly, Gas6 suppressed lipopolysaccharide-induced expression of the inflammatory molecules IL-1β and iNOS. Gas6 inhibited iNOS expression through suppression of promoter activity. The present data provide direct evidence for the role of Gas6 receptors in mediating an anti-inflammatory response to ligands found on apoptotic cells with the simultaneous stimulation

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“…Two ligands are known for the TAM receptors, Gas6 (growth arrest gene 6) and the structurally related protein S (Stitt et al, 1995;Nagata et al, 1996;Prasad et al, 2006). To date, the function of Gas6 as a ligand for the TAM receptors has been better studied than protein S. In particular, Gas6 has been shown to have both mitogenic and survival activities for a variety of cell types, including neurons, Schwann cells, and human and mouse oligodendrocytes (Li et al, 1996;Yagami et al, 2002;Shankar et al, 2003Shankar et al, , 2006.…”

Section: Introductionmentioning

confidence: 99%

Gas6 Deficiency Increases Oligodendrocyte Loss and Microglial Activation in Response to Cuprizone-Induced Demyelination

Binder¹,

Cate²,

Prieto³

et al. 2008

J. Neurosci.

116

110

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The TAM family of receptor protein tyrosine kinases comprises three known members, namely Tyro3, Axl, and Mer. These receptors are widely expressed in the nervous system, including by oligodendrocytes, the cell type responsible for myelinating the CNS. We examined the potential role of the TAM family and of their principle cognate ligand, Gas6 (growth arrest gene 6), in modulating the phenotype of the cuprizone model of demyelination. We found that the expression profiles of Axl, Mer, and Gas6 mRNA were increased in the corpus callosum in a temporal profile correlating with the increased migration and proliferation of microglia/macrophages in this model. In contrast, expression of Tyro3 decreased, correlating with the loss of oligodendrocytes. Gas6 both promoted in vitro survival of oligodendrocytes (39.3 Ϯ 3.1 vs 11.8 Ϯ 2.4%) and modulated markers of activation in purified cultures of microglia (tumor necrosis factor ␣ mRNA expression was reduced ϳ48%). In Gas6 Ϫ/Ϫ mice subjected to cuprizone-challenge, demyelination was greater than in control mice, within the rostral region of the corpus callosum, as assessed by luxol fast blue staining (myelination reduced by 36%) and by ultrastructural analysis. An increased loss of Gst-(glutathione S-transferase-)-positive oligodendrocytes was also identified throughout the corpus callosum of Gas6 Ϫ/Ϫ mice. Microglial marker expression (ionized calcium-binding adapter molecule 1) was increased in Gas6 Ϫ/Ϫ mice but was restricted to the rostral corpus callosum. Therefore, TAM receptor activation and regulation can independently influence both oligodendrocyte survival and the microglial response after CNS damage.

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Gas6 rescues cortical neurons from amyloid β protein-induced apoptosis

Cited by 83 publications

References 26 publications

Axl and Growth Arrest–Specific Gene 6 Are Frequently Overexpressed in Human Gliomas and Predict Poor Prognosis in Patients with Glioblastoma Multiforme

Axl and Growth Arrest–Specific Gene 6 Are Frequently Overexpressed in Human Gliomas and Predict Poor Prognosis in Patients with Glioblastoma Multiforme

Regulation of Microglial Phagocytosis and Inflammatory Gene Expression by Gas6 Acting on the Axl/Mer Family of Tyrosine Kinases

Gas6 Deficiency Increases Oligodendrocyte Loss and Microglial Activation in Response to Cuprizone-Induced Demyelination

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