Alternative titles; symbols
HGNC Approved Gene Symbol: GAS6
Cytogenetic location: 13q34 Genomic coordinates (GRCh38): 13:113,820,549-113,864,076 (from NCBI)
Manfioletti et al. (1993) described a growth arrest-specific gene whose cDNA was isolated from NIH 3T3 cells starved for serum. The gene, designated gas6 by the authors, is expressed as an abundant 2.6-kb mRNA in starved cells but decreases significantly upon stimulation of cells with serum or fibroblast growth factor. A human homolog was isolated from HeLa cells and was predicted to encode a 678-amino acid protein with 81% identity to the mouse protein and 44% identity to human protein S (176880), a vitamin K-dependent negative coregulator in the blood coagulation pathway. Regions of greatest similarity between Gas6 and protein S occur in a gamma carboxylated glutamic acid-rich domain and in 4 EGF-like domains.
Studying the function of the AXL receptor tyrosine kinase (109135), Varnum et al. (1995) postulated that AXL may be involved in the stimulation of cell proliferation in response to an appropriate signal, i.e., a ligand that activates the receptor. They purified an AXL stimulatory factor and showed that it is identical to the product of the GAS6 gene.
Stitt et al. (1995) likewise found that protein S and its relative GAS6 are ligands for the TYRO3 (600341) and AXL family of receptor tyrosine kinases found in rodent and human. The function of GAS6 was unknown, although its homology to protein S and its ability to bind AXL suggested roles both in clotting and in other systems.
The product of the GAS6 gene, a ligand for the AXL, MER (604705), and TYRO3 tyrosine kinase receptors, is a vitamin K-dependent protein, structurally related to anticoagulant protein S but lacking its anticoagulant activity. Gas6 deficient mice are protected against thrombosis (Angelillo-Scherrer et al., 2001; Yanagita et al., 2002), demonstrating the importance of this protein in the cardiovascular system. Munoz et al. (2004) determined the intron-exon structure of GAS6 and analyzed the gene for the presence of allelic variants that could be associated with atherothrombotic disease. Using in silico analyses, they determined the sequence of the GAS6 gene, which spans 43.8 kb of DNA and consists of 15 exons. They also identified 8 different variants that were confirmed to be SNPs. A preliminary analysis of 5 of these SNPs in a group of 110 healthy controls and 188 patients with atherothrombotic disease suggested a statistically significant difference between controls and stroke patients in the allelic distributions of one of these variants, 834+7G-A.
Pseudotypes are viral particles that carry the genome of one virus and 1 or more proteins of another virus (Temperton and Wright, 2009). Morizono et al. (2011) studied the infectivity of lentivirus pseudotypes lacking envelope binding and observed residual high infectivity for some cell types. The retained infectivity was conferred by soluble bovine protein S in the culture medium. Morizono et al. (2011) showed that bovine protein S and its human homolog, GAS6, mediated binding of the virus to target cells by bridging virion envelope phosphatidylserine to AXL present on target cells.
Fourgeaud et al. (2016) demonstrated that the TAM receptor tyrosine kinases Mer and Axl regulate the microglial functions of damage sensing and routine noninflammatory clearance of dead brain cells. Fourgeaud et al. (2016) found that adult mice deficient in microglial Mer and Axl exhibit a marked accumulation of apoptotic cells specifically in neurogenic regions of the central nervous system (CNS), and that microglial phagocytosis of the apoptotic cells generated during adult neurogenesis is normally driven by both TAM receptor ligands Gas6 and protein S. Using live 2-photon imaging, the authors demonstrated that the microglial response to brain damage is also TAM-regulated, as TAM-deficient microglia display reduced process motility and delayed convergence to sites of injury. Fourgeaud et al. (2016) also showed that microglial expression of Axl is prominently upregulated in the inflammatory environment that develops in a mouse model of Parkinson disease (168600). Fourgeaud et al. (2016) concluded that these results established TAM receptors as both controllers of microglial physiology and potential targets for therapeutic intervention in CNS disease.
Saccone et al. (1995) mapped human GAS6 to chromosome 13q34 by fluorescence in situ hybridization. Colombo et al. (1992) mapped the Gas6 gene to mouse chromosome 8.
Angelillo-Scherrer et al. (2001) generated Gas6 -/- mice and found that they were protected against venous and arterial thrombosis but did not display spontaneous bleeding and had normal bleeding after tail clipping. Gas6 antibodies inhibited platelet aggregation in vitro and protected mice against fatal thromboembolism without causing bleeding in vivo. Gas6 amplified platelet aggregation and secretion in response to known agonists. The platelet dysfunction in Gas6 -/- mice resembled that of patients with platelet signaling transduction defects. Angelillo-Scherrer et al. (2001) concluded that although GAS6 appears to be redundant for baseline hemostasis, it is a platelet response amplifier that plays a significant role in pathologic thrombosis.
Angelillo-Scherrer et al. (2005) generated mice lacking 1 of the 3 Gas6 receptors: Tyro3, Axl, or Mertk. Loss of any 1 of the Gas6 receptors or delivery of a soluble extracellular domain of Axl that traps Gas6 protected the mice against life-threatening thrombosis. Loss of a Gas6 receptor did not prevent initial platelet aggregation but impaired subsequent stabilization of platelet aggregates, at least in part by reducing outside-in signaling and platelet granule secretion. Gas6, through its receptors, activated PI3K and Akt (see 164730) and stimulated tyrosine phosphorylation of the beta-3 integrin (173470), thereby amplifying outside-in signaling via alpha-IIb (607759)-beta-3.
Angelillo-Scherrer, A., Burnier, L., Flores, N., Savi, P., DeMol, M., Schaeffer, P., Herbert, J.-M., Lemke, G., Goff, S. P., Matsushima, G. K., Earp, H. S., Vesin, C., Hoylaerts, M. F., Plaisance, S., Collen, D., Conway, E. M., Wehrle-Haller, B., Carmeliet, P. Role of Gas6 receptors in platelet signaling during thrombus stabilization and implications for antithrombotic therapy. J. Clin. Invest. 115: 237-246, 2005. [PubMed: 15650770] [Full Text: https://doi.org/10.1172/JCI22079]
Angelillo-Scherrer, A., Garcia de Frutos, P., Aparicio, C., Melis, E., Savi, P., Lupu, F., Arnout, J., Dewerchin, M., Hoylaerts, M. F., Herbert, J.-M., Collen, D., Dahlback, B., Carmeliet, P. Deficiency or inhibition of Gas6 causes platelet dysfunction and protects mice against thrombosis. Nature Med. 7: 215-221, 2001. [PubMed: 11175853] [Full Text: https://doi.org/10.1038/84667]
Colombo, M. P., Martinotti, A., Howard, T. A., Schneider, C., D'Eustachio, P., Seldin, M. F. Localization of growth arrest-specific genes on mouse chromosomes 1, 7, 8, 11, 13, and 16. Mammalian Genome 2: 130-134, 1992. [PubMed: 1347472] [Full Text: https://doi.org/10.1007/BF00353861]
Fourgeaud, L., Traves, P. G., Tufail, Y., Leal-Bailey, H., Lew, E. D., Burrola, P. G., Callaway, P., Zagorska, A., Rothlin, C. V., Nimmerjahn, A., Lemke, G. TAM receptors regulate multiple features of microglial physiology. Nature 532: 240-244, 2016. [PubMed: 27049947] [Full Text: https://doi.org/10.1038/nature17630]
Manfioletti, G., Brancolini, C., Avanzi, G., Schneider, C. The protein encoded by a growth arrest-specific gene (gas6) is a new member of the vitamin K-dependent proteins related to protein S, a negative coregulator in the blood coagulation cascade. Molec. Cell. Biol. 13: 4976-4985, 1993. [PubMed: 8336730] [Full Text: https://doi.org/10.1128/mcb.13.8.4976-4985.1993]
Morizono, K., Xie, Y., Olafsen, T., Lee, B., Dasgupta, A., Wu, A. M., Chen, I. S. Y. The soluble serum protein Gas6 bridges virion envelope phosphatidylserine to the TAM receptor tyrosine kinase Axl to mediate viral entry. Cell Host Microbe 9: 286-298, 2011. [PubMed: 21501828] [Full Text: https://doi.org/10.1016/j.chom.2011.03.012]
Munoz, X., Sumoy, L., Ramirez-Lorca, R., Villar, J., Garcia de Frutos, P., Sala, N. Human vitamin K-dependent GAS6: gene structure, allelic variation, and association with stroke. Hum. Mutat. 23: 506-512, 2004. [PubMed: 15108283] [Full Text: https://doi.org/10.1002/humu.20025]
Saccone, S., Marcandalli, P., Gotissa, M., Schneider, C., Della Valle, G. Assignment of the human GAS6 gene to chromosome 13q34 by fluorescence in situ hybridization. Genomics 30: 129-131, 1995. [PubMed: 8595896] [Full Text: https://doi.org/10.1006/geno.1995.0027]
Stitt, T. N., Conn, G., Gore, M., Lai, C., Bruno, J., Radziejewski, C., Mattsson, K., Fisher, J., Gies, D. R., Jones, P. F., Masiakowski, P., Ryan, T. E., Tobkes, N. J., Chen, D. H., DiStefano, P. S., Long, G. L., Basilico, C., Goldfarb, M. P., Lemke, G., Glass, D. J., Yancopoulos, G. D. The anticoagulation factor protein S and its relative, Gas6, are ligands for the Tyro 3/Axl family of receptor tyrosine kinases. Cell 80: 661-670, 1995. [PubMed: 7867073] [Full Text: https://doi.org/10.1016/0092-8674(95)90520-0]
Temperton, N. J., Wright, E. Retroviral pseudotypes. In: Encyclopedia of Life Sciences. Chichester, England: John Wiley & Sons, Ltd. 2009.
Varnum, B. C., Young, C., Elliott, G., Garcia, A., Bartley, T. D., Fridell, Y.-W., Hunt, R. W., Trail, G., Clogston, C., Toso, R. J., Yanagihara, D., Bennett, L., Sylber, M., Merewether, L. A., Tseng, A., Escobar, E., Liu, E. T., Yamane, H. K. Axl receptor tyrosine kinase stimulated by the vitamin K-dependent protein encoded by growth-arrest-specific gene 6. Nature 373: 623-626, 1995. [PubMed: 7854420] [Full Text: https://doi.org/10.1038/373623a0]
Yanagita, M., Ishimoto, Y., Arai, H., Nagai, K., Ito, T., Nakano, T., Salant, D. J., Fukatsu, A., Doi, T., Kita, T. Essential role of Gas6 for glomerular injury in nephrotoxic nephritis. J. Clin. Invest. 110: 239-246, 2002. [PubMed: 12122116] [Full Text: https://doi.org/10.1172/JCI14861]