Disease relevance of Gas6

• The Gas6/Axl system is implicated in several types of human cancer as well as inflammatory, autoimmune, vascular and kidney diseases [1].
• Furthermore, "trapping" Gas6 prevents pathological thrombosis, which indicates that blocking this novel cross-talk between the Gas6-Rs and alpha(IIb)beta(3) integrin may constitute a novel target for antithrombotic therapy [2].
• Essential role of Gas6 for glomerular injury in nephrotoxic nephritis [3].
• We found less mortality and proteinuria in Gas6(-/-) mice than in wild-type mice following injection of nephrotoxic serum [3].
• To investigate whether Gas6 is essential for progressive glomerular injury, we constructed Gas6(-/-) mice and examined the role of Gas6 in accelerated nephrotoxic nephritis (NTN), a model of progressive glomerulonephritis [3].

High impact information on Gas6

• Role of Gas6 receptors in platelet signaling during thrombus stabilization and implications for antithrombotic therapy [4].
• Glomerular cell proliferation, glomerular sclerosis, crescent formation, and deposition of fibrin/fibrinogen in glomeruli were also reduced in Gas6(-/-) mice [3].
• Growth-arrest specific gene 6 (Gas6) is a vitamin K-dependent growth factor for mesangial and epithelial cells [3].
• We demonstrate that Axl and its ligand Gas6 are overexpressed in human glioma cell lines and that Axl is activated under baseline conditions [5].
• The carboxylation process is vitamin K dependent, and current evidence suggests that GAS6 must be gamma-carboxylated to bind and activate any of the cognate tyrosine kinase receptors [6].

Chemical compound and disease context of Gas6

• Mechanism of stimulation of osteoclastic bone resorption through Gas6/Tyro 3, a receptor tyrosine kinase signaling, in mouse osteoclasts [7].
• Gas6, warfarin, and kidney diseases [8].

Biological context of Gas6

• In contrast, recombinant Gas6 from cells treated with warfarin, which prevents the gamma-carboxylation reaction, neither stimulated fibroblast proliferation nor activated Axl tyrosine phosphorylation [9].
• Gas6-induced cell proliferation was additive to the effects of epidermal growth factor, suggesting activation of discrete signalling pathways [9].
• In vitro phagocytosis studies showed that Gas6 enhanced the uptake of PS liposomes approximately threefold and that the interaction of Gas6 with the surface of macrophages was essential for this enhancement [10].
• Thus, Gas6 may play a critical role in homeostasis by facilitating the clearance of PS-expressing cells [10].
• The early release of Gas6 by agonists perpetuates platelet activation through its three receptors, reinforcing outside-in alpha(IIb)beta(3) signaling by activation of PI3K and Akt signaling and stimulation of tyrosine phosphorylation of the beta(3) integrin [2].

Anatomical context of Gas6

• In conclusion, Gas6 appears to be a unique growth factor for fibroblasts and post-translational gamma-carboxylation is necessary for its biological activity [9].
• Like that of PS liposomes, the uptake of apoptotic cells by macrophages was also enhanced, approximately twofold, in the presence of Gas6 [10].
• Transfection of the cDNA encoding GAS6 into 3T3 fibroblasts is sufficient to render this previously nonsupportive cell line capable of supporting long-term hematopoietic cultures [6].
• Here, we show that expression of GAS6 is highly correlated with the capacity of bone marrow stromal cells to support hematopoiesis in culture [6].
• Hematopoietic support by genetically engineered 3T3 is not vitamin K dependent, and soluble recombinant GAS6 does not substitute for coculturing the hematopoietic progenitors with genetically modified 3T3 cells [6].

Associations of Gas6 with chemical compounds

• The protein product of growth arrest specific gene 6 (Gas6), is the biological ligand for the Axl subfamily of receptor tyrosine kinases [9].
• Recombinant Gas6, containing N terminal gamma-carboxyglutamic acid residues formed from a vitamin K-dependent reaction, stimulated both DNA synthesis and proliferation of cardiac fibroblasts under serum-free conditions [9].
• These findings suggest that Gas6 may help phagocytic cells recognize cells with PS exposed on their surfaces, which is considered to be one of the mechanisms for clearing away dying cells [10].
• Analyses of the mechanism of the uptake of PS liposome suggested that Gas6 interacts with PS liposome via its N-terminal Gla domain and with macrophages via its C-terminal domain [10].
• In addition, the Gas6 mRNA level in bone marrow was up-regulated by ovariectomy and was reduced by estrogen replacement [7].

Physical interactions of Gas6

• In our previous study, we demonstrated that Gas6 specifically binds to phosphatidylserine (PS) and links Axl-expressing cells to the PS-coated surface [10].

Regulatory relationships of Gas6

• Gas6 stimulated tyrosine phosphorylation of Axl as well as phosphorylation of ERK kinase [9].
• Interestingly, Gas6 or CDMer failed to stimulate p130(CAS) tyrosine phosphorylation or phagocytosis in beta5-deficient CS-1 cells or in mutant beta5DeltaC-expressing cells, suggesting that Mer is directionally and functionally linked to the integrin pathway [11].

Other interactions of Gas6

• Soluble Axl is generated by ADAM10-dependent cleavage and associates with Gas6 in mouse serum [12].
• (Cell 54 (1988) 787) identified six genes (Gas1 through Gas6) whose expressions are upregulated in serum-deprived NIH3T3 cells [13].
• On the contrary we found that the late constitutive increase of p38 MAPK activity associated with cell death was downregulated in Gas6-treated NIH3T3 cells thus suggesting that Gas6 might promote survival by interfering with this pathway [14].
• Taken together, the evidence presented here identifies elements involved in the Gas6 transduction pathway that are responsible for its antiapoptotic effect and suggests that Src is involved in the events regulating cell survival [15].
• In the present study, we examined the role of Ark and its ligand, Gas6 (encoded by growth arrest-specific gene 6), in GnRH neuron migration [16].

Analytical, diagnostic and therapeutic context of Gas6

• MEASUREMENTS AND MAIN RESULTS: Gas6 plasma levels were quantified using enzyme-linked immunosorbent assay [17].
• Further epitope mapping identified a Gas6 peptide sequence recognized by the CNTO300 antibody [18].
• Flow cytometry revealed that Gas 6 treatment resulted in 28% fewer apoptosing cells [19].
• Growth arrest specific gene 1 (Gas1) has been implicated in inhibiting cell-cycle progression in cell culture studies (G. Del Sal et al., 1992, Cell 70, 595--607) [20].

References