Studied on physiological functions of Gas6 and development of its inhibitors

Gas6的生理功能研究及其抑制剂的开发

基本信息

批准号：
12558079
负责人：
MIZUNO Kensaku
金额：
$ 8.7万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12558079/
关键词：
Gas6 growth factor apoptosis mesangial cell glomerulonephritis Axl STAT3 腎メサンジウム細胞ワルファリン

项目摘要

The product of growth arrest-specific gene 6 (Gas6) is a ligand for receptor tyrbsjne kinases, Axl, Sky, and Mer. We showed that Gas6 specifically binds to phosphatidylserine through the N-terminal Gla domain. We found that Gas6 enhanced the uptake of phosphatidylserine liposomes and apoptotic cells by macrophages. These results suggest that Gas6 help phagocytic cells recognize cells with phosphatidylserine exposed on their cell surfaces and may play a role in the clearance of apoptotic cells. Gas6 stimulates mesangial cell proliferation through stimulation of its cell-surface receptor Axl. We showed that warfarin and the extracellular domain of Axl inhibit mesangial cell proliferation by interfering the Gas6/Axl pathway in vitro. In an experimental model of mesangial proliferative glomerulonephritis induced by anti Thy1 antibody, expression of Qas6 and Axl was increased in glomeruli. Administration of warfarin or Axl-Fc inhibited mesangial cell proliferation. These results suggest that Gas6/Axl pathway plays a key role in mesangial cell proliferation in vivo, and could be a potentially important therapeutic target for the treatment of renal disease. We also found that STAT3 is phosphorylated and activated by Gas6 stimulation and plays a key role in the signaling pathway in Gas6-mediated mesangial cell proliferation in vitro and in vivo.

生长停滞特异性基因 6 (Gas6) 的产物是受体酪氨酸激酶、Axl、Sky 和 Mer 的配体。我们发现 Gas6 通过 N 末端 Gla 结构域特异性结合磷脂酰丝氨酸。我们发现Gas6增强了巨噬细胞对磷脂酰丝氨酸脂质体和凋亡细胞的摄取。这些结果表明Gas6帮助吞噬细胞识别细胞表面暴露有磷脂酰丝氨酸的细胞，并可能在清除凋亡细胞中发挥作用。 Gas6 通过刺激其细胞表面受体 Axl 来刺激系膜细胞增殖。我们在体外证明华法林和 Axl 胞外结构域通过干扰 Gas6/Axl 通路抑制系膜细胞增殖。在抗Thy1抗体诱导的系膜增生性肾小球肾炎实验模型中，肾小球中Qas6和Axl的表达增加。施用华法林或Axl-Fc抑制系膜细胞增殖。这些结果表明Gas6/Axl通路在体内系膜细胞增殖中发挥关键作用，并且可能成为治疗肾脏疾病的潜在重要治疗靶点。我们还发现STAT3在Gas6刺激下被磷酸化和激活，并且在体外和体内Gas6介导的系膜细胞增殖的信号通路中发挥关键作用。