Studied on physiological functions of Gas6 and development of its inhibitors

生长停滞特异基因6(Gas6)的产物是酪氨酸激酶受体AX1、Sky和Mer的配体。我们发现Gas6通过N-末端的GLA结构域与磷脂酰丝氨酸特异性结合。我们发现Gas6促进了巨噬细胞对磷脂酰丝氨酸脂质体的摄取和细胞的凋亡。这些结果表明，Gas6有助于吞噬细胞识别暴露在其表面的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刺激系膜细胞增殖。我们发现，华法林和Axl的胞外区在体外通过干扰Gas6/Axl途径抑制系膜细胞的增殖。在抗Thy1抗体诱导的系膜增生性肾小球肾炎模型中，肾小球中Qas6和Ax1的表达增加。华法林或Axl-Fc可抑制系膜细胞的增殖。这些结果提示，Gas6/Axl通路在体内系膜细胞增殖中起关键作用，可能成为治疗肾脏疾病的重要靶点。我们还发现，STAT3在Gas6刺激下被磷酸化并激活，在Gas6介导的体外和体内系膜细胞增殖的信号通路中发挥关键作用。

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.