Studied on physiological functions of Gas6 and development of its inhibitors

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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.