A Soluble Truncated Form of the Mer Tyrosine Kinase Inhibits Gas6 Activity in Platelets and Monocytes.

Several receptor tyrosine kinases generate soluble ligand binding domains either by proteolytic cleavage of the extracellular domain or differential splicing yielding in a truncated RNA transcript. Mer is a member of a receptor tyrosine kinase family which includes Axl and Tyro-3. All three members of this family have an extracellular domain which includes two immunoglobulin and two fibronectin type III motifs. Mer, Axl, and Tyro-3 are transforming in vitro in numerous cell types and are overexpressed in several different human cancers. In addition, Mer, Axl, and Tyro-3 and the common ligand Gas6 are all expressed in platelets and directly affect platelet activation and clot stability. We have found that the 205 kD Mer protein in platelets and monocytes is post-translationally processed by cleavage of the extracellular domain via a TACE-like metalloprotease. The cleavage results in a soluble extracellular domain protein (approximately 150kD) and a membrane-bound kinase domain. The proteolytic cleavage of Mer can be enhanced by LPS and PMA, and specifically inhibited by a TAPI, a TACE inhibitor. Significant amounts of the soluble Mer protein are present in human and mouse serum. The soluble Mer protein directly binds the ligand Gas6, and inhibits Gas6 stimulation of full-length Mer. Gas6, related to anticoagulant protein S, is also a ligand for Axl and Tyro-3. The cleavage of Mer may represent a mechanism of directly regulating the numerous functions of Gas6 including promoting platelet adhesion and clot stability, stimulating cell proliferation, inducing cell adhesion and chemotaxis, and preventing apoptosis. Furthermore, the ability of soluble Mer to inhibit Gas6 activity in platelets may provide a potential novel therapeutic intervention in the treatment of clotting disorders.