STIMULATION OF SKY RECEPTOR TYROSINE KINASE BY THE PRODUCT OF GROWTH ARREST-SPECIFIC GENE-6

Sky (also called Rse, Brt, and Tyro3) is a member of a subfamily of re lated receptor tyrosine kinases, including Axl/Ufo/Ark. and c-Eyk/Mer. We obtained evidence that Case (the product of growth arrest-specific gene 6) is a ligand of the Sky receptor tyrosine kinase, Gas6, but no t protein S (an anticoagulant protein structurally similar to Gas6), s pecifically bound to the soluble form of Sky (Sky-Fc), composed of the extracellular domain of Sky fused to the Fc domain of human immunoglo bulin G1. The native and recombinant Case, but not protein S, stimulat ed tyrosine phosphorylation of Sky ectopically expressed in Chinese ha mster ovary cells. Stimulation of Sky in response to Case was inhibite d by Sky-Fc, The half-maximal concentration of Gas6 that stimulated Sk y was about 1 nm. Thus, Case as a ligand for Sky specifically binds to and stimulates Sky receptor tyrosine kinase.