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 related 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 not protein S (an anticoagulant protein structurally similar to Gas6), specifically bound to the soluble form of Sky (Sky-Fc), composed of the extracellular domain of Sky fused to the Fc domain of human immunoglobulin G1. The native and recombinant Case, but not protein S, stimulated tyrosine phosphorylation of Sky ectopically expressed in Chinese hamster ovary cells. Stimulation of Sky in response to Case was inhibited by Sky-Fc, The half-maximal concentration of Gas6 that stimulated Sky was about 1 nm. Thus, Case as a ligand for Sky specifically binds to and stimulates Sky receptor tyrosine kinase.