Most receptor tyrosine kinases are activated by dimerization induced by their cognate ligands. Protein S, an abundant serum protein previously shown to be a potent anticoagulation factor, has been proposed to be a ligand for the Sky tyrosine kinase (Stitt et al., 1995). Here we show that Sky, when expressed to high levels, is tyrosine phosphorylated even in the absence of a ligand. Furthermore, a version of Sky (termed Sky delta SS) engineered to be overexpressed in the cytoplasm and thus in a ligand-free environement, can function as a dimeric tyrosine kinase. Sky delta SS can transform RatB1a fibroblasts and thus retains all the properties of the full-length Sky kinase. These data suggest that Sky, when overexpressed either at the cell surface or in the cytoplasm, is competent to form dimers even in the absence of its ligand. We also demonstrate that an isoform of Sky, originally reported as Brt and here termed Sky Isoform I, resides in the cytoplasm. Therefore, the activities of Sky delta SS we describe may reflect those of the naturally occurring Isoform I.