THE TYROSINE KINASE RECEPTORS RON AND SEA CONTROL SCATTERING AND MORPHOGENESIS OF LIVER PROGENITOR CELLS IN-VITRO

The mammalian RON and the avian sea genes encode tyrosine kinase recep tors of poorly characterized biological functions. We recently identif ied macrophage-stimulating protein as the ligand for Ron; no ligand ha s yet been found for Sea. In this work we investigated the biological response to macrophage-stimulating protein in mouse Liver progenitor c ells expressing Ron. These cells were also transfected with a chimeric cDNA encoding the cytoplasmic domain of Sea, fused to the extracellul ar domain of Trk (nerve growth factor receptor). In the presence of na nomolar concentrations of the respective ligands, both receptors induc ed cell ''scattering,'' extracellular matrix invasion, and DNA synthes is. When liver progenitor cells were grown in a tri-dimensional type-I collagen matrix, ligand-induced stimulation of either Ron or Sea indu ced sprouting of branched cell cords, evolving into ductular-like tubu les. The motogenic, mitogenic, and morphogenic responses were also eli cited by triggering the structurally related hepatocyte growth factor receptor (Met) but not epidermal growth factor or platelet-derived gro wth factor receptors. These data show that Ron, Sea, and Met belong to a receptor subfamily that elicits a distinctive biological response i n epithelial cells.