Ron is a heterodimeric tyrosine kinase receptor activated by the HGF homologue MSP

RON, a cDNA homologous to the hepatocyte growth factor (HGF) receptor gene (MET), encodes a putative tyrosine kinase. Here we show that the RON gene is expressed in several epithelial tissues as well as in granulocytes and monocytes. The major RON transcript is translated into a glycosylated single chain precursor, cleaved into a 185 kDa heterodimer (p185(RON)) of 35 (α) and 150 kDa (β) disulfide-linked chains, before exposure at the cell surface. The Ron,β-chain displays intrinsic tyrosine kinase activity in vitro, after immunoprecipitation by specific antibodies. In vivo, tyrosine phosphorylation of p185(RON) is induced by stimulation with macrophage stimulating protein (MSP), a protease-like factor containing four 'kringle' domains, homologous to HGF. In epithelial cells, MSP-induced tyrosine phosphorylation of p185(RON) is followed by DNA synthesis. p185(RON) is not activated by HGF, nor is the HGF receptor activated by MSP in biochemical and biological assays. p185(RON) is also activated by a pure recombinant protein containing only the N-terminal two kringles of MSP. These data show that p185(RON) is a tyrosine kinase activated by MSP and that it is member of a family of growth factor receptors with distinct specificities for structurally related ligands.