Related Experiment Videos
RON is a heterodimeric tyrosine kinase receptor activated by the HGF homologue MSP
G Gaudino1, A Follenzi, L Naldini
1Department of Biomedical Sciences and Oncology, University of Torino Medical School, Italy.
Abstract:
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 (p185RON) of 35 (alpha) and 150 kDa (beta) disulfide-linked chains, before exposure at the cell surface. The Ron beta-chain displays intrinsic tyrosine kinase activity in vitro, after immunoprecipitation by specific antibodies. In vivo, tyrosine phosphorylation of p185RON 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 p185RON is followed by DNA synthesis. p185RON is not activated by HGF, nor is the HGF receptor activated by MSP in biochemical and biological assays. p185RON is also activated by a pure recombinant protein containing only the N-terminal two kringles of MSP. These data show that p185RON 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.
Insights
The RON gene encodes a tyrosine kinase involved in cell growth. Macrophage stimulating protein (MSP) activates p185RON, leading to DNA synthesis in epithelial cells.
Area of Science:
- Molecular Biology
- Cell Signaling
- Biochemistry
Background:
- The RON gene is homologous to the MET gene, encoding a receptor tyrosine kinase.
- RON is expressed in epithelial cells, granulocytes, and monocytes.
Purpose of the Study:
- To characterize the RON gene product, p185RON, and its activation by macrophage stimulating protein (MSP).
- To investigate the functional consequences of p185RON activation in epithelial cells.
Main Methods:
- Western blotting and immunoprecipitation to analyze RON protein expression and phosphorylation.
- Biochemical and biological assays to assess receptor activation and downstream signaling.
- Use of recombinant MSP fragments to identify functional domains.
Main Results:
- The RON transcript is translated into a precursor that is processed into a mature heterodimer, p185RON.
- The beta-chain of p185RON possesses intrinsic tyrosine kinase activity.
- MSP binding induces tyrosine phosphorylation of p185RON, triggering DNA synthesis in epithelial cells.
- p185RON is specifically activated by MSP, not by hepatocyte growth factor (HGF), and vice versa.
Conclusions:
- p185RON is a distinct tyrosine kinase receptor activated by MSP.
- This activation pathway plays a role in epithelial cell proliferation.
- p185RON represents a new family of growth factor receptors with specific ligand interactions.