The soluble sema domain of the RON receptor inhibits macrophage-stimulating protein-induced receptor activation.
RON is a receptor tyrosine kinase of the MET family that is involved in cell proliferation, cell survival, and cell motility in both normal and disease states. Macrophage-stimulating protein (MSP) is the RON ligand whose binding to RON causes receptor activation. RON is a trans-membrane heterodimer comprised of one alpha- and one beta-chain originating from a single-chain precursor and held together by several disulfide bonds. The intracellular part of RON contains the kinase domain and regulatory elements. The extracellular region is characterized by the presence of a sema domain (a stretch of approximately 500 amino acids with several highly conserved cysteine residues), a PSI (plexin, semaphorins, integrins) domain, and four immunoglobulin-like folds. Here we show that a soluble, secreted molecule representing the sema domain of RON (referred to as ron-sema) has a dominant negative effect on the ligand-induced receptor activation and is capable of inhibiting RON-dependent signaling pathways and cellular responses. Results suggest that the sema domain of RON participates in ligand binding by the full-length receptor. The ability of ron-sema to suppress growth of MSP-responsive cells in culture, including cancer cells, points to a potential therapeutic use of this molecule, and forced expression of it could potentially be used as a gene therapy tool for treating MSP-dependent types of cancer.
Laboratory of Immunobiology, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702-1201, USA.
Debora
D
Angeloni
Alla
A
Danilkovitch-Miagkova
Alexei
A
Miagkov
Edward J
EJ
Leonard
Michael I
MI
Lerman
D000818:Animals; D015153:Blotting, Western; D002455:Cell Division; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000378:metabolism; D019281:Dimerization; D004220:Disulfides / Q000737:chemistry; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000378:metabolism; D015316:Genetic Therapy; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008957:Models, Genetic; D009369:Neoplasms / Q000378:metabolism; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D014176:Protein Biosynthesis; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry*; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism
D018076:DNA, Complementary; D004220:Disulfides; D008024:Ligands; D011518:Proto-Oncogene Proteins; C082332:macrophage stimulating protein; D014443:Tyrosine; D017228:Hepatocyte Growth Factor; D066246:ErbB Receptors; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases