Abstract
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.
Highlights
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
The extracellular region is characterized by the presence of a sema domain, a PSI domain, and four immunoglobulin-like folds
The sema domain is represented by a block of ϳ500 amino acids with 15 conserved cysteine residues intermingled with stretches of conserved amino acids and a conserved potential glycosylation site [18]
Summary
Vol 279, No 5, Issue of January 30, pp. 3726 –3732, 2004 Printed in U.S.A. The Soluble Sema Domain of the RON Receptor Inhibits Macrophage-stimulating Protein-induced Receptor Activation*. The sema domain (whose presence in RON and MET makes them a unique family among the approximate 20 receptor tyrosine kinase families identified by the Human Genome Project) is represented by a block of ϳ500 amino acids with 15 conserved cysteine residues intermingled with stretches of conserved amino acids and a conserved potential glycosylation site [18] This domain is present in semaphorins and plexins (a class of semaphorin receptors). We found that these secreted soluble molecules have a highly specific dominant-negative effect on RON kinase activation Such activity extends to inhibiting the proliferation of MSP-sensitive cells in culture, including cancer cell lines. The forced expression of these secreted soluble molecules could represent a gene therapy tool to treat MSP-dependent types of cancer
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