Abstract
Recepteur d'origine nantais (RON) belongs to a subfamily of receptor tyrosine kinases (RTK) with unique expression patterns and biological activities. RON is activated by a serum-derived growth factor macrophage stimulating protein (MSP). The RON gene transcription is essential for embryonic development and critical in regulating certain physiological processes. Recent studies have indicated that altered RON expression contributes significantly to cancer progression and malignancy. In primary tumors, such as colon and breast cancers, overexpression of RON exists in large numbers and is often accompanied by the generation of different splicing variants. These RON variants direct a unique program that controls cell transformation, growth, migration, and invasion, indicating that altered RON expression has the ability to regulate motile/invasive phenotypes. These activities were also seen in transgenic mice, in which targeted expression of RON in lung epithelial cells resulted in numerous tumors with pathological features of human bronchioloalveolar carcinoma. Thus, abnormal RON activation is a pathogenic factor that transduces oncogenic signals leading to uncontrolled cell growth and subsequent malignant transformation. Considering these facts, RON and its variants can be considered as potential targets for therapeutic intervention. Experiments using small interfering RNA and neutralizing monoclonal antibodies demonstrated that suppressing RON expression and activation decreases cancer cell proliferation, increases apoptotic death, prevents tumor formation in nude mice, and reduces malignant phenotypes. Thus, blocking RON expression and activation has clinical significance in reversing malignant phenotypes and controlling tumor growth.
Similar content being viewed by others
Article PDF
References
Robertson SC, Tynan JA, Donoghue DJ . RTK mutations and human syndromes: when good receptors turn bad. Trends Genet 2000; 16: 265–71.
Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S . The protein kinase complement of the human genome. Science 2002; 298: 1912–34.
Van de Woude GF, Jeffers M, Cortner J, Alvord G, Tsarfaty I, Resau J . Met-HGF/SF: tumorigenesis, invasion and metastasis. Ciba Found Symp 1997; 212: 119–30.
Yarden Y . Biology of HER2 and its importance in breast cancer. Oncology 2001; 61: 1–13.
Schlessinger J . Cell signaling by receptor tyrosine kinases. Cell 2000; 103: 211–25.
van der Geer P, Hunter T, Lindberg RA . Receptor protein-tyrosine kinases and their signal transduction pathways. Annu Rev Cell Biol 1994; 10: 251–337.
Hanahan D, Weinberg RA . The hallmarks of cancer. Cell 2000; 100: 57–70.
Hortobagyi GN . Overview of treatment results with trastuzumab (Herceptin) in metastatic breast cancer. Semin Oncol 2001; 6: 43–7.
Ronsin C, Muscatelli F, Mattei MG, Breathnach R . A novel putative receptor protein tyrosine kinase of the met family. Oncogene 1993; 8: 1195–202.
Wang MH, Wang D, Chen YQ . Oncogenic and metastatic potentials of human macrophage stimulating protein receptor, the RON receptor tyrosine kinase. Carcinogenesis 2003; 23: 1291–300.
Wang MH, Zhou YQ, Chen YQ . Macrophage stimulating protein and RON receptor tyrosine kinase: potential regulators of macrophage inflammatory activities. Scan J Immunol 2002; 56: 545–53.
Muraoka RS, Sun WY, Colbert MC . The Ron/STK receptor tyrosine kinase is essential for peri-implantation development in the mouse. J Clin Invest 1999; 103: 1277–85.
Angeloni D, Danilkovitch-Miagkova A, Ivanov SV, Breathnach R, Johnson BE, Leonard EJ, et al. Gene structure of the human receptor tyrosine kinase RON and mutation analysis in lung cancer samples. Genes Chromosomes Cancer 2000; 29: 147–56.
Zabarovsky ER, Lerman MI, Minna JD . Tumor suppressor genes on chromosome 3p involved in the pathogenesis of lung and other cancers. Oncogene 2002; 21: 6915–35.
Iwama A, Okano K, Sudo T, Matsuda Y, Suda T . Molecular cloning of a novel receptor tyrosine kinase gene, STK, derived from enriched hematopoietic stem cells. Blood 1994; 83: 3160–9.
Gaudino G, Follenzi A, Naldini L . RON is a heterodimeric tyrosine kinase receptor activated by the HGF homologue MSP. EMBO J 1994; 13: 3524–32.
Wang MH, Ronsin C, Gesnel MC, Coupeym L, Skeel A, Leonard EJ, et al. Identification of the ron gene product as the receptor for the human macrophage stimulating protein. Science 1994; 266: 117–9.
Gaudino G, Avantaggiato V, Follenzi A, Acampora D, Simeone A, Comoglio PM . The proto-oncogene RON is involved in development of epithelial, bone and neuro-endocrine tissues. Oncogene 1995; 11: 2627–37.
Del Gatto F, Gilbert E, Ronsin C, Breathnach R . Structure of the promoter for the human macrophage stimulating protein receptor gene. Biochim Biophy Acta 1995; 1263: 93–5.
Penengo L, Rubin C, Yarden Y, Gaudino G . c-CBl is a critical modulator of the RON tyrosine kinase receptor. Oncogene 2003; 22: 3669–79.
Rubin JS, Bottaro DP, Aaronson SA . Hepatocyte growth factor/scatter factor and its receptor, the c-met proto-oncogene product. Biochem Biophys Acta 1993; 1155: 357–71.
Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S . The protein kinase complement of the human genome. Science 2002; 298: 1912–34.
Bottaro DP, Rubin JS, Faletto DL, Chan AM, Kmiecik TE, Van de Woude GF, et al. Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science 1991; 251: 802–4.
Wang MH, Iwama A, Skeel A, Suda T, Leonard EJ . The murine stk gene product, a transmembrane protein tyrosine kinase, is a receptor for macrophage-stimulating protein. Proc Natl Acad SciUSA 1995; 92: 3933–7.
Huff JL, Jelinek MA, Borgman CA, Lancing TL, Parsons JT . The protooncogene c-sea encodes a transmembrane protein-tyrosine kinase related to the Met/hepatocyte growth factor/scatter factor receptor. Proc Natl Acad Sci USA 1993; 90: 6140–4.
Wahl RC, Hsu RY, Huff JL . Chicken macrophage stimulating protein is a ligand of the receptor protein-tyrosine kinase Sea. J Biol Chem 1999; 274: 26361–8.
Nakamura T, Aoki S, Takahashi T, Matsumoto K, Kiyohara T, Nakamura T . Cloning and expression of Xenopus HGF-like protein (HLP) and Ron/HLP receptor implicate their involvement in early neural development. Biochem Biophys Res Commun 1996; 224: 564–73.
Cottage A, Clark M, Hawker K, Umrania Y, Wheller D, Bishop M, et al. Three receptor genes for plasminogen related growth factors in the genome of the puffer fish Fugu rubripes. FEBS Lett 1999; 443: 370–4.
Bos TJ, Beug H, Graf T, Hayman M, Maki Y, Uckert W, et al. Two new retroviral onc genes, sea and jun. Princess Takamatsu Symp 1986; 17: 23–30.
Smith DR, Vogt PK, Hayman MJ . The v-sea oncogene of avian erythroblastosis retrovirus S13: another member of the protein-tyrosine kinase gene family. Proc Natl Acad Sci USA 1989; 86: 5291–5.
Agazie Y, Ischenko I, Hayman MJ . Concomitant activation of the PI3K-Akt and the Ras-ERK signaling pathways is essential for transformation by the V-SEA tyrosine kinase oncogene. Oncogene 2002; 21: 697–707.
Hayman MJ, Kitchener G, Vogt PK, Beug H . The putative transforming protein of S13 avian erythroblastosis virus is a transmembrane glycoprotein with an associated protein kinase activity. Proc Natl Acad Sci USA 1985; 82: 8237–41.
Skeel A, Yoshimura T, Showalter SD, Tanaka S, Appella E, Leonard EJ . Macrophage-stimulating protein: purification, partial amino acid sequence, and cellular activity. J Exp Med 1991; 173: 1227–34.
Yoshimura T, Yuhki N, Wang MH, Skeel A, Leonard EJ . Cloning, sequencing, and expression of human macrophage stimulating protein (MSP, MST1) confirms MSP as a member of the family of kringle proteins and locates the MSP gene on chromosome 3. J Biol Chem 1993; 268: 15461–8.
Wang MH, Montero-Julian FA, Breathnach R, Godowski PJ, Takehara T, Yoshikawa W, et al. Macrophage stimulating protein (MSP) binds to its receptor via the MSP beta chain. J Biol Chem 1997; 272: 16999–7004.
Carafoli F, Chirgadze DY, Blundell TL, Gherardi E . Crystal structure of the beta-chain of human hepatocyte growth factor-like/macrophage stimulating protein. FEBS J 2005; 272: 5799–807.
Degen FSJ, Stuart LA, Han S, Jamison CS . Characterization of the mouse cDNA and gene coding for a hepatocyte growth factor-like protein: expression during development. Biochemistry 1991; 30: 9781–91.
Bezerra JA, Witte DP, Aronow BJ, Degen SJ . Hepatocyte-specific expression of the mouse hepatocyte growth factor-like protein. Hepatology 1993; 8: 394–9.
Rampino T, Collesi C, Gregorini M, Maggio M, Soccio G, Guallini P, et al. Macrophage-stimulating protein is produced by tubular cells and activates mesangial cells. J Am Soc Nephrol 2002; 13: 649–57.
Willett CG, Smith DI, Shridhar V, Wang MH, Emanuel RL, Patidar K, et al. Differential screening of a human chromosome 3 library identifies hepatocyte growth factor-like/macrophage-stimulating protein and its receptor in injured lung. Possible implications for neuroendocrine cell survival. J Clin Invest 1997; 99: 2979–91.
Wang MH, Skeel A, Yoshimuram T, Copeland TD, Sakaguchi K, Leonard EJ . Antibodies to macrophage stimulating protein (MSP): specificity, epitope interactions, and immuno-assay of MSP in human serum. J Leukoc Biol 1993; 54: 289–95.
Wang MH, Yoshimura T, Skeel A, Leonard EJ . Proteolytic conversion of single chain precursor macrophage stimulating protein to a biologically active heterodimer by contact enzymes of the coagulation cascade. J Biol Chem 1994; 269: 3436–40.
Bezerra JA, Carrick TL, Degen JL, Witte D, Degen FSJ . Biological effects of targeted inactivation of hepatocyte growth factor-like protein in mice. J Clin Invest 1998; 101: 1175–83.
Maggiora P, Marchio S, Stella MC, Giai M, Belfiore A, De Bortoli M, et al. Overexpression of the RON gene in human breast carcinoma. Oncogene 1998; 16: 2927–33.
Zhou YQ, He C, Chen YQ, Wang D, Wang MH . Altered expression of the RON receptor tyrosine kniase in primary human colorectal adenocarcinomas: generation of different splicing variants and their oncogenic potential. Oncogene 2003; 22: 186–97.
Lee WY, Chen HH, Chow NH, Su WC, Lin PW, Guo HR . Prognostic significance of co-expression of RON and MET receptors in node-negative breast cancer patients. Clin Cancer Res 2005; 11: 2222–8.
Cheng HL, Liu HS, Lin YJ, Chen HH, Hsu PY, Chang TY, et al. Co-expression of RON and MET is a prognostic indicator for patients with transitional-cell carcinoma of the bladder. Br J Cancer 2005; 92: 1906–14.
Maggiora P, Lorenzato A, Fracchioli S, Costa B, Castagnaro M, Arisio R, et al. The RON and MET oncogenes are coexpressed in human ovarian carcinomas and cooperate in activating invasiveness. Exp Cell Res 2003; 288: 382–9.
Chen YQ, Zhou YQ, Angeloni-Andreazzoli D, Kurtz AL, Qiang XZ, Wang MH . Overexpression and activation of the RON receptor tyrosine kinase in a panel of human colorectal carcinoma cells lines. Exp Cell Res 2000; 261: 229–38.
Montero-Julian FA, Dauny I, Flavetta S, Ronsin C, Andre F, Xerri L, et al. Characterization of two monoclonal antibodies against the RON tyrosine kinase receptor. Hybridoma 1998; 17: 541–51.
Wang MH, Kurtz AL, Chen YQ . Identification of a novel splicing product of the RON receptor tyrosine kinase in human colorectal carcinoma cells. Carcinogenesis 2000; 21: 1507–12.
Angeloni D, Duh FM, Moody M, Dean M, Zabarovsky ER, Sentchenkom V, et al. C to A single nucleotide polymorphism in intron 18 of the human MST1R (RON) gene that maps at 3p21.3. Mol Cell Probes 2003; 17: 55–7.
Collesi C, Santoro MM, Gaudino G, Comoglio PM . A splicing variant of the RON gene transcript induces constitutive tyrosine kinase activity and an invasive phenotype. Mol Cell Biol 1996; 16: 5518–26.
Okino T, Egami H, Ohmachi H, Takai E, Tamori Y, Nakagawa K, et al. Presence of RON receptor tyrosine kinase and its splicing variant in malignant and non-malignant human colonic mucosa. Intern J Oncol 1999; 13: 709–14.
Nishigaki K, Thompson D, Hanson C, Yugawa T, Ruscetti S . The envelope glycoprotein of friend spleen focus-forming virus covalently interacts with and constitutively activates a truncated form of the receptor tyrosine kinase Stk. J Virol 2001; 75: 7893–903.
Persons DA, Paulson RF, Loyd MR, Herley MT, Bodner SM, Bernstein A, et al. Fv2 encodes a truncated form of the Stk receptor tyrosine kinase. Nat Genet 1999; 23: 159–65.
Bardella C, Costa B, Maggiora P, Patane' S, Olivero M, Ranzani GN, et al. Truncated RON tyrosine kinase drives tumor cell progression and abrogates cell-cell adhesion through E-cadherin transcriptional repression. Cancer Res 2004; 64: 5154–61.
Ghigna C, Giordano S, Shen H, Benvenuto F, Castiglioni F, Comoglio PM, et al. Cell motility is controlled by SF2/ASF through alternative splicing of the Ron protooncogene. Mol Cell 2005; 20: 881–90.
Santoro MM, Collesi C, Grisendi S, Gaudino G, Comoglio PM . Constitutive activation of the RON gene promotes invasive growth but not transformation. Mol Cell Biol 1996; 16: 7072–83.
Xu XM, Wang D, Shen Q, Chen YQ, Wang MH . RNA-mediated gene silencing of the RON receptor tyrosine kinase alters oncogenic phenotypes of human colorectal carcinoma cells. Oncogene 2004; 23: 8464–74.
Santoro MM, Penengo L, Minetto M, Orecchia S, Cilli M, Gaudino G . Point mutations in the tyrosine kinase domain release the oncogenic and metastatic potential of the Ron receptor. Oncogene 1998; 17: 741–9.
Peace BE, Hughes MJ, Degen SJ, Waltz SE . Point mutations and overexpression of Ron induce transformation, tumor formation, and metastasis. Oncogene 2001; 20: 6142–51.
Williams TA, Longati P, Pugliese L, Gual P, Bardelli A, Michieli P . MET(PRC) mutations in the RON receptor result in upregulation of tyrosine kinase activity and acquisition of oncogenic potential. J Cell Physiol 1999; 181: 507–14.
Chen YQ, Zhou YQ, Fu LH, Wang D, Wang MH . Multiple pulmonary adenomas in the lung of transgenic mice overexpressing the RON receptor tyrosine kinase. Carcinogenesis 2002; 23: 1811–9.
Zhou YQ, Chen YQ, Fisher JH, Wang MH . Targeted expression of the receptor tyrosine kinase RON in distal lung epithelial cells results in multiple tumor formation: oncogenic potential of RON in vivo. Oncogene 2002; 21: 6382–6.
Barkley JE, Green MR . Bronchioloalveolar carcinoma. J Clin Oncol 1996; 14: 2377–86.
Thiery JP, Chopin D . Epithelial cell plasticity in development and tumor progression. Cancer Metastasis Rev 1999; 18: 31–42.
Savagner P . Leaving the neighborhood: molecular mechanisms involved during epithelial-mesenchymal transition. Bioessays 2001; 23: 912–23.
Wang D, Shen Q, Chen YQ, Wang MH . Collaborative activities of macrophage-stimulating protein and transforming growth factor-beta1 in induction of epithelial to mesenchymal transition: roles of the RON receptor tyrosine kinase. Oncogene 2004; 23: 1668–80.
Miyazono K . TGF-beta signaling by Smad proteins. Cytokine Growth Factor Rev 2000; 11: 15–22.
Santoro MM, Gaudino G, Marchisio PC . The MSP receptor regulates α6β4 and α3β1 integrins via 14-3-3 proteins in keratinocyte migration. Dev Cell 2003; 5: 257–71.
Li BQ, Wang MH, Kung HF . Macrophage-stimulating protein activates Ras by both activation and translocation of SOS nucleotide exchange factor. Biochem Biophys Res Commun 1996; 216: 110–8.
Danilkovitch A, Skeel A, Leonard EJ . Macrophage stimulating protein-induced epithelial cell adhesion is mediated by a PI3-K-dependent, but FAK-independent mechanism. Exp Cell Res 1999; 248: 575–82.
Wang MH, Montero-Julian FA, Leonard EJ . Requirement of PI-3 kinase for epithelial cell migration activated by human macrophage stimulating protein. Oncogene 1996; 13: 2167–75.
Danilkovitch-Miagkova A, Miagkov A, Skeel A, Nakaigawa N, Zbar B, Leonard EJ . Oncogenic mutants of RON and MET receptor tyrosine kinases cause activation of the beta-catenin pathway. Mol Cell Biol 2001; 21: 5857–68.
Ponzetto C, Bardelli A, Zhen Z, Maina F, Dalla Zonca P, Giordano S, et al. A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family. Cell 1994; 77: 261–71.
Danilkovitch-Miagkova A, Angeloni D, Skeel A, Donley S, Lerman M, Leonard EJ . Integrin-mediated RON growth factor receptor phosphorylation requires tyrosine kinase activity of both the receptor and c-Src. J Biol Chem 2000; 275: 14783–6.
Zhou YQ, Chen YQ, Fisher JH, Wang MH . Activation of the RON receptor tyrosine kinase by macrophage-stimulating protein inhibits inducible cyclooxygenase-2 expression in murine macrophages. J Biol Chem 2002; 277: 38104–10.
Xiao ZQ, Chen YQ, Wang MH . Requirement of both tyrosine kinase residues 1330 and 1337 in the c-terminal tail of the RON receptor tyrosine kinase for epithelial cell scattering and migration. Biochem Biophy Res Commun 2000; 267: 669–75.
Santoro MM, Penengo L, Orecchia S, Cilli M, Gaudino G . The Ron oncogenic activity induced by the MEN2B-like substitution overcomes the requirement for the multifunctional docking site. Oncogene 2000; 19: 5208–11.
Yokoyama N, Ischenko I, Hayman MJ, Miller WT . The C terminus of RON tyrosine kinase plays an autoinhibitory role. J Biol Chem 2005; 280: 8893–900.
Angeloni D, Danilkovitch-Miagkova A, Miagkov A, Leonard EJ, Lerman MI . The soluble sema domain of the RON receptor inhibits macrophage-stimulating protein-induced receptor activation. J Biol Chem 2004; 279: 3726–32.
Christensen JG, Schreck R, Burrows J, Kuruganti P, Chan E, Le P, et al. A selective small molecule inhibitor of c-Met kinase inhibits c-Met-dependent phenotypes in vitro and exhibits cytoreductive antitumor activity in vivo. Cancer Res 2003; 63: 7345–55.
Author information
Authors and Affiliations
Corresponding author
Additional information
Project supported by US National Institute of Health R01 (CA91980) and the National Natural Science Foundation of China (No 30430700).
Rights and permissions
About this article
Cite this article
Wang, Mh., Yao, Hp. & Zhou, Yq. Oncogenesis of RON receptor tyrosine kinase: a molecular target for malignant epithelial cancers. Acta Pharmacol Sin 27, 641–650 (2006). https://doi.org/10.1111/j.1745-7254.2006.00361.x
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1111/j.1745-7254.2006.00361.x
Keywords
This article is cited by
-
Splicing factors control triple-negative breast cancer cell mitosis through SUN2 interaction and sororin intron retention
Journal of Experimental & Clinical Cancer Research (2021)
-
Molecular landscape and subtype-specific therapeutic response of nasopharyngeal carcinoma revealed by integrative pharmacogenomics
Nature Communications (2021)
-
mTORC1 is a key mediator of RON-dependent breast cancer metastasis with therapeutic potential
npj Breast Cancer (2018)
-
Knockdown of RON Inhibits AP-1 Activity and Induces Apoptosis and Cell Cycle Arrest Through the Modulation of Akt/FoxO Signaling in Human Colorectal Cancer Cells
Digestive Diseases and Sciences (2012)
-
Deletion or insertion in the first immunoglobulin-plexin-transcription (IPT) domain differentially regulates expression and tumorigenic activities of RON receptor Tyrosine Kinase
Molecular Cancer (2010)