Pathogenesis of RON receptor tyrosine kinase in cancer cells: Activation mechanism, functional crosstalk, and signaling addiction

Journal of Biomedical Research

Volumn 27, Issue 5, 2013, Pages 345-356

  Wang, Ming Hai ^a   Zhang, Ruiwen ^a   Zhou, Yong Qing ^b   Yao, Hang Ping ^c  

^a TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER   (United States)

^b ZHEJIANG UNIVERSITY   (China)

^c ZHEJIANG UNIVERSITY   (China)

Author keywords

Activation mechanism; Oncogene addiction; Receptor tyrosine kinase (RON); Signaling crosstalk; Signaling pathway; Tumorigenesis

Indexed keywords

EID: 84908698721     PISSN: 16748301     EISSN: None     Source Type: Journal    
DOI: 10.7555/JBR.27.20130038     Document Type: Review

References (124)

1. Ronsin C, Muscatelli F, Mattei MG, Breathnach R. A novel putative receptor protein tyrosine kinase of the met family. Oncogene 1993; 8: 1195-202.
2. Gherardi E, Sharpe M, Lane K, Sirulnik A, Stoker, M. Hepatocyte growth factor/scatter factor (HGF/SF), the c-met receptor and the behavior of epithelial cells. Symp Soc Exp Biol 1993; 47: 163-81.
3. Park M, Dean M, Kaul K, Braun MJ, Gonda MA, Vande Woude G. Sequence of MET protooncogene cDNA has features characteristic of the tyrosine kinase family of growth-factor receptors. Proc Natl Acad Sci USA 1987; 84: 6379-83.
4. 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.
5. De Maria R, Maggiora P, Biolatti B, Prat M, Comoglio PM, Castagnaro M, et al. Feline STK gene expression in mammary carcinomas. Oncogene 2002; 21: 1785-90.
6. Bassett DI. Identification and developmental expression of a macrophage stimulating 1/hepatocyte growth factor-like 1 orthologue in the zebrafish. Dev Genes Evol 2003; 213: 360-2.
7. Huitema LF, Renn J, Logister I, Gray JK, Waltz SE, Flik G, et al. Macrophage-stimulating protein and calcium homeostasis in zebrafish. FASEB J 2012; 26: 4092-101.
8. Théry C, Sharpe MJ, Batley SJ, Stern CD, Gherardi E. Expression of HGF/SF, HGF1/MSP, and c-met suggests new functions during early chick development. Dev Genet 1995; 17: 90-101.
9. HuffJL, Jelinek MA, Jamieson TA, Parsons JT. Expression and maturation of the cellular sea receptor, a member of the hepatocyte growth factor (HGF) receptor family of protein tyrosine kinases. Oncogene 1996; 12: 299-307.
10. Wahl RC, Hsu RY, HuffJL, Jelinek MA, Chen K, Courchesne P, et al. Chicken macrophage stimulating protein is a ligand of the receptor protein-tyrosine kinase Sea. J Biol Chem 1999; 274: 26361-8.
11. 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.
12. 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.
13. 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.
14. 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 Sci USA 1995; 92: 3933-7.
15. Wang MH, Ronsin C, Gesnel MC, Coupey 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.
16. Gaudino G, Follenzi A, Naldini L, Collesi C, Santoro M, Gallo KA, et al. RON is a heterodimeric tyrosine kinase receptor activated by the HGF homologue MSP. EMBO J 1994; 13: 3524-32.
17. Wang MH, Lee W, Luo YL, Weis MT, Yao HP. Altered expression of the RON receptor tyrosine kinase in various epithelial cancers and its contribution to tumorigenic phenotypes in thyroid cancer cells. J Pathol 2007; 213: 402-11.
18. Thomas RM, Toney K, Fenoglio-Preiser C, Revelo-Penafiel MP, Hingorani SR, Tuveson DA, et al. The RON receptor tyrosine kinase mediates oncogenic phenotypes in pancreatic cancer cells and is increasingly expressed during pancreatic cancer progression. Cancer Res 2007; 67: 6075-82.
19. Kanteti R, Krishnaswamy S, Catenacci D, Tan YH, EL-Hashani E, Cervantes G, et al. Differential expression of RON in small and non-small cell lung cancers. Genes Chromosomes Cancer 2012; 51: 841-51.
20. Camp ER, Yang A, Gray MJ, Fan F, Hamilton SR, Evans DB, et al. Tyrosine kinase receptor RON in human pancreatic cancer: expression, function, and validation as a target. Cancer 2007; 109: 1030-9.
21. 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.
22. Catenacci DV, Cervantes G, Yala S, Nelson EA, El-Hashani E, Kanteti R, et al. RON (MST1R) is a novel prognostic marker and therapeutic target for gastroesophageal adenocarcinoma. Cancer Biol Ther 2011; 12: 9-46.
23. Ren X, Daa T, Yada N, Kashima K, Fujitomi Y, Yokoyama S. Expression and mutational status of RON in neoplastic lesions of the breast: analysis of MSP/RON signaling in ductal carcinoma in situ and invasive ductal carcinoma. APMIS 2012; 120: 358-67.
24. Chou YC, Chen CL, Yeh TH, Lin SJ, Chen MR, Doong SL, et al. Involvement of recepteur d'origine nantais receptor tyrosine kinase in Epstein-Barr virus-associated nasopharyngeal carcinoma and its metastasis. Am J Pathol 2012; 181: 1773-81.
25. Collesi, C., Santoro, M. M., Gaudino, G. & Comoglio, P. M. A splicing variant of the RON transcript induces constitutive tyrosine kinase activity and an invasive phenotype. Mol Cell Biol 1996; 16: 5518-26.
26. Santoro, M. M., Collesi, C., Grisendi, S., Gaudino, G. & Comoglio, P. M. Constitutive activation of the RON gene promotes invasive growth but not transformation. Mol. Cell Biol 1996; 16: 7072-83.
27. Zhou, Y. Q., He, C., Chen, Y. Q., Wang, D. & Wang, M. H. Altered expression of the RON receptor tyrosine kinase in primary human colorectal adenocarcinomas: generation of different splicing RON variants and their oncogenic potential. Oncogene 2003; 22: 186-97.
28. Liu X, Zhao L, Derose YS, Lin YC, Bieniasz M, Eyob H, et al. Short-Form Ron Promotes Spontaneous Breast Cancer Metastasis through Interaction with Phosphoinositide 3-Kinase. Genes Cancer 2011; 2: 753-62.
29. Eckerich C, Schulte A, Martens T, Zapf S, Westphal M, Lamszus K. RON receptor tyrosine kinase in human gliomas: expression, function, and identification of a novel soluble splice variant. J Neurochem 2009; 109: 969-80.
30. Ma Q, Zhang K, Guin S, Zhou YQ, Wang MH. Deletion or insertion in the first immunoglobulin-plexin-transcription (IPT) domain differentially regulates expression and tumorigenic activities of RON receptor Tyrosine Kinase. Mol Cancer 2010; 9: 307-136.
31. Wei X, Hao L, Ni S, Liu Q, Xu J, Correll PH. Altered exon usage in the juxtamembrane domain of mouse and human RON regulates receptor activity and signaling specificity. J Biol Chem 2005; 280: 40241-51.
32. 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.
33. Fialin C, Larrue C, Vergez F, Sarry JE, Bertoli S, Mansat-De Mas V, et al. The short form of RON is expressed in acute myeloid leukemia and sensitizes leukemic cells to cMET inhibitors. Leukemia 2013; 27: 325-35.
34. 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.
35. Wang, M. H., Kurtz, A. L. & Chen, Y. Q. Identification of a novel splicing product of the RON receptor tyrosine kinase in human colorectal carcinoma cells. Carcinogenesis 2000; 21: 1507-12.
36. Follenzi A, Bakovic S, Gual P, Stella MC, Longati P, Comoglio PM. Cross-talk between the proto-oncogenes Met and Ron. Oncogene 2000; 19: 3041-9.
37. Benvenuti S, Lazzari L, Arnesano A, Li Chiavi G, Gentile A, Comoglio PM. Ron kinase transphosphorylation sustains MET oncogene addiction. Cancer Res 2011; 71: 1945-55.
38. Peace BE, Hill KJ, Degen SJ, Waltz SE. Cross-talk between the receptor tyrosine kinases Ron and epidermal growth factor receptor. Exp Cell Res 2003; 289: 317-25.
39. Kobayashi T, Furukawa Y, Kikuchi J, Ito C, Miyata Y, Muto S, et al. Transactivation of RON receptor tyrosine kinase by interaction with PDGF receptor beta during steady-state growth of human mesangial cells. Kidney Int 2009; 75: 1173-83.
40. Potratz JC, Saunders DN, Wai DH, Ng TL, McKinney SE, Carboni JM, et al. Sorensen PH. Synthetic lethality screens reveal RPS6 and MST1R as modifiers of insulinlike growth factor-1 receptor inhibitor activity in childhood sarcomas. Cancer Res 2010; 70: 8770-81.
41. Jaquish DV, Yu PT, Shields DJ, French RP, Maruyama KP, Niessen S, et al. IGF1-R signals through the RON receptor to mediate pancreatic cancer cell migration. Carcinogenesis 2011; 32: 1151-6.
42. Thomas CY, Theodorescu D. Collaboration of RON and epidermal growth factor receptor in human bladder carcinogenesis. J Urol 2006; 176: 1909-10.
43. Liu HS, Hsu PY, Lai MD, Chang HY, Ho CL, Cheng HL, et al. An unusual function of RON receptor tyrosine kinase as a transcriptional regulator in cooperation with EGFR in human cancer cells. Carcinogenesis 2010; 31: 1456-64.
44. Wang MH, Julian FM, 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.
45. Danilkovitch A, Miller M, Leonard EJ. Interaction of macrophage-stimulating protein with its receptor. Residues critical for beta chain binding and evidence for independent alpha chain binding. J Biol Chem 1999; 274: 29937-43.
46. 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.
47. 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.
48. 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.
49. Iwama A, Yamaguchi N, Suda T. STK/RON receptor tyrosine kinase mediates both apoptotic and growth signals via the multifunctional docking site conserved among the HGF receptor family. EMBO J 1996; 15: 5866-75.
50. Xiao ZQ, Chen YQ, Wang MH. Requirement of both tyrosine residues 1330 and 1337 in the C-terminal tail of the RON receptor tyrosine kinase for epithelial cell scattering and migration. Biochem Biophys Res Commun 2000; 267: 669-75.
51. Wang J, Rajput A, Kan JL, Rose R, Liu XQ, Kuropatwinski K, et al. Knockdown of Ron kinase inhibits mutant phosphatidylinositol 3-kinase and reduces metastasis in human colon carcinoma. J Biol Chem 2009; 284: 10912-22.
52. Chaudhuri A, Xie MH, Yang B, Mahapatra K, Liu J, Marsters S, et al. Distinct involvement of the Gab1 and Grb2 adaptor proteins in signal transduction by the related receptor tyrosine kinases RON and MET. J Biol Chem 2011; 286: 32762-74.
53. Wang MH, Montero-Julian FA, Dauny I, Leonard EJ. Requirement of phosphatidylinositol-3 kinase for epithelial cell migration activated by human macrophage stimulating protein. Oncogene 1996; 13: 2167-75.
54. 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.
55. Park JS, Park JH, Khoi PN, Joo YE, Jung YD. MSP-induced RON activation upregulates uPAR expression and cell invasiveness via MAPK, AP-1 and NF-κB signals in gastric cancer cells. Carcinogenesis 20111; 32: 175-81.
56. Danilkovitch A, Donley S, Skeel A, Leonard EJ. Two independent signaling pathways mediate the antiapoptotic action of macrophage-stimulating protein on epithelial cells. Mol. Cell Biol 2000; 20: 2218-27.
57. Santoro MM, Gaudino G, Marchisio PC. The MSP receptor regulates alpha6beta4 and alpha3beta1 integrins via 14-3-3 proteins in keratinocyte migration. Dev Cell 2003; 5: 257-71.
58. Wang MH, Dlugosz AA, Sun Y, Suda T, Skeel A, Leonard EJ. Macrophage-stimulating protein induces proliferation and migration of murine keratinocytes. Exp Cell Res 1996; 226: 39-46.
59. 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.
60. Côté M, Miller AD, Liu SL. Human RON receptor tyrosine kinase induces complete epithelial-to-mesenchymal transition but causes cellular senescence. Biochem Biophys Res Commun 2007; 360: 219-25.
61. Yu PT, Babicky M, Jaquish D, French R, Marayuma K, Mose E, et al. The RON-receptor regulates pancreatic cancer cell migration through phosphorylation-dependent breakdown of the hemidesmosome. Int J Cancer 2012; 131: 1744-54.
62. McClaine RJ, Marshall AM, Wagh PK, Waltz SE. Ron receptor tyrosine kinase activation confers resistance to tamoxifen in breast cancer cell lines. Neoplasia 2010; 12: 650-8.
63. Logan-Collins J, Thomas RM, Yu P, Jaquish D, Mose E, French R, et al. Silencing of RON receptor signaling promotes apoptosis and gemcitabine sensitivity in pancreatic cancers. Cancer Res 2010; 70: 1130-40.
64. 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.
65. Han S, Stuart LA, Degen SJ. Characterization of the DNF15S2 locus on human chromosome 3: identification of a gene coding for four kringle domains with homology to hepatocyte growth factor. Biochemistry 1991; 30: 9768-80.
66. 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.
67. 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.
68. Wang MH, Gonias SL, Skeel A, Wolf BB, Yoshimura T, Leonard EJ. Proteolytic activation of single-chain precursor macrophage-stimulating protein by nerve growth factor-gamma and epidermal growth factor-binding protein, members of the kallikrein family. J Biol Chem 1994; 269: 13806-10.
69. Kawaguchi M, Orikawa H, Baba T, Fukushima T, Kataoka H. Hepatocyte growth factor activator is a serum activator of single-chain precursor macrophage-stimulating protein. FEBS J 2009; 276: 3481-90.
70. Ganesan R, Kolumam GA, Lin SJ, Xie MH, Santell L, Wu TD, et al. Proteolytic activation of pro-macrophage-stimulating protein by hepsin. Mol Cancer Res 2011; 9: 1175-86.
71. Chao KL, Tsai IW, Chen C, Herzberg O. Crystal structure of the Sema-PSI extracellular domain of human RON receptor tyrosine kinase. PLoS One 2012; 7: e41912-8.
72. 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.
73. Holmes O, Pillozzi S, Deakin JA, Carafoli F, Kemp L, Butler PJ, et al. Insights into the structure/function of hepatocyte growth factor/scatter factor from studies with individual domains. J Mol Biol 2007; 367: 395-408.
74. Wang MH, Lao WF, Wang D, Luo YL, Yao HP. Blocking tumorigenic activities of colorectal cancer cells by a splicing RON receptor variant defective in the tyrosine kinase domain. Cancer Biol Ther 2007; 6: 1121-9.
75. Angeloni D, Danilkovitch-Miagkova A, Ivanova T, Braga E, Zabarovsky E, Lerman MI. Hypermethylation of Ron proximal promoter associates with lack of fulllength Ron and transcription of oncogenic short-Ron from an internal promoter. Oncogene 2007; 26: 4499-512.
76. Lu Y, Yao HP, Wang MH. Multiple variants of the RON receptor tyrosine kinase: biochemical properties, tumorigenic activities, and potential drug targets. Cancer Lett 2007; 257: 157-64.
77. Zhang K, Zhou YQ, Yao HP, Wang MH. Alterations in a defined extracellular region of the RON receptor tyrosine kinase promote RON-mediated motile and invasive phenotypes in epithelial cells. Int J Oncol 2010; 36: 255-64.
78. Ma Q, Zhang K, Yao HP, Zhou YQ, Padhye S, Wang MH. Inhibition of MSP-RON signaling pathway in cancer cells by a novel soluble form of RON comprising the entire sema sequence. Int J Oncol 2010; 36: 1551-61.
79. Angeloni, D., Danilkovitch-Miagkova, A., Miagkov, A., Leonard, E. J. & Lerman, M. I. The soluble sema domain of the RON receptor inhibits macrophage-stimulating protein-induced receptor activation. J Biol Chem 2004; 279: 3726-32.
80. 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.
81. 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.
82. Compérat E, Roupret M, Chartier-Kastler E, Bitker MO, Richard F, Camparo P, et al. Prognostic value of MET, RON and histoprognostic factors for urothelial carcinoma in the upper urinary tract. J Urol 2008; 179: 868-72.
83. Lee CT, Chow NH, Su PF, Lin SC, Lin PC, Lee JC. The prognostic significance of RON and MET receptor co-expression in patients with colorectal cancer. Dis Colon Rectum 2008; 51: 1268-74.
84. Ferrandina G, Martinelli E, Petrillo M, Prisco MG, Zucconi A, Santaguida S, et al. Prognostic role of the re-cepteur d'origine nantais (RON) expression in ovarian cancer patients. Gynecol Oncol 2008; 111: 237-43.
85. Zhou D, Pan G, Zheng C, Zheng J, Yian L, Teng X. Expression of the RON receptor tyrosine kinase and its association with gastric carcinoma versus normal gastric tissues. BMC Cancer 2008; 8: 353-9.
86. Tactacan CM, Chang DK, Cowley MJ, Humphrey ES, Wu J, Gill AJ, et al. RON is not a prognostic marker for resectable pancreatic cancer. BMC Cancer 2012; 12: 395-403.
87. 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.
88. Thangasamy A, Rogge J, Ammanamanchi S. Recepteur d'origine nantais tyrosine kinase is a direct target of hypoxia-inducible factor-1alpha-mediated invasion of breast carcinoma cells. J Biol Chem 2009; 284: 14001-10.
89. Furitsu T, Tsujimura T, Tono T, Ikeda H, Kitayama H, Koshimizu U, et al. Identification of mutations in the coding sequence of the proto-oncogene c-kit in a human mast cell leukemia cell line causing ligand-independent activation of c-kit product. J Clin Invest 1993; 92: 1736-44.
90. Hanks SK, Quinn AM, Hunter T. The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science 1988; 241: 42-52.
91. Longley BJ, Tyrrell L, Lu SZ, Ma YS, Langley K, Ding TG, et al. Somatic c-KIT activating mutation in urticaria pigmentosa and aggressive mastocytosis: establishment of clonality in a human mast cell neoplasm. Nat Genet 1996; 12: 312-4.
92. Carlson KM, Dou S, Chi D, Scavarda N, Toshima K, Jackson CE, et al. Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B. Proc Natl Acad Sci USA 1994; 91: 1579-83.
93. Wang J, Steinbacher S, Augustin M, Schreiner P, Epstein D, Mulvihill MJ, et al. The crystal structure of a constitutively active mutant RON kinase suggests an intramolecular autophosphorylation hypothesis. Biochemistry 2010; 49: 7972-4.
94. Gaudino G, Avantaggiato V, Follenzi A, Acampora D, Simeone A, Comoglio PM. The proto-oncogene RON is involved in development of epithelial, bone and neuroendocrine tissues. Oncogene 1995; 11: 2627-37.
95. Li BQ, Wang MH, Kung HF, Ronsin C, Breathnach R, Leonard EJ, et al. Macrophage-stimulating protein activates Ras by both activation and translocation of SOS nucleotide exchange factor. Biochem Biophys Res Commun 1995; 216: 110-8.
96. Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF. Met, metastasis, motility and more. Nat Rev Mol Cell Biol 2003; 4: 915-25.
97. Zhou YQ, Luo YL, Zhou ZW, Yao HP, Wang MH. β-Arrestin-1-dependent activation of extracellular signal-regulated kinases in RON receptor-mediated tumorigenic activities in colon cancer cells. J. Cancer Mol 2010, 5: 55-62.
98. 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.
99. Germano S, Barberis D, Santoro MM, Penengo L, Citri A, Yarden Y, Gaudino G. Geldanamycins trigger a novel Ron degradative pathway, hampering oncogenic signaling. J Biol Chem 2006; 281: 21710-9.
100. Santoro, M. M., Gaudino, G. & Villa-Moruzzi, E. Protein phosphatase 1 binds to phospho-Ser-1394 of the macrophage-stimulating protein receptor. Biochem J 2003; 376: 587-94.
101. Ma Q, Guin S, Padhye SS, Zhou YQ, Zhang RW, Wang MH. Ribosomal protein S6 kinase (RSK)-2 as a central effector molecule in RON receptor tyrosine kinase mediated epithelial to mesenchymal transition induced by macrophage-stimulating protein. Mol Cancer 2011; 10: 66-76.
102. Doehn U, Hauge C, Frank SR, Jensen CJ, Duda K, Nielsen JV, et al. RSK is a principal effector of the RAS-ERK pathway for eliciting a coordinate promotile/invasive gene program and phenotype in epithelial cells. Mol Cell 2009; 35: 511-22.
103. Smolen GA, Zhang J, Zubrowski MJ, Edelman EJ, Luo B, Yu M, et al. A genome-wide RNAi screen identifies multiple RSK-dependent regulators of cell migration. Genes Dev 2010; 24: 2654-65.
104. 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.
105. 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.
106. Umehara D, Watanabe S, Ochi H, Anai Y, Ahmed N, Kannagi M, et al. Role of phosphatidylinositol 3-kinase in friend spleen focus-forming virus-induced erythroid disease. J Virol 2010; 84: 7675-82.
107. Danilkovitch-Miagkova A, Duh FM, Kuzmin I, Angeloni D, Liu SL, Miller AD, et al. Hyaluronidase 2 negatively regulates RON receptor tyrosine kinase and mediates transformation of epithelial cells by jaagsiekte sheep retrovirus. Proc Natl Acad Sci USA 2003; 100: 4580-5.
108. Varela M, Chow YH, Sturkie C, Murcia P, Palmarini M. Association of RON tyrosine kinase with the Jaagsiekte sheep retrovirus envelope glycoprotein. Virology 2006; 350: 347-57.
109. Chou YC, Lin SJ, Lu J, Yeh TH, Chen CL, Weng PL, et al. Requirement for LMP1-induced RON receptor tyrosine kinase in Epstein-Barr virus-mediated B-cell proliferation. Blood 2011; 118: 1340-9.
110. He S, Ni S, Hegde S, Wang X, Sharda DR, August A, et al. Activation of the N-terminally truncated form of the Stk receptor tyrosine kinase Sf-Stk by Friend virus-encoded gp55 is mediated by cysteine residues in the ecotropic domain of gp55 and the extracellular domain of Sf-Stk. J Virol 2010; 84: 2223-35.
111. Palmarini M, Fan H. Retrovirus-induced ovine pulmonary adenocarcinoma, an animal model for lung cancer. J Natl Cancer Inst 2001; 93: 1603-14.
112. Liu SL, Miller AD. Oncogenic transformation by the jaagsiekte sheep retrovirus envelope protein. Oncogene 2007; 26: 789-801.
113. 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.
114. Zou HY, Li Q, Lee JH, Arango ME, Burgess K, Qiu M, et al. Sensitivity of selected human tumor models to PF-04217903, a novel selective c-Met kinase inhibitor. Mol Cancer Ther 2012; 11: 1036-47.
115. 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.
116. Yao HP, Zhuang CM, Zhou YQ, Zeng JY, Zhang WR, Wang MH. Oncogenic Variant RON160 Expression in Breast Cancer and its Potential as a Therapeutic Target by Small Molecule Tyrosine Kinase Inhibitor. Curr Cancer Drug Target 2013 (in revision).
117. Zhang Y, Kaplan-Lefko PJ, Rex K, Yang Y, Moriguchi J, Osgood T, et al. Identification of a novel recepteur d'origine nantais/c-met small-molecule kinase inhibitor with antitumor activity in vivo. Cancer Res 2008; 68: 6680-7.
118. Schroeder GM, An Y, Cai ZW, Chen XT, Clark C, Cornelius LA, et al. Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily. J Med Chem 2009; 52: 1251-4.
119. Sharma S, Zeng JY, Zhuang CM, Zhou YQ, Yao HP, Hu X, Zhang RW, Wang MH. Small-Molecule Inhibitor BMS-777607 Induces Breast Cancer Cell Polyploidy with Increased Resistance to Cytotoxic Chemotherapy Agents. Mol Cancer Ther 2013; Mar 6 [Epub ahead of print]
120. O'Toole JM, Rabenau KE, Burns K, Lu D, Mangalampalli V, Balderes P, et al. Therapeutic implications of a human neutralizing antibody to the macrophage-stimulating protein receptor tyrosine kinase (RON), a c-MET family member. Cancer Res 2006; 66: 9162-70.
121. Yao HP, Zhou YQ, Ma Q, Guin S, Padhye SS, Zhang RW, et al. The monoclonal antibody Zt/f2 targeting RON receptor tyrosine kinase as potential therapeutics against tumor growth-mediated by colon cancer cells. Mol Cancer. 2011; 10: 82-93.
122. Welm AL, Sneddon JB, Taylor C, Nuyten DS, van de Vijver MJ, Hasegawa BH, et al. The macrophage-stimulating protein pathway promotes metastasis in a mouse model for breast cancer and predicts poor prognosis in humans. Proc Natl Acad Sci USA 2007; 104: 7570-5.
123. Xu XM, Zhou YQ, Wang MH. Mechanisms of cytoplasmic {beta}-catenin accumulation and its involvement in tumorigenic activities mediated by oncogenic splicing variant of the receptor originated from Nantes tyrosine kinase. J Biol Chem 2005; 280: 25087-94.
124. Wagh PK, Gray JK, Zinser GM, Vasiliauskas J, James L, Monga SP, et al. β-Catenin is required for Ron receptor-induced mammary tumorigenesis. Oncogene 2011; 30: 3694-704.