MSP-RON signalling in cancer: Pathogenesis and therapeutic potential

Nature Reviews Cancer

Volumn 13, Issue 7, 2013, Pages 466-481

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

^a ZHEJIANG UNIVERSITY SCHOOL OF MEDICINE   (China)

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

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

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; BMS 777607; DOCETAXEL; ERLOTINIB; FORETINIB; LAPATINIB; MACROPHAGE STIMULATING PROTEIN; MEMBRANE PROTEIN; MGCD 265; MK 2461; MK 8033; MONOCLONAL ANTIBODY; MONOCLONAL ANTIBODY IMC 41A10; NARNATUMAB; ONCOPROTEIN; RECEPTOR TYROSINASE KINASE SHORT FORM RON; RECEPTOR TYROSINE KINASE RON; TRANSCRIPTION FACTOR SP1; TYROSINE KINASE RECEPTOR; UNCLASSIFIED DRUG;

CANCER CELL; CANCER PROGNOSIS; CANCER THERAPY; CPG ISLAND; EXON; GENE ACTIVATION; GENE CONTROL; GENETIC ANALYSIS; GENETIC TRANSCRIPTION; HUMAN; IMMUNOHISTOCHEMISTRY; INTRON; LUNG NON SMALL CELL CANCER; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN PROCESSING; PROTEIN PROTEIN INTERACTION; REVIEW; RNA SPLICING; SIGNAL TRANSDUCTION; TUMOR MICROENVIRONMENT;

ANTINEOPLASTIC AGENTS; HEPATOCYTE GROWTH FACTOR; HUMANS; NEOPLASMS; PROTO-ONCOGENE PROTEINS; RECEPTOR PROTEIN-TYROSINE KINASES; SIGNAL TRANSDUCTION;

EID: 84881089423     PISSN: 1474175X     EISSN: 14741768     Source Type: Journal    
DOI: 10.1038/nrc3545     Document Type: Review

References (175)

1. Leonard, E. J. & Skeel, A. H. Isolation of macrophage stimulating protein (MSP) from human serum. Exp. Cell. Res. 114, 117-126 (1978).
2. Leonard, E. J. & Skeel, A. H. Enhancement of spreading, phagocytosis and chemotaxis by macrophage stimulating protein (MSP). Adv. Exp. Med. Biol. 121B, 181-194 (1979).
3. Skeel, A. et al. Macrophage stimulating protein: Purification, partial amino acid sequence, and cellular activity. J. Exp. Med. 173, 1227-1234 (1991).
4. Han, S. Stuart, L. A., & Degen, S. J. 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 30, 9768-9780 (1991).
5. Degen, S. J., Stuart, L. A., Han, S. & Jamison, C. S. Characterization of the mouse cDNA and gene coding for a hepatocyte growth factor-like protein: Expression during development. Biochemistry 30, 9781-9791 (1991).
6. Yoshimura, T., Yuhki, N., Wang, M. H., Skeel, A. & Leonard, E. J. 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. 268, 15461-15468 (1993).
7. Ronsin, C., Muscatelli, F., Mattei, M. G. & Breathnach, R. A novel putative receptor protein tyrosine kinase of the met family. Oncogene 8, 1195-1202 (1993).
8. Gherardi, E., Sharpe, M., Lane, K., Sirulnik, A. & Stoker, M. Hepatocyte growth factor/scatter factor (HGF/SF), the cmet receptor and the behaviour of epithelial cells. Symp. Soc. Exp. Biol. 47, 163-181 (1993).
9. Park, M. et al. Sequence of MET protooncogene cDNA has features characteristic of the tyrosine kinase family of growth-factor receptors. Proc. Natl Acad. Sci. USA 84, 6379-6383 (1987).
10. Bottaro, D. P. et al. Identification of the hepatocyte growth factor receptor as the cmet proto-oncogene product. Science 251, 802-804 (1991).
11. Iwama, A., Okano, K., Sudo, T., Matsudam, Y. & Suda, T. Molecular cloning of a novel receptor tyrosine kinase gene, STK, derived from enriched hematopoietic stem cells. Blood 83, 3160-3169 (1994).
12. De Maria, R. et al. Feline STK gene expression in mammary carcinomas. Oncogene 21, 1785-1790 (2002).
13. Bassett, D. I. Identification and developmental expression of a macrophage stimulating 1/ hepatocyte growth factor-like 1 orthologous in the zebrafish. Dev. Genes Evol. 213, 360-362 (2003).
14. Huitema, L. F. et al. Macrophage-stimulating protein and calcium homeostasis in zebrafish. FASEB J. 26, 4092-4101 (2012).
15. Théry, C., Sharpe, M. J., Batley, S. J., Stern, C. D. & Gherardi, E. Expression of HGF/SF, HGF1/MSP, and cmet suggests new functions during early chick development. Dev. Genet. 17, 90-101 (1995).
16. Huff, J. L., Jelinek, M. A., Jamieson, T. A. & Parsons, J. T. Expression and maturation of the cellular sea receptor, a member of the hepatocyte growth factor (HGF) receptor family of protein tyrosine kinases. Oncogene 12, 299-307 (1996).
17. Wahl, R. C. et al. Chicken macrophage stimulating protein is a ligand of the receptor protein-tyrosine kinase Sea. J. Biol. Chem. 274, 26361-26368 (1999).
18. Nakamura, T. et al. Cloning and expression of Xenopus HGF-like protein (HLP) and Ron/HLP receptor implicate their involvement in early neural development. Biochem. Biophys. Res. Commun. 224, 564-573 (1996).
19. Hayman, M. J., Kitchener, G., Vogt, P. K. & 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 82, 8237-8241 (1985).
20. Ith, D. R., Vogt, P. K. & Hayman, M. J. The vsea oncogene of avian erythroblastosis retrovirus S13: Another member of the protein-tyrosine kinase gene family. Proc. Natl Acad. Sci. USA 86, 5291-5295 (1989).
21. Wang, M. H. et al. Identification of the Ron gene product as the receptor for the human macrophage stimulating protein. Science 266, 117-119 (1994).
22. Gaudino, G. et al. RON is a heterodimeric tyrosine kinase receptor activated by the HGF homologue MSP. EMBO J. 13, 3524-3532 (1994).
23. Wang, M. H., Iwama, A., Skeel, A., Suda, T. & Leonard, E. J. The murine stk gene product, a transmembrane protein tyrosine kinase, is a receptor for macrophage-stimulating protein. Proc. Natl Acad. Sci. USA 92, 3933-3937 (1995).
24. Bezerra, J. A., Carrick, T. L., Degen, J. L., Witte, D. & Degen, S. J. Biological effects of targeted inactivation of hepatocyte growth factor-like protein in mice. J. Clin. Invest. 101, 1175-1183 (1998).
25. Gaudino, G. et al. The proto-oncogene RON is involved in development of epithelial, bone and neuro-endocrine tissues. Oncogene 11, 2627-2637 (1995).
26. Quantin, B., Schuhbaur, B., Gesnel, M. C., Doll'e, P. & Breathnach, R. Restricted expression of the ron gene encoding the macrophage stimulating protein receptor during mouse development. Dev. Dyn. 204, 383-390 (1995).
27. Muraoka, R. S. et al. The Ron/STK receptor tyrosine kinase is essential for peri-implantation development in the mouse. J. Clin. Invest. 103, 1277-1285 (1999).
28. Krawczyk, M. et al. Macrophage stimulating protein variation enhances the risk of sporadic extrahepatic cholangiocarcinoma. Dig. Liver Dis. 16 Feb 2013 (doi:10.1016/j.dld.2012.12.017).
29. Häuser, F. et al. Macrophage-stimulating protein polymorphism rs3197999 is associated with a gain of function: Implications for inflammatory bowel disease. Genes Immun. 13, 321-327 (2012).
30. Wang, M. H., Lee, W., Luo, Y. L., Weis, M. T. & Yao, H. P. Altered expression of the RON receptor tyrosine kinase in various epithelial cancers and its contribution to tumorigenic phenotypes in thyroid cancer cells. J. Pathol. 213, 402-411 (2007).
31. Thomas, R. M. et al. The RON receptor tyrosine kinase mediates oncogenic phenotypes in pancreatic cancer cells and is increasingly expressed during pancreatic cancer progression. Cancer Res. 67, 6075-6082 (2007).
32. Kanteti, R. et al. Differential expression of RON in small and non-small cell lung cancers. Genes Chromosomes Cancer 51, 841-851 (2012).
33. Camp, E. R. et al. Tyrosine kinase receptor RON in human pancreatic cancer: Expression, function, and validation as a target. Cancer 109, 1030-1039 (2007).
34. Maggiora, P. et al. Overexpression of the RON gene in human breast carcinoma. Oncogene 16, 2927-2933 (1998).
35. Catenacci, D. V. et al. RON (MST1R) is a novel prognostic marker and therapeutic target for gastroesophageal adenocarcinoma. Cancer Biol. Ther. 12, 9-46 (2011).
36. Ren, X. et al. 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 120, 358-367 (2012).
37. Chou, Y. C. et al. Involvement of recepteur d'origine nantais receptor tyrosine kinase in Epstein-Barr virus-associated nasopharyngeal carcinoma and its metastasis. Am. J. Pathol. 181, 1773-1781 (2012).
38. 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. 16, 5518-5526 (1996).
39. 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. 16, 7072-7083 (1996).
40. 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 22, 186-197 (2003).
41. Liu, X. et al. Short-form ron promotes spontaneous breast cancer metastasis through interaction with phosphoinositide 3kinase. Genes Cancer 2, 753-762 (2011).
42. Eckerich, C. et al. RON receptor tyrosine kinase in human gliomas: Expression, function, and identification of a novel soluble splice variant. J. Neurochem. 109, 969-980 (2009).
43. Ma, Q. et al. Deletion or insertion in the first immunoglobulin-plexin- transcription (IPT) domain differentially regulates expression and tumorigenic activities of RON receptor Tyrosine Kinase. Mol. Cancer 9, 307-316 (2010).
44. Wei, X. et al. Altered exon usage in the juxtamembrane domain of mouse and human RON regulates receptor activity and signaling specificity. J. Biol. Chem. 280, 40241-44051 (2005).
45. Ghigna, C. et al. Cell motility is controlled by SF2/ASF through alternative splicing of the Ron proto-oncogene. Mol. Cell. 20, 881-890 (2005).
46. Fialin, C. et al. The short form of RON is expressed in acute myeloid leukemia and sensitizes leukemic cells to cMET inhibitors. Leukemia 2013 27, 325-335 (2013).
47. Bardella, C. et al. Truncated RON tyrosine kinase drives tumor cell progression and abrogates cell-cell adhesion through Ecadherin transcriptional repression. Cancer Res. 64, 5154-5161 (2004).
48. 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 21, 1507-1512 (2000).
49. Wang, J. et al. Knockdown of Ron kinase inhibits mutant phosphatidylinositol 3kinase and reduces metastasis in human colon carcinoma. J. Biol. Chem. 284, 10912-10922 (2009).
50. Wang, D., Shen, Q., Chen, Y. Q. & Wang, M. H. Collaborative activities of macrophage-stimulating protein and transforming growth factorβ1 in induction of epithelial to mesenchymal transition: Roles of the RON receptor tyrosine kinase. Oncogene 23, 1668-1680 (2004).
51. Chen, Y. Q., Zhou, Y. Q., Fisher, J. H. & Wang, M. H. 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 21, 6382-6386 (2002).
52. Sato, S. et al. Macrophage stimulating protein promotes liver metastases of small cell lung cancer cells by affecting the organ microenvironment. Clin. Exp. Metastasis 30, 333-344 (2012).
53. Thobe, M. N. et al. The Ron receptor promotes prostate tumor growth in the TRAMP mouse model. Oncogene 30, 4990-4998 (2011).
54. Thobe, M. N., Gurusamy, D., Pathrose, P. & Waltz, S. E. The Ron receptor tyrosine kinase positively regulates angiogenic chemokine production in prostate cancer cells. Oncogene. 29, 214-226 (2010).
55. McClaine, R. J., Marshall, A. M., Wagh, P. K. & Waltz, S. E. Ron receptor tyrosine kinase activation confers resistance to tamoxifen in breast cancer cell lines. Neoplasia 12, 650-658 (2010).
56. Logan-Collins, J. et al. Silencing of RON receptor signaling promotes apoptosis and gemcitabine sensitivity in pancreatic cancers. Cancer Res. 70, 1130-1140 (2010).
57. Chan, E. L., Peace, B. E., Collins, M. H., Toney-Earley, K. & Waltz, S. E. Ron tyrosine kinase receptor regulates papilloma growth and malignant conversion in a murine model of skin carcinogenesis. Oncogene 24, 479-488 (2005).
58. Zinser, G. M. et al. Mammary-specific Ron receptor overexpression induces highly metastatic mammary tumors associated with β-catenin activation. Cancer Res. 66, 11967-11974 (2006).
59. Welm, A. L. 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 104, 7570-7575 (2007).
60. Feres, K. J., Ischenko, I. & Hayman, M. J. The RON receptor tyrosine kinase promotes MSP-independent cell spreading and survival in breast epithelial cells. Oncogene 28, 279-288 (2009).
61. Wang, M. H., Yoshimura, T., Skeel, A. & Leonard, E. J. Proteolytic conversion of single chain precursor macrophage-stimulating protein to a biologically active heterodimer by contact enzymes of the coagulation cascade. J. Biol. Chem. 269, 3436-3440 (1994).
62. Wang, M. H. et al. Proteolytic activation of single-chain precursor macrophage-stimulating protein by nerve growth factor-γ and epidermal growth factor-binding protein, members of the kallikrein family. J. Biol. Chem. 269, 13806-13810 (1994).
63. 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. 276, 3481-3490 (2009).
64. Ganesan, R. et al. Proteolytic activation of pro-macrophage-stimulating protein by hepsin. Mol. Cancer Res. 9, 1175-1186 (2011).
65. Wang, M. H. et al. Macrophage stimulating protein (MSP) binds to its receptor via the MSP β chain. J. Biol. Chem. 272, 16999-17004 (1997).
66. Danilkovitch, A., Miller, M. & Leonard, E. J. Interaction of macrophage-stimulating protein with its receptor. Residues critical for β chain binding and evidence for independent α chain binding. J. Biol. Chem. 274, 29937-29943 (1999).
67. Yokoyama, N., Ischenko, I., Hayman, M. J. & Miller, W. T. The C terminus of RON tyrosine kinase plays an autoinhibitory role. J. Biol. Chem. 280, 8893-8900 (2005).
68. Carafoli, F., Chirgadze, D. Y., Blundell, T. L. & Gherardi, E. Crystal structure of the β-chain of human hepatocyte growth factor-like/macrophage stimulating protein. FEBS J. 272, 5799-5807 (2005).
69. Wang, J. et al. The crystal structure of a constitutively active mutant RON kinase suggests an intramolecular autophosphorylation hypothesis. Biochemistry 49, 7972-7974 (2010).
70. Willett, C. G. 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. 99, 2979-2991 (1997).
71. Ueda, A. & Yoshimura, T. Characterization of cis-acting elements of the gene for macrophage-stimulating protein from the human. The involvement of positive and negative regulatory elements. J. Biol. Chem. 271, 20265-20272 (1996).
72. Waltz, S. E., Gould, F. K., Air, E. L., McDowell, S. A. & Degen, S. J. Hepatocyte nuclear factor4 is responsible for the liver-specific expression of the gene coding for hepatocyte growth factor-like protein. J. Biol. Chem. 271, 9024-9032 (1996).
73. Ueda, A., Takeshita, F., Yamashiro, S. & Yoshimura, T. Positive regulation of the human macrophage stimulating protein gene transcription. Identification of a new hepatocyte nuclear factor4 (HNF4) binding element and evidence that indicates direct association between NFY and HNF4. J. Biol. Chem. 273, 19339-19347 (1998).
74. Muraoka, R. S., Waltz, S. E. & Degen, S. J. Expression of hepatocyte growth factor-like protein is repressed by retinoic acid and enhanced by cyclic adenosine 3Ŷ,5Ŷmonophosphate response element-binding protein (CREB)-binding protein (CBP). Endocrinology 140, 187-196 (1999).
75. Wang, M. H., Skeel, A. & Leonard, E. J. Proteolytic cleavage and activation of pro-macrophage-stimulating protein by resident peritoneal macrophage membrane proteases. J. Clin. Invest. 97, 720-727 (1996).
76. Orikawa, H. et al. Activation of macrophage-stimulating protein by human airway trypsin-like protease. FEBS Lett. 586, 217-221 (2012).
77. Bhatt, A. S. et al. Coordinate expression and functional profiling identify an extracellular proteolytic signaling pathway. Proc. Natl Acad. Sci. USA 104, 5771-5776 (2007).
78. Del Gatto, F., Gilbert, E., Ronsin, C. & Breathnach, R. Structure of the promoter for the human macrophage stimulating protein receptor gene. Biochim. Biophys. Acta 1263, 93-95 (1995).
79. Angeloni, D. et al. Gene structure of the human receptor tyrosine kinase RON and mutation analysis in lung cancer samples. Genes Chromosomes Cancer 29, 147-156 (2000).
80. Thangasamy, A., Rogge, J. & Ammanamanchi, S. Regulation of RON tyrosine kinase-mediated invasion of breast cancer cells. J. Biol. Chem. 283, 5335-5343 (2008).
81. Thangasamy, A., Rogge, J. & Ammanamanchi, S. Recepteur d'origine nantais tyrosine kinase is a direct target of hypoxia-inducible factor-1αmediated invasion of breast carcinoma cells. J. Biol. Chem. 284, 14001-14010 (2009).
82. Zhao, S. et al. Smad4dependent TGF-β signaling suppresses RON receptor tyrosine kinase-dependent motility and invasion of pancreatic cancer cells. J. Biol. Chem. 283, 11293-11301 (2008).
83. Thangasamy, A., Rogge, J., Krishnegowda, N. K., Freeman, J. W. & Ammanamanchi, S. Novel function of transcription factor Nrf2 as an inhibitor of RON tyrosine kinase receptor-mediated cancer cell invasion. J. Biol. Chem. 286, 32115-28622 (2011).
84. Lee, K. E. et al. Upregulation of recepteur d'origine nantais tyrosine kinase and cell invasiveness via early growth response1 in gastric cancer cells. J. Cell. Biochem. 113, 1217-1223 (2012).
85. Angeloni, D. et al. Hypermethylation of Ron proximal promoter associates with lack of full-length Ron and transcription of oncogenic short-Ron from an internal promoter. Oncogene 26, 4499-4512 (2007).
86. Lu, Y., Yao, H. P. & Wang, M. H. Multiple variants of the RON receptor tyrosine kinase: Biochemical properties, tumorigenic activities, and potential drug targets. Cancer Lett. 257,-164 (2007).
87. Wang, M. H., Lao, W. F., Wang, D., Luo, Y. L. & Yao, H. P. Blocking tumorigenic activities of colorectal cancer cells by a splicing RON receptor variant defective in the tyrosine kinase domain. Cancer Biol. Ther. 6, 1121-1129 (2007).
88. Zhang, K., Zhou, Y. Q., Yao, H. P. & Wang, M. H. 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. 36, 255-264 (2010).
89. Ma, Q. et al. Inhibition of MSP-RON signaling pathway in cancer cells by a novel soluble form of RON comprising the entire sema sequence. Int. J. Oncol. 36, 1551-1561 (2010).
90. 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. 279, 3726-3732 (2004).
91. Ghigna, C. et al. Pro-metastatic splicing of Ron proto-oncogene mRNA can be reversed: Therapeutic potential of bifunctional oligonucleotides and indole derivatives. RNA Biol. 7, 495-503 (2010).
92. Chao, K. L., Tsai, I. W., Chen, C. & Herzberg, O. Crystal structure of the Sema-PSI extracellular domain of human RON receptor tyrosine kinase. PLoS ONE 7, e41912 (2012).
93. Ponzetto, C. et al. A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family. Cell 77, 261-271 (1994).
94. 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. 15, 5866-5875 (1996).
95. Xiao, Z. Q., Chen, Y. Q. & Wang, M. H. Requirement of both tyrosine residues 1330 and 1337 in the Cterminal tail of the RON receptor tyrosine kinase for epithelial cell scattering and migration. Biochem. Biophys. Res. Commun. 267, 669-675 (2000).
96. Santoro, M. M. et al. Point mutations in the tyrosine kinase domain release the oncogenic and metastatic potential of the Ron receptor. Oncogene 17, 741-749 (1998).
97. Chaudhuri, A. 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. 286, 32762-33274 (2011).
98. Wang, M. H., Montero-Julian, F. A., Dauny, I. & Leonard, E. J. Requirement of phosphatidylinositol3 kinase for epithelial cell migration activated by human macrophage stimulating protein. Oncogene 13, 2167-2175 (1996).
99. Danilkovitch-Miagkova, A. et al. Oncogenic mutants of RON and MET receptor tyrosine kinases cause activation of the β-catenin pathway. Mol. Cell. Biol. 21, 5857-5868 (2001).
100. Park, J. S., Park, J. H., Khoi, P. N., Joo, Y. E. & Jung, Y. D. MSP-induced RON activation upregulates uPAR expression and cell invasiveness via MAPK, AP1 and NFκB signals in gastric cancer cells. Carcinogenesis 32, 175-181 (2011).
101. Danilkovitch, A., Donley, S., Skeel, A. & Leonard, E. J. Two independent signaling pathways mediate the antiapoptotic action of macrophage-stimulating protein on epithelial cells. Mol. Cell. Biol. 20, 2218-2227 (2000).
102. Santoro, M. M., Gaudino, G. & Marchisio, P. C. The MSP receptor regulates α6β4 and α3β1 integrins via 1433 proteins in keratinocyte migration. Dev. Cell 5, 257-271.
103. Wang, M. H. et al. Macrophage-stimulating protein induces proliferation and migration of murine keratinocytes. Exp. Cell Res. 226, 39-46 (1996).
104. Ct, M., Miller, A. D. & Liu, S. L. Human RON receptor tyrosine kinase induces complete epithelial-tomesenchymal transition but causes cellular senescence. Biochem. Biophys. Res. Commun. 360, 219-225 (2007).
105. Yu, P. T. et al. The RON-receptor regulates pancreatic cancer cell migration through phosphorylation-dependent breakdown of the hemidesmosome. Int. J. Cancer 131, 1744-1754 (2012).
106. Li, B. Q. et al. Macrophage-stimulating protein activates Ras by both activation and translocation of SOS nucleotide exchange factor. Biochem. Biophys. Res. Commun. 216, 110-118 (1995).
107. Eyob, H. et al. Inhibition of Ron kinase blocks conversion of micrometastases to overt metastases by boosting anti-tumor immunity. Cancer Discov. 23 Apr 2013 (doi:10.1158/21598290.CD120480).
108. Birchmeier, C., Birchmeier, W., Gherardi, E. & Vande Woude, G. F. Met, metastasis, motility and more. Nature Rev. Mol. Cell. Biol. 4, 915-925 (2003).
109. Xu, X. M., Zhou, Y. Q. & Wang, M. H. Mechanisms of cytoplasmic β-catenin accumulation and its involvement in tumorigenic activities mediated by oncogenic splicing variant of the receptor originated from Nantes tyrosine kinase. J. Biol. Chem. 280, 25087-25094 (2005).
110. Zhou, Y. Q., Luo, Y. L., Zhou, Z. W., Yao, H. P. & Wang, M. H. βArrestin-1dependent activation of extracellular signal-regulated kinases in RON receptor-mediated tumorigenic activities in colon cancer cells. J. Cancer Mol. 5, 55-62 (2010).
111. Danilkovitch-Miagkova, A. et al. Integrin-mediated RON growth factor receptor phosphorylation requires tyrosine kinase activity of both the receptor and cSrc. J. Biol. Chem. 275, 14783-14786 (2000).
112. Penengo, L., Rubin, C., Yarden, Y. & Gaudino, G. cCbl is a critical modulator of the Ron tyrosine kinase receptor. Oncogene 22, 3669-3679 (2003).
113. Germano, S. et al. Geldanamycins trigger a novel Ron degradative pathway, hampering oncogenic signaling. J. Biol. Chem. 281, 21710-21719 (2006).
114. Santoro, M. M., Gaudino, G. & Villa-Moruzzi, E. Protein phosphatase 1 binds to phospho-Ser1394 of the macrophage-stimulating protein receptor. Biochem. J. 376, 587-594 (2003).
115. Ma, Q. et al. 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 10, 66-75 (2010).
116. Doehn, U. 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 35, 511-522 (2009).
117. Smolen, G. A. et al. A genome-wide RNAi screen identifies multiple RSK-dependent regulators of cell migration. Genes Dev. 24, 2654-2665 (2010).
118. Gurusamy, D. et al. Myeloid-specific expression of Ron receptor kinase promotes prostate tumor growth. Cancer Res. 73, 1752-1763 (2013).
119. Sharda, D. R. et al. Regulation of macrophage arginase expression and tumor growth by the Ron receptor tyrosine kinase. J. Immunol. 187, 2181-2192 (2011).
120. Follenzi, A. et al. Cross-talk between the proto-oncogenes Met and Ron. Oncogene 19, 3041-3049 (2000).
121. Benvenuti, S. et al. Ron kinase transphosphorylation sustains MET oncogene addiction. Cancer Res. 71, 1945-1955 (2011).
122. Peace, B. E., Hill, K. J., Degen, S. J. & Waltz, S. E. Cross-talk between the receptor tyrosine kinases Ron and epidermal growth factor receptor. Exp. Cell Res. 289, 317-225 (2003).
123. Thomas, C. Y. & Theodorescu, D. Collaboration of RON and epidermal growth factor receptor in human bladder carcinogenesis. J. Urol. 176, 1909-1910 (2006).
124. Liu, H. S. et al. An unusual function of RON receptor tyrosine kinase as a transcriptional regulator in cooperation with EGFR in human cancer cells. Carcinogenesis 31, 1456-1464 (2010).
125. Kobayashi, T. et al. Transactivation of RON receptor tyrosine kinase by interaction with PDGF receptor β during steady-state growth of human mesangial cells. Kidney Int. 75, 1173-1183 (2009).
126. Potratz, J. C. et al. Synthetic lethality screens reveal RPS6 and MST1R as modifiers of insulin-like growth factor1 receptor inhibitor activity in childhood sarcomas. Cancer Res. 70, 8770-8781 (2010).
127. Jaquish, D. V. et al. IGF1R signals through the RON receptor to mediate pancreatic cancer cell migration. Carcinogenesis 32, 1151-1156 (2011).
128. Persons, D. A. et al. Fv2 encodes a truncated form of the Stk receptor tyrosine kinase. Nature Genet. 23, 159-165 (1999).
129. 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. 75, 7893-7903 (2001).
130. Danilkovitch-Miagkova, A. 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 100, 4580-4585 (2003).
131. Varela, M., Chow, Y. H., Sturkie, C., Murcia, P. & Palmarini, M. Association of RON tyrosine kinase with the Jaagsiekte sheep retrovirus envelope glycoprotein. Virology 350, 347-357 (2006).
132. Chou, Y. C. et al. Requirement for LMP1induced RON receptor tyrosine kinase in Epstein-Barr virus-mediated Bcell proliferation. Blood 118, 1340-1349 (2011).
133. Wagh, P. K. et al. βCatenin is required for Ron receptor-induced mammary tumorigenesis. Oncogene 30, 3694-3704 (2011).
134. Wagh, P. K., Zinser, G. M., Gray, J. K., Shrestha, A. & Waltz, S. E. Conditional deletion of βcatenin in mammary epithelial cells of Ron receptor, Mst1r, overexpressing mice alters mammary tumorigenesis. Endocrinology 153, 2735-2746 (2012).
135. Peace, B. E., Toney-Earley, K., Collins, M. H. & Waltz, S. E. Ron receptor signaling augments mammary tumor formation and metastasis in a murine model of breast cancer. Cancer Res. 65, 1285-1293 (2005).
136. He, S. et al. Activation of the Nterminally truncated form of the Stk receptor tyrosine kinase SfStk by Friend virus-encoded gp55 is mediated by cysteine residues in the ecotropic domain of gp55 and the extracellular domain of SfStk. J. Virol. 84, 2223-2235 (2010).
137. Xu, X. M., Wang, D., Shen, Q., Chen, Y. Q. & Wang, M. H. RNA-mediated gene silencing of the RON receptor tyrosine kinase alters oncogenic phenotypes of human colorectal carcinoma cells. Oncogene 23, 8464-8474 (2004).
138. Zou, H. Y. et al. Sensitivity of selected human tumor models to PF04217903, a novel selective cMet kinase inhibitor. Mol. Cancer Ther. 11, 1036-1047 (2012).
139. Christensen, J. G. et al. A selective small molecule inhibitor of cMet kinase inhibits cMet-dependent phenotypes in vitro and exhibits cytoreductive antitumor activity in vivo. Cancer Res. 63, 7345-7355 (2003).
140. Yao, H. P. et al. Oncogenic variant RON160 expression in breast cancer and its potential as a therapeutic target by small molecule tyrosine kinase inhibitor. Curr. Cancer Drug Target 17 Apr 2013 [epub ahead of print].
141. Zhang, Y. et al. Identification of a novel recepteur d'origine nantais/cmet small-molecule kinase inhibitor with antitumor activity in vivo. Cancer Res. 68, 6680-6687 (2008).
142. Schroeder, G. M. et al. Discovery of N-(4-(2amino3chloropyridin-4yloxy)- 3fluorophenyl)-4ethoxy1-(4fluorophenyl)-2oxo1,2dihydropyridine-3carboxamide (BMS777607), a selective and orally efficacious inhibitor of the Met kinase superfamily. J. Med. Chem. 52, 1251-1254 (2009).
143. Sharma, S. et al. Small molecule inhibitor BMS777607 induces breast cancer cell polyploidy with increased resistance to cytotoxic chemotherapy agents. Mol. Cancer Ther. 12, 725-736 (2013).
144. O'Toole, J. M. et al. Therapeutic implications of a human neutralizing antibody to the macrophage-stimulating protein receptor tyrosine kinase (RON), a cMET family member. Cancer Res. 66, 9162-9170 (2006).
145. Yao, H. P. 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 10, 82-91 (2011).
146. Lee, W. Y. et al. Prognostic significance of coexpression of RON and MET receptors in node-negative breast cancer patients. Clin. Cancer Res. 11, 2222-2228 (2005).
147. Cheng, H. L. et al. Coexpression of RON and MET is a prognostic indicator for patients with transitional-cell carcinoma of the bladder. Br. J. Cancer. 92, 1906-1914 (2005).
148. Compat, E. et al. Prognostic value of MET, RON and histoprognostic factors for urothelial carcinoma in the upper urinary tract. J. Urol. 179, 868-872 (2008).
149. Lee, C. T. et al. The prognostic significance of RON and MET receptor coexpression in patients with colorectal cancer. Dis. Colon Rectum. 51, 1268-1274 (2008).
150. Ferrandina, G. et al. Prognostic role of the recepteur d'origine nantais (RON) expression in ovarian cancer patients. Gynecol. Oncol. 111, 237-243 (2008).
151. Zhou, D. et al. Expression of the RON receptor tyrosine kinase and its association with gastric carcinoma versus normal gastric tissues. BMC Cancer 8, 353-359 (2008).
152. Tactacan, C. M. et al. RON is not a prognostic marker for resectable pancreatic cancer. BMC Cancer 12, 395-403 (2012).
153. Schmidt, L. et al. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nature Genet. 16, 68-73 (1997).
154. Ma, P. C. et al. Expression and mutational analysis of MET in human solid cancers. Genes Chromosomes Cancer 47, 1025-1037 (2008).
155. Hui, M. K. et al. Prognostic significance of phosphorylated RON in esophageal squamous cell carcinoma. Med. Oncol. 29, 1699-1706 (2012).
156. Yoon, T. M. et al. Expression of the receptor tyrosine kinase recepteur d'origine nantais and its association with tumor progression in hypopharyngeal cancer. Head Neck 6 Aug 2013 (doi:10.1002/hed.23090).
157. Li, Z. et al. Monoclonal antibody (mAb)-induced down-regulation of RON receptor tyrosine kinase diminishes tumorigenic activities of colon cancer cells. Int. J. Oncol. 37, 473-482 (2010).
158. Gunes, Z. et al. Isolation of fully human antagonistic RON Antibodies showing efficient block of downstream signaling and cell migration. Transl. Oncol. 4, 38-46 (2011).
159. Guin, S., Yao, H. P. & Wang, M. H. RON receptor tyrosine kinase as a target for delivery of chemodrugs by antibody directed pathway for cancer cell cytotoxicity. Mol. Pharmaceutics. 7, 386-397 (2010).
160. Guin, S. et al. Targeting acute hypoxic cancer cells by doxorubicin-immunoliposomes directed by monoclonal antibodies specific to RON receptor tyrosine kinase. Cancer Chemother. Pharmacol. 67, 1073-1083 (2011).
161. Padhye, S. S. et al. Sustained expression of the RON receptor tyrosine kinase by pancreatic cancer stem cells as a potential targeting moiety for antibody-directed chemotherapeutics. Mol. Pharm. 8, 2310-2319 (2011).
162. Sievers, E. L. & Senter, P. D. Antibody-drug conjugates in cancer therapy. Annu. Rev. Med. 64, 15-29 (2013).
163. Verma, S. et al. EMILIA Study Group. Trastuzumab emtansine for HER2positive advanced breast cancer. N. Engl. J. Med. 367, 1783-1791 (2012).
164. Katz, J., Janik, J. E. & Younes, A. Brentuximab Vedotin (SGN35). Clin. Cancer Res. 17, 6428-6436 (2011).
165. Moldenhauer, G. et al. Therapeutic potential of amanitin-conjugated anti-epithelial cell adhesion molecule monoclonal antibody against pancreatic carcinoma. J. Natl Cancer Inst. 104, 622-634 (2012).
166. Narasimhan, M. & Ammanamanchi, S. Curcumin blocks RON tyrosine kinase-mediated invasion of breast carcinoma cells. Cancer Res. 68, 5185-5192 (2008).
167. Ni, S., Zhao, C., Feng, G. S., Paulson, R. F. & Correll, P. H. A novel Stat3 binding motif in Gab2 mediates transformation of primary hematopoietic cells by the Stk/Ron receptor tyrosine kinase in response to Friend virus infection. Mol. Cell. Biol. 27, 3708-3715 (2007).
168. Umehara, D. et al. Role of phosphatidylinositol 3kinase in friend spleen focus-forming virus-induced erythroid disease. J. Virol. 84, 7675-7682 (2010).
169. Choueiri, T. K. et al. Phase II and biomarker study of the dual MET/VEGFR2 inhibitor foretinib in patients with papillary renal cell carcinoma. J. Clin. Oncol. 31, 181-186 (2013).
170. Qian, F. et al. Inhibition of tumor cell growth, invasion, and metastasis by EXEL2880 (XL880, GSK1363089), a novel inhibitor of HGF and VEGF receptor
171. Eder, J. P. et al. A phase I study of foretinib, a multi-targeted inhibitor of cMet and vascular endothelial growth factor receptor 2. Clin. Cancer Res. 16, 3507-3516 (2010).
172. Belalcazar, A., Aza, D., Perez, C. A., Raez, L. E. & Santos, E. S. Targeting the Met pathway in lung cancer. Expert Rev. Anticancer Ther. 12, 519-528 (2012).
173. Katz, J. D. et al. Discovery of a 5Hbenzo[4,5]cyclohepta[1,2b]pyridin- 5one (MK2461) inhibitor of cMet kinase for the treatment of cancer. J. Med. Chem. 54, 4092-4108 (2011).
174. Pan, B. S. et al. MK2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated cMet receptor. Cancer Res. 70, 1524-1533 (2010).
175. Northrup, A. B. et al. Discovery of 1-[3-(1Methyl-1Hpyrazol-4yl)- 5oxo5Hbenzo [4,5]cyclohepta[1,2b]pyridin-7yl]-N-(pyridin-2ylmethyl)methanesul- fonamide (MK8033): A specific cMet/Ron dual kinase inhibitor with preferential affinity for the activated state of cMet. J. Med. Chem. 56, 2294-2310 (2013).