Abstract
The receptor tyrosine kinase Ron is a member of the receptor family that includes the proto-oncogene Met and the avian oncogene Sea. The interaction of Ron with its ligand, known as hepatocyte growth factor-like protein (HGFL) or macrophage stimulating protein (MSP), induces crucial cellular responses including invasive growth, proliferation, cell scattering, and branching morphogenesis. Based on the homology and functional similarities between Met and Ron it was hypothesized that Ron may be important in tumor formation and metastasis. To test this hypothesis, wild-type mouse Ron and three mutant forms of Ron containing mutations similar to those found in the Met gene in human hereditary papillary renal carcinoma (HPRC), were expressed in NIH3T3 cells. A transformed phenotype was produced in cell lines expressing either wild-type Ron or the mutated Ron proteins. Further, these cell lines displayed oncogenic potential by exhibiting increased proliferation and constitutive phosphorylation of Ron. These cell lines were also tested for the ability to form solid tumors. Cells expressing wild-type Ron and the three proteins with single amino acid substitutions were highly tumorigenic in vivo. In a model of experimental metastasis, two of the cell lines with altered Ron protein formed highly aggressive tumors in the lungs. These results suggest that Ron may be an aggressive oncogene when either overexpressed or when activated by mutation.
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References
Bezerra JA, Han S, Danton MJ, Degen SJ . 1993a Protein Sci. 2: 666–668
Bezerra JA, Witte DP, Aronow BJ, Degen SJ . 1993b Hepatology 18: 394–399
Carlson KM, Dou S, Chi D, Scavarda N, Toshima K, Jackson CE, Wells Jr SA, Goodfellow PJ, Donis-Keller H . 1994 Proc. Natl. Acad. Sci. USA 91: 1579–1583
Chen Q, Seol DW, Carr B, Zarnegar R . 1997 Hepatology 26: 59–66
Chen YQ, Fisher JH, Wang MH . 1998 J. Immunol. 161: 4950–4959
Cirafici AM, Salvatore G, De Vita G, Carlomagno F, Dathan NA, Visconti R, Melillo RM, Fusco A, Santoro M . 1997 Endocrinology 138: 1450–1455
Collesi C, Santoro MM, Gaudino G, Comoglio PM . 1996 Mol. Cell. Biol. 16: 5518–5526
Di Renzo MF, Olivero M, Martone T, Maffe A, Maggiora P, Stefani AD, Valente G, Giordano S, Cortesina G, Comoglio PM . 2000 Oncogene 19: 1547–1555
Follenzi A, Bakovic S, Gual P, Stella MC, Longati P, Comoglio PM . 2000 Oncogene 19: 3041–3049
Gaudino G, Avantaggiato V, Follenzi A, Acampora D, Simeone A, Comoglio PM . 1995 Oncogene 11: 2627–2637
Gaudino G, Follenzi A, Naldini L, Collesi C, Santoro M, Gallo KA, Godowski PJ, Comoglio PM . 1994 EMBO J. 13: 3524–3532
Geran RI, Greenberg NH, MacDonald MM, Schumacher AM, Abbot BJ . 1972 Cancer Chemother. Rep. 3: 1–16
Han S, Stuart LA, Degen SJF . 1991 Biochemistry 30: 9768–9780
Hanks SK, Quinn AM, Hunter T . 1988 Science 241: 42–52
Ho SN, Hunt HD, Horton RM, Pullen JK, Pease LR . 1989 Gene. 77: 51–59
Hofstra RM, Landsvater RM, Ceccherini I, Stulp RP, Stelwagen T, Luo Y, Pasini B, Hoppener JW, van Amstel HK, Romeo G, Lips CJM, Buys CH . 1994 Nature 367: 375–376
Iwama A, Okano K, Sudo T, Matsuda Y, Suda T . 1994 Blood 83: 3160–3169
Jeffers M, Schmidt L, Nakaigawa N, Webb CP, Weirich G, Kishida T, Zbar B, Vande Woude GF . 1997 Proc. Natl. Acad. Sci. USA. 94: 11445–11450
Kitayama H, Kanakura Y, Furitsu T, Tsujimura T, Oritani K, Ikeda H, Sugahara H, Mitsui H, Kanayama Y, Kitamura Y, Matsuzawa Y . 1995 Blood 85: 790–798
Kurihara N, Iwama A, Tatsumi J, Ikeda K, Suda T . 1996 Blood 87: 3704–3710
Longati P, Bardelli A, Ponzetto C, Naldini L, Comoglio PM . 1994 Oncogene 9: 49–57
Longley BJ, Tyrrell L, Lu SZ, Ma YS, Langley K, Ding TG, Duffy T, Jacobs P, Tang LH, Modlin I . 1996 Nat. Genet. 12: 312–314
Maggiora P, Marchio S, Stella MC, Giai M, Belfiore A, De Bortoli M, Di Renzo MF, Costantino A, Sismondi P, Comoglio PM . 1998 Oncogene 16: 2927–2933
Mera A, Suga M, Ando M, Suda T, Yamaguchi N . 1999 J. Biol. Chem. 274: 15766–15774
Nagata H, Worobec AS, Oh CK, Chowdhury BA, Tannenbaum S, Suzuki Y, Metcalfe DD . 1995 Proc. Natl. Acad. Sci. USA 92: 10560–10564
Okino T, Egami H, Ohmachi H, Takai E, Tamori Y, Nakagawa K, Nakano S, Akagi J, Sakamoto O, Suda T, Ogawa M . 1999 Int. J. Oncol. 15: 709–714
Persons DA, Paulson RF, Loyd MR, Herley MT, Bodner SM, Bernstein A, Correll PH, Ney PA . 1999 Nat. Genet. 23: 159–165
Piao X, Bernstein A . 1996 Blood 87: 3117–3123
Piao X, Paulson R, van der Geer P, Pawson T, Bernstein A . 1996 Proc. Natl. Acad. Sci. USA. 93: 14665–14669
Quantin B, Schuhbaur B, Gesnel MC, Doll'e P, Breathnach R . 1995 Dev. Dyn. 204: 383–390
Rong S, Bodescot M, Blair D, Dunn J, Nakamura T, Mizuno K, Park M, Chan A, Aaronson S, Vande Woude GF . 1992 Mol. Cell. Biol. 12: 5152–5158
Ronsin C, Muscatelli F, Mattei MG, Breathnach R . 1993 Oncogene 8: 1195–1202
Santoro M, Carlomagno F, Romano A, Bottaro DP, Dathan NA, Grieco M, Fusco A, Vecchio G, Matoskova B, Kraus MH, DiFiore PP . 1995 Science 267: 381–383
Santoro MM, Penengo L, Minetto M, Orecchia S, Cilli M, Gaudino G . 1998 Oncogene 17: 741–749
Schmidt L, Duh FM, Chen F, Kishida T, Glenn G, Choyke P, Scherer SW, Zhuang Z, Lubensky I, Dean M, Allikmets R, Chidambaram A, Bergerheim UR, Feltis JT, Casadevall C, Zamarron A, Bernues M, Richard S, Lips CJ, Walther MM, Tsui LC, Geil L, Orcutt ML, Stackhouse T, Lipan J, Slife L, Brauch H, Decker J, Niehans G, Hughson MD, Moch H, Storkel S, Lerman MI, Livehan WM, Zbar B . 1997 Nat. Genet. 16: 68–73
Waltz SE, Gould FK, Air EL, McDowell SA, Degen SJ . 1996 J. Biol. Chem. 271: 9024–9032
Waltz SE, McDowell SA, Muraoka RS, Air EL, Flick LM, Chen YQ, Wang MH, Degen SJ . 1997 J. Biol. Chem. 272: 30526–30537
Waltz SE, Toms CL, McDowell SA, Clay LA, Muraoka RS, Air EL, Sun WY, Thomas MB, Degen SJ . 1998 Oncogene 16: 27–42
Wang MH, Cox GW, Yoshimura T, Sheffler LA, Skeel A, Leonard EJ . 1994 J. Biol. Chem. 269: 14027–14031
Wang MH, Dlugosz AA, Sun Y, Suda T, Skeel A, Leonard EJ . 1996a Exp. Cell Res. 226: 39–46
Wang MH, Iwama A, Skeel A, Suda T, Leonard EJ . 1995 Proc. Natl. Acad. Sci. USA 92: 3933–3937
Wang MH, Montero-Julian FA, Dauny I, Leonard EJ . 1996b Oncogene 13: 2167–2175
Willett CG, Wang MH, Emanuel RL, Graham SA, Smith DI, Shridhar V, Sugarbaker DJ, Sunday ME . 1998 Am. J. Respir. Cell Mol. Biol. 18: 489–496
Williams TA, Longati P, Pugliese L, Gual P, Bardelli A, Michieli P . 1999 J. Cell. Physiol. 181: 507–514
Yoshimura T, Yuhki N, Wang MH, Skeel A, Leonard EJ . 1993 J. Biol. Chem. 268: 15461–15468
Acknowledgements
The authors wish to acknowledge Kenya Toney-Earley, Kara Hill, and Dr Joseph Palumbo for their helpful contributions to this work. This work was supported in part by Public Health Service Grants HD-36888 (SE Waltz), DK-47003 (SJF Degen) and DK-58182 (SJF Degen) from the N.I.H., Training Grant T-32-HL07752 (BE Peace) from the N.I.H., and a Board of Trustees grant from the Children's Hospital Research Foundation (SE Waltz).
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Peace, B., Hughes, M., Degen, S. et al. Point mutations and overexpression of Ron induce transformation, tumor formation, and metastasis. Oncogene 20, 6142–6151 (2001). https://doi.org/10.1038/sj.onc.1204836
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DOI: https://doi.org/10.1038/sj.onc.1204836
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