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The RON receptor tyrosine kinase promotes MSP-independent cell spreading and survival in breast epithelial cells

Oncogene volume 28, pages 279–288 (2009)Cite this article

Abstract

The recepteur d'origine nantais (RON) is a receptor tyrosine kinase (RTK) in the scatter factor family, which includes the c-Met receptor. RON exhibits increased expression in a significant number of human breast cancer tissues as well as in many established breast cancer cell lines. Recent studies have indicated that in addition to ligand-dependent signaling events, RON also promotes signals in the absence of its only known ligand, MSP, when expressed in epithelial cells. In this study, we found that when expressed in MCF-10A breast epithelial cells, RON exhibits both MSP-dependent and MSP-independent signaling, which lead to distinct biological outcomes. In the absence of MSP, RON signaling promotes cell survival, increased cell spreading and enhanced migration in response to other growth factors. However, both RON-mediated proliferation and migration require the addition of MSP in MCF-10A cells. Both MSP-dependent and MSP-independent signaling by RON are mediated in part by Src family kinases. These data suggest that RON has two alternative modes of signaling that can contribute to oncogenic behavior in normal breast epithelial cells.

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Abbreviations

EGF:

epidermal growth factor

HGF:

hepatocyte growth factor

MAPK:

mitogen-activated protein kinase

MSP:

macrophage-stimulating protein

References

  • Bezerra JA, Carrick TL, Degen JL, Witte D, Degen SJ . (1998). Biological effects of targeted inactivation of hepatocyte growth factor-like protein in mice. J Clin Invest 101: 1175–1183.

    Article  CAS  Google Scholar 

  • Biscardi JS, Ishizawar RC, Silva CM, Parsons SJ . (2000). Tyrosine kinase signalling in breast cancer: epidermal growth factor receptor and c-Src interactions in breast cancer. Breast Cancer Res 2: 203–210.

    Article  CAS  Google Scholar 

  • Chen YQ, Zhou YQ, Angeloni D, Kurtz AL, Qiang XZ, Wang MH . (2000). Overexpression and activation of the RON receptor tyrosine kinase in a panel of human colorectal carcinoma cell lines. Exp Cell Res 261: 229–238.

    Article  CAS  Google Scholar 

  • Cote M, Miller AD, Liu SL . (2007). Human RON receptor tyrosine kinase induces complete epithelial-to-mesenchymal transition but causes cellular senescence. Biochem Biophys Res Commun 360: 219–225.

    Article  CAS  Google Scholar 

  • Danilkovitch-Miagkova A . (2003). Oncogenic signaling pathways activated by RON receptor tyrosine kinase. Curr Cancer Drug Targets 3: 31–40.

    Article  CAS  Google Scholar 

  • Danilkovitch-Miagkova A, Angeloni D, Skeel A, Donley S, Lerman M, Leonard EJ . (2000). Integrin-mediated RON growth factor receptor phosphorylation requires tyrosine kinase activity of both the receptor and c-Src. J Biol Chem 275: 14783–14786.

    Article  CAS  Google Scholar 

  • Danilkovitch A, Donley S, Skeel A, Leonard EJ . (2000). Two independent signaling pathways mediate the antiapoptotic action of macrophage-stimulating protein on epithelial cells. Mol Cell Biol 20: 2218–2227.

    Article  CAS  Google Scholar 

  • Debnath J, Muthuswamy SK, Brugge JS . (2003). Morphogenesis and oncogenesis of MCF-10A mammary epithelial acini grown in three-dimensional basement membrane cultures. Methods 30: 256–268.

    Article  CAS  Google Scholar 

  • Emaduddin M, Bicknell DC, Bodmer WF, Feller SM . (2008). Cell growth, global phosphotyrosine elevation, and c-Met phosphorylation through Src family kinases in colorectal cancer cells. Proc Natl Acad Sci USA 105: 2358–2362.

    Article  CAS  Google Scholar 

  • Hofmann C, Obermeier F, Artinger M, Hausmann M, Falk W, Schoelmerich J et al. (2007). Cell-cell contacts prevent anoikis in primary human colonic epithelial cells. Gastroenterology 132: 587–600.

    Article  CAS  Google Scholar 

  • Hsu PY, Liu HS, Cheng HL, Tzai TS, Guo HR, Ho CL et al. (2006). Collaboration of RON and epidermal growth factor receptor in human bladder carcinogenesis. J Urol 176: 2262–2267.

    Article  CAS  Google Scholar 

  • Ishizawar R, Parsons SJ . (2004). c-Src and cooperating partners in human cancer. Cancer Cell 6: 209–214.

    Article  CAS  Google Scholar 

  • Ishizawar RC, Tice DA, Karaoli T, Parsons SJ . (2004). The C terminus of c-Src inhibits breast tumor cell growth by a kinase-independent mechanism. J Biol Chem 279: 23773–23781.

    Article  CAS  Google Scholar 

  • Kang HG, Jenabi JM, Zhang J, Keshelava N, Shimada H, May WA et al. (2007). E-cadherin cell-cell adhesion in ewing tumor cells mediates suppression of anoikis through activation of the ErbB4 tyrosine kinase. Cancer Res 67: 3094–3105.

    Article  CAS  Google Scholar 

  • Lee WY, Chen HH, Chow NH, Su WC, Lin PW, Guo HR . (2005). Prognostic significance of co-expression of RON and MET receptors in node-negative breast cancer patients. Clin Cancer Res 11: 2222–2228.

    Article  CAS  Google Scholar 

  • Maggiora P, Marchio S, Stella MC, Giai M, Belfiore A, De Bortoli M et al. (1998). Overexpression of the RON gene in human breast carcinoma. Oncogene 16: 2927–2933.

    Article  CAS  Google Scholar 

  • Mehlen P, Puisieux A . (2006). Metastasis: a question of life or death. Nat Rev Cancer 6: 449–458.

    Article  CAS  Google Scholar 

  • Montesano R, Soriano JV, Malinda KM, Ponce ML, Bafico A, Kleinman HK et al. (1998). Differential effects of hepatocyte growth factor isoforms on epithelial and endothelial tubulogenesis. Cell Growth Differ 9: 355–365.

    CAS  PubMed  Google Scholar 

  • Moro L, Dolce L, Cabodi S, Bergatto E, Boeri Erba E, Smeriglio M et al. (2002). Integrin-induced epidermal growth factor (EGF) receptor activation requires c-Src and p130Cas and leads to phosphorylation of specific EGF receptor tyrosines. J Biol Chem 277: 9405–9414.

    Article  CAS  Google Scholar 

  • Muller EJ, Williamson L, Kolly C, Suter MM . (2008). Outside-in signaling through integrins and cadherins: a central mechanism to control epidermal growth and differentiation? J Invest Dermatol 128: 501–516.

    Article  CAS  Google Scholar 

  • Muraoka RS, Waltz SE, Degen SJ . (1999). Expression of hepatocyte growth factor-like protein is repressed by retinoic acid and enhanced by cyclic adenosine 3′,5′-monophosphate response element-binding protein (CREB)-binding protein (CBP). Endocrinology 140: 187–196.

    Article  CAS  Google Scholar 

  • Muthuswamy SK, Li D, Lelievre S, Bissell MJ, Brugge JS . (2001). ErbB2, but not ErbB1, reinitiates proliferation and induces luminal repopulation in epithelial acini. Nat Cell Biol 3: 785–792.

    Article  CAS  Google Scholar 

  • O’Toole JM, Rabenau KE, Burns K, Lu D, Mangalampalli V, Balderes P et al. (2006). Therapeutic implications of a human neutralizing antibody to the macrophage-stimulating protein receptor tyrosine kinase (RON), a c-MET family member. Cancer Res 66: 9162–9170.

    Article  Google Scholar 

  • Ottenhoff-Kalff AE, Rijksen G, van Beurden EA, Hennipman A, Michels AA, Staal GE . (1992). Characterization of protein tyrosine kinases from human breast cancer: involvement of the c-src oncogene product. Cancer Res 52: 4773–4778.

    CAS  PubMed  Google Scholar 

  • Petrenko O, Beavis A, Klaine M, Kittappa R, Godin I, Lemischka IR . (1999). The molecular characterization of the fetal stem cell marker AA4. Immunity 10: 691–700.

    Article  CAS  Google Scholar 

  • Riggins RB, Thomas KS, Ta HQ, Wen J, Davis RJ, Schuh NR et al. (2006). Physical and functional interactions between Cas and c-Src induce tamoxifen resistance of breast cancer cells through pathways involving epidermal growth factor receptor and signal transducer and activator of transcription 5b. Cancer Res 66: 7007–7015.

    Article  CAS  Google Scholar 

  • Ronsin C, Muscatelli F, Mattei MG, Breathnach R . (1993). A novel putative receptor protein tyrosine kinase of the met family. Oncogene 8: 1195–1202.

    CAS  Google Scholar 

  • Santoro MM, Gaudino G, Marchisio PC . (2003). The MSP receptor regulates alpha6beta4 and alpha3beta1 integrins via 14-3-3 proteins in keratinocyte migration. Dev Cell 5: 257–271.

    Article  CAS  Google Scholar 

  • Stahl S, Weitzman S, Jones JC . (1997). The role of laminin-5 and its receptors in mammary epithelial cell branching morphogenesis. J Cell Sci 110 (Pt 1): 55–63.

    CAS  PubMed  Google Scholar 

  • Stommel JM, Kimmelman AC, Ying H, Nabioullin R, Ponugoti AH, Wiedemeyer R et al. (2007). Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science 318: 287–290.

    Article  CAS  Google Scholar 

  • Tagliaferri P, Tassone P, Blotta S, Viscomi C, Grillone F, Budillon A et al. (2005). Antitumor therapeutic strategies based on the targeting of epidermal growth factor-induced survival pathways. Curr Drug Targets 6: 289–300.

    Article  CAS  Google Scholar 

  • Thomas RM, Toney K, Fenoglio-Preiser C, Revelo-Penafiel MP, Hingorani SR, Tuveson DA et al. (2007). 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.

    Article  CAS  Google Scholar 

  • Tice DA, Biscardi JS, Nickles AL, Parsons SJ . (1999). Mechanism of biological synergy between cellular Src and epidermal growth factor receptor. Proc Natl Acad Sci USA 96: 1415–1420.

    Article  CAS  Google Scholar 

  • Van Slambrouck S, Grijelmo C, De Wever O, Bruyneel E, Emami S, Gespach C et al. (2007). Activation of the FAK-src molecular scaffolds and p130Cas-JNK signaling cascades by alpha1-integrins during colon cancer cell invasion. Int J Oncol 31: 1501–1508.

    CAS  PubMed  Google Scholar 

  • Wang D, Shen Q, Chen YQ, Wang MH . (2004). 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 23: 1668–1680.

    Article  CAS  Google Scholar 

  • Wang MH, Wang D, Chen YQ . (2003). Oncogenic and invasive potentials of human macrophage-stimulating protein receptor, the RON receptor tyrosine kinase. Carcinogenesis 24: 1291–1300.

    Article  CAS  Google Scholar 

  • Wang R, Ferrell LD, Faouzi S, Maher JJ, Bishop JM . (2001). Activation of the Met receptor by cell attachment induces and sustains hepatocellular carcinomas in transgenic mice. J Cell Biol 153: 1023–1034.

    Article  CAS  Google Scholar 

  • Wang R, Kobayashi R, Bishop JM . (1996). Cellular adherence elicits ligand-independent activation of the Met cell-surface receptor. Proc Natl Acad Sci USA 93: 8425–8430.

    Article  CAS  Google Scholar 

  • Wei X, Ni S, Correll PH . (2005). Uncoupling ligand-dependent and -independent mechanisms for mitogen-activated protein kinase activation by the murine Ron receptor tyrosine kinase. J Biol Chem 280: 35098–35107.

    Article  CAS  Google Scholar 

  • Weiss FU, Daub H, Ullrich A . (1997). Novel mechanisms of RTK signal generation. Curr Opin Genet Dev 7: 80–86.

    Article  CAS  Google Scholar 

  • Welm AL, Sneddon JB, Taylor C, Nuyten DS, van de Vijver MJ, Hasegawa BH et al. (2007). 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.

    Article  CAS  Google Scholar 

  • Wilson LK, Luttrell DK, Parsons JT, Parsons SJ . (1989). pp60c-src tyrosine kinase, myristylation, and modulatory domains are required for enhanced mitogenic responsiveness to epidermal growth factor seen in cells overexpressing c-src. Mol Cell Biol 9: 1536–1544.

    Article  CAS  Google Scholar 

  • Wu W, Graves LM, Gill GN, Parsons SJ, Samet JM . (2002). Src-dependent phosphorylation of the epidermal growth factor receptor on tyrosine 845 is required for zinc-induced Ras activation. J Biol Chem 277: 24252–24257.

    Article  CAS  Google Scholar 

  • Yamaguchi H, Wyckoff J, Condeelis J . (2005). Cell migration in tumors. Curr Opin Cell Biol 17: 559–564.

    Article  CAS  Google Scholar 

  • Yamamoto N, Mammadova G, Song RX, Fukami Y, Sato K . (2006). Tyrosine phosphorylation of p145met mediated by EGFR and Src is required for serum-independent survival of human bladder carcinoma cells. J Cell Sci 119: 4623–4633.

    Article  CAS  Google Scholar 

  • Yokoyama N, Ischenko I, Hayman MJ, Miller WT . (2005). The C terminus of RON tyrosine kinase plays an autoinhibitory role. J Biol Chem 280: 8893–8900.

    Article  CAS  Google Scholar 

  • Zalcenstein A, Weisz L, Stambolsky P, Bar J, Rotter V, Oren M . (2006). Repression of the MSP/MST-1 gene contributes to the antiapoptotic gain of function of mutant p53. Oncogene 25: 359–369.

    Article  CAS  Google Scholar 

  • Zinser GM, Leonis MA, Toney K, Pathrose P, Thobe M, Kader SA et al. (2006). Mammary-specific Ron receptor overexpression induces highly metastatic mammary tumors associated with beta-catenin activation. Cancer Res 66: 11967–11974.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Roger Daly and Joan S. Brugge for providing the MCF-10A/ecoR cell line, James Keller for RT–PCR assistance, Dr W Todd Miller for the DN-Src construct, Kyeisha Hodge for generating the K114M mutant and Dr Edward Chan for various reagents used throughout this study. We also thank members of our laboratory plus Dr Mina Bissell for helpful discussions. The studies were funded by NCI grant CA28146, the Walk for Beauty Foundation and Long Island League to Abolish Cancer (LILAC) to MJH. KJF was supported by NIH T32-CA009176.

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  1. Department of Molecular Genetics & Microbiology, Stony Brook University, Stony Brook, NY, USA

    K J Feres, I Ischenko & M J Hayman

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  1. K J Feres
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Correspondence to M J Hayman.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Feres, K., Ischenko, I. & Hayman, M. The RON receptor tyrosine kinase promotes MSP-independent cell spreading and survival in breast epithelial cells. Oncogene 28, 279–288 (2009). https://doi.org/10.1038/onc.2008.383

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