Advertisement

RON Receptor Tyrosine Kinase in Pancreatic Cancer Progression

  • Tapan K. Barik
  • Surya N. Swain
Chapter

Abstract

The receptor d’origine nantais (RON) is a tyrosine kinase (TK) receptor, an oncogene expressed on several tissue occupant macrophage populations. Overexpression as well as constitutive actuation of RON receptor TK has been identified in a variety of tumors including pancreatic cancer, leading to tumor progression. RON is among the two individuals that belongs to MET receptor tyrosine kinase family, along with parent receptor MET. In pancreatic cells, RON is an essential K-Ras effector, and its biological response is intervened by authoritative of its ligand, macrophage-stimulating protein/hepatocyte growth factor-like protein. Under physiological conditions, ligand-mediated receptor activation and its stimulation through its receptor-binding sites are the significant reasons for RON activation. Various oncogenic signaling pathways involved in cell growth, migration, apoptosis, and survival were instigated by activated RON. However, in pancreatic cancer, overexpression and mutations, generations of splicing variants, and, seldom amplified gene copy numbers are responsible for RON activation. The pathobiological noteworthiness of RON overexpression in pancreatic cancer presently cannot seem to be fully elucidated. This chapter explains the contemporary state of information about RON biology in relation to pancreatic cancer and also reviews its probable role as a therapeutic target.

Keywords

Pancreatic cancer Tyrosine kinases Receptor d’origine nantais Progression 

References

  1. 1.
    Ahnfelt-Ronne J, Hald J, Bodker A, Yassin H, Serup P, HecksherSorensen J (2007) Preservation of proliferating pancreatic progenitor cells by Delta-Notch signaling in the embryonic chicken pancreas. BMC Dev Biol 7:63CrossRefGoogle Scholar
  2. 2.
    Angeloni D, Danilkovitch-Miagkova A, Ivanov SV, Breathnach R, Johnson BE, Leonard EJ et al (2000) Gene structure of the human receptor tyrosine kinase RON and mutation analysis in lung cancer samples. Genes Chromosom Cancer 29:147–156CrossRefGoogle Scholar
  3. 3.
    Angeloni D, Danilkovitch-Miagkova A, Miagkov A, Leonard EJ, Lerman MI (2004) The soluble sema domain of the RON receptor inhibits macrophage-stimulating protein-induced receptor activation. J Biol Chem 279:3726–3732CrossRefGoogle Scholar
  4. 4.
    Bassett DI (2003) Identification and developmental expression of a macrophage stimulating 1/hepatocyte growth factor-like 1 orthologue in the zebrafish. Dev Genes Evol 213:360–362CrossRefGoogle Scholar
  5. 5.
    Bramhall SR, Neoptolemos JP, Stamp GWH, Lemoine NR (1997) Imbalance of expression of matrix metalloproteinases (MMPS) and tissue inhibitors of the matrix metalloproteinases (TIMPs) in human pancreatic carcinoma. J Pathol 182:347–355CrossRefGoogle Scholar
  6. 6.
    Camp ER, Liu W, Fan F, Yang A, Somcio R, Ellis LM (2005) RON a tyrosine kinase receptor involved in tumor progression and metastasis. Ann Surg Oncol 12:273–281CrossRefGoogle Scholar
  7. 7.
    Chen YQ, Zhou YQ, Angeloni-Andreazzoli D, Kurtz AL, Qiang XZ, Wang MH (2000) Overexpression and activation of the RON receptor tyrosine kinase in a panel of human colorectal carcinoma cells lines. Exp Cell Res 261:229–238CrossRefGoogle Scholar
  8. 8.
    Correll PH, Iwama A, Tondat S, Mayrhofer G, Suda T, Bernstein A (1997) Deregulated inflammatory response in mice lacking the STK/RON receptor tyrosine kinase. Genes Funct 1:69–83CrossRefGoogle Scholar
  9. 9.
    Danilkovitch A, Miller M, Leonard EJ (1999a) Interaction of macrophage-stimulating protein with its receptor. Residues critical for beta chain binding and evidence for independent alpha chain binding. J Biol Chem 274:29937–29934CrossRefGoogle Scholar
  10. 10.
    Danilkovitch A, Skeel A, Leonard EJ (1999b) Macrophage stimulating protein-induced epithelial cell adhesion is mediated by a PI3-K-dependent, but FAK-independent mechanism. Exp Cell Res 248:575–582CrossRefGoogle Scholar
  11. 11.
    Danilkovitch A, Leonard EJ (1999) Kinases involved in MSP/RON signaling. J Leukoc Biol 65:345–348CrossRefGoogle Scholar
  12. 12.
    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 275:14783–14786CrossRefGoogle Scholar
  13. 13.
    Danilkovitch-Miagkova A, Miagkov A, Skeel A, Nakaigawa N, Zbar B, Leonard EJ (2001) Oncogenic mutants of RON and MET receptor tyrosine kinases cause activation of the beta-catenin pathway. Mol Cell Biol 21:5857–5868CrossRefGoogle Scholar
  14. 14.
    De Maria R, Maggiora P, Biolatti B, Prat M, Comoglio PM, Castagnaro M et al (2002) Feline STK gene expression in mammary carcinomas. Oncogene 21:1785–1790CrossRefGoogle Scholar
  15. 15.
    Fantl WJ, Johnson DE, Williams LT (1993) Signaling by receptor tyrosine kinases. Annu Rev Biochem 62:453–481CrossRefGoogle Scholar
  16. 16.
    Gao J, Long B, Wang Z (2017) Role of Notch signaling pathway in pancreatic cancer. Am J Cancer Res 7(2):173–186PubMedPubMedCentralGoogle Scholar
  17. 17.
    Germano S, Barberis D, Santoro MM, Penengo L, Citri A, Yarden Y et al (2006) Geldanamycins trigger a novel Ron degradative pathway, hampering oncogenic signaling. J Biol Chem 281:21710–21719CrossRefGoogle Scholar
  18. 18.
    Gaudino G, Avantaggiato V, Follenzi A, Acampora D, Simeone A, Comoglio PM (1995) The proto-oncogene RON is involved in development of epithelial, bone and neuro-endocrine tissues. Oncogene 11:2627–2637PubMedGoogle Scholar
  19. 19.
    Gaudino G, Follenzi A, Naldini L, Collesi C, Santoro M, Gallo KA et al (1994) RON is a heterodimeric tyrosine kinase receptor activated by the HGF homologue MSP. EMBO J 13:3524–3532CrossRefGoogle Scholar
  20. 20.
    Gherardi E, Love CA, Esnouf RM, Jones EY (2004) The sema domain. Curr Opin Struct Biol 14:669–678CrossRefGoogle Scholar
  21. 21.
    Gurel B, Lucia MS, Thompson IM, Goodman PJ, Tangen CM, Kristal AR et al (2014) Chronic inflammation in benign prostate tissue is associated with high-grade prostate cancer in the placebo arm of the prostate cancer prevention trial. Cancer Epidemiol Biomark Prev 23:847–856CrossRefGoogle Scholar
  22. 22.
    Iwama A, Okano K, Sudo T, Matsuda Y, Suda T (1994) Molecular cloning of a novel receptor tyrosine kinase gene, STK, derived from enriched hematopoietic stem cells. Blood 83:3160–3169PubMedGoogle Scholar
  23. 23.
    Iwama A, Wang MH, Yamaguchi N, Ohno N, Okano K, Sudo T et al (1995) Terminal differentiation of murine resident peritoneal macrophages is characterized by expression of the STK protein tyrosine kinase, a receptor for macrophage-stimulating protein. Blood 86:3394–3403PubMedGoogle Scholar
  24. 24.
    Kleespies A, Jauch KW, Bruns CJ (2006) Tyrosine kinase inhibitors and gemcitabine: new treatment options in pancreatic cancer? Drug Resist Updat 9:1–18CrossRefGoogle Scholar
  25. 25.
    Lapraz F, Rottinger E, Duboc V, Range R, Duloquin L, Walton K et al (2006) RTK and TGF-beta signaling pathways genes in the sea urchin genome. Dev Biol 300:132–152CrossRefGoogle Scholar
  26. 26.
    Leonard EJ, Skeel AH (1978) Isolation of macrophage stimulating protein (MSP) from human serum. Exp Cell Res 114:117–126CrossRefGoogle Scholar
  27. 27.
    Li BQ, Wang MH, Kung HF (1996) Macrophage-stimulating protein activates Ras by both activation and translocation of SOS nucleotide exchange factor. Biochem Biophys Res Commun 216:110–118CrossRefGoogle Scholar
  28. 28.
    Okino T, Egami H, Ohmachi H, Takai E, Tamori Y, Nakagawa A et al (2001) Immunohistochemical analysis of distribution of RON receptor tyrosine kinase in human digestive organs. Dig Dis Sci 46:424–429CrossRefGoogle Scholar
  29. 29.
    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 66:9162–9170CrossRefGoogle Scholar
  30. 30.
    Ponzetto C, Bardelli A, Zhen Z, Maina F, dalla Zonca P, Giordano S et al (1994) A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family. Cell 77:261–271CrossRefGoogle Scholar
  31. 31.
    Ray M, Yu S, Sharda DR, Wilson CB, Liu Q, Kaushal N et al (2010) Inhibition of TLR4 induced IkappaB kinase activity by the RON receptor tyrosine kinase and its ligand, macrophage-stimulating protein. J Immunol 185:7309–7316CrossRefGoogle Scholar
  32. 32.
    Ronsin C, Muscatelli F, Mattei MG, Breathnach R (1993) A novel putative receptor protein tyrosine kinase of the met family. Oncogene 8:1195–1202PubMedGoogle Scholar
  33. 33.
    Santoro MM, Penengo L, Orecchia S, Cilli M, Gaudino G (2000) The Ron oncogenic activity induced by the MEN2B-like substitution overcomes the requirement for the multifunctional docking site. Oncogene 19:5208–5211CrossRefGoogle Scholar
  34. 34.
    Sawey ET, Crawford HC (2008) Metalloproteinases and cell fate: notch just ADAMs anymore. Cell Cycle 7:566–569CrossRefGoogle Scholar
  35. 35.
    Schlessinger J, Ullrich A (1992) Growth factor signaling by receptor tyrosine kinases. Neuron 9:383–391CrossRefGoogle Scholar
  36. 36.
    Sharda DR, Yu S, Ray M, Squadrito ML, De Palma M, Wynn TA et al (2011) Regulation of macrophage arginase expression and tumor growth by the Ron receptor tyrosine kinase. J Immunol 187:2181–2192CrossRefGoogle Scholar
  37. 37.
    Tremblay I, Paré E, Arsenault D, Douziech M, Boucher MJ (2013) The MEK/ERK pathway promotes NOTCH signalling in pancreatic cancer cells. PLoS One 8(12):e85502CrossRefGoogle Scholar
  38. 38.
    Ullrich A, Schlessinger J (1990) Signal transduction by receptors with tyrosine kinase activity. Cell 61:203–212CrossRefGoogle Scholar
  39. 39.
    Wagh PK, Gray JK, Zinser G, James L, Satdarshan M, Waltz S (2011) Beta-catenin is required for Ron receptor induced mammary tumorigenesis. Clin Exp Metastasis 28:236–236Google Scholar
  40. 40.
    Waltz SE, McDowell SA, Muraoka RS, Air EL, Flick LM, Chen YQ et al (1997) Functional characterization of domains contained in hepatocyte growth factor-like protein. J Biol Chem 272:30526–30537CrossRefGoogle Scholar
  41. 41.
    Wang MH, Ronsin C, Gesnel MC, Coupey L, Skeel A, Leonard EJ et al (1994) Identification of the ron gene product as the receptor for the human macrophage stimulating protein. Science 266:117–119CrossRefGoogle Scholar
  42. 42.
    Wang MH, Skeel A, Leonard EJ (1996) Proteolytic cleavage and activation of pro-macrophage-stimulating protein by resident peritoneal macrophage membrane proteases. J Clin Invest 97:720–727CrossRefGoogle Scholar
  43. 43.
    Wang MH, Wang D, Chen YQ (2003) Oncogenic and metastatic potentials of human macrophage stimulating protein receptor, the RON receptor tyrosine kinase. Carcinogenesis 23:1291–1300CrossRefGoogle Scholar
  44. 44.
    Wang D, Shen Q, Chen YQ, Wang MH (2004) Collaborative activities of macrophage-stimulating protein and transforming growth factor-β1 in induction of epithelial to mesenchymal transition: roles of the RON. Oncogene 23:1668–1680CrossRefGoogle Scholar
  45. 45.
    Wang X, Yennawar N, Hankey PA (2014) Autoinhibition of the Ron receptor tyrosine kinase by the juxtamembrane domain. Cell Commun Signal 12:28CrossRefGoogle Scholar
  46. 46.
    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 U S A 104:7570–7575CrossRefGoogle Scholar
  47. 47.
    Yarden Y, Ullrich A (1988) Growth factor receptor tyrosine kinases. Annu Rev Biochem 57:443–478CrossRefGoogle Scholar
  48. 48.
    Yu PT, Babicky M, Jaquish D, French R, Marayuma K, Mose E, Niessen S, Hoover H, Shields D, Cheresh D, Cravatt BF, Lowy AM (2012) The RON-receptor regulates pancreatic cancer cell migration through phosphorylation dependent breakdown of the hemidesmosome. Int J Cancer 131:1744–1754CrossRefGoogle Scholar
  49. 49.
    Zeng G, Apte U, Micsenyi A, Bell A, Monga SP (2006) Tyrosine residues 654 and 670 in beta-catenin are crucial in regulation of Met-beta-catenin interactions. Exp Cell Res 312:3620–3630CrossRefGoogle Scholar
  50. 50.
    Zhou YQ, Chen YQ, Fisher JH, Wang MH (2002) Activation of the RON receptor tyrosine kinase by macrophage-stimulating protein inhibits inducible cyclooxygenase-2 expression in murine macrophages. J Biol Chem 277:38104–38110CrossRefGoogle Scholar
  51. 51.
    Zhou YQ, Chen YQ, Wang D, Wang MH (2003) Altered expression of the RON receptor tyrosine kinase in primary human colorectal adenocarcinomas: generation of different splicing RON variants and their oncogenic potential. Oncogene 22:186–197CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Tapan K. Barik
    • 1
  • Surya N. Swain
    • 1
  1. 1.P.G. Department of ZoologyBerhampur UniversityBerhampurIndia

Personalised recommendations