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Increase in hepatocyte growth factor receptor tyrosine kinase activity in renal carcinoma cells is associated with increased motility partly through phosphoinositide 3-kinase activation

Oncogene volume 20, pages 7610–7623 (2001)Cite this article

Abstract

Dysregulated cell motility is one of the major characteristics of invasion and metastatic potentials of malignant tumor cells. Here, we examined the hepatocyte growth factor (HGF)-induced cell motility of two human renal carcinoma cell lines, ACHN and VMRC-RCW. Scattering and migration was induced in ACHN in an HGF-dependent manner, whereas they were maintained in VMRC-RCW even in the absence of HGF. In VMRC-RCW, HGF receptor (HGFR) tyrosine kinase was constitutively active, and sequence analysis showed N375S, A1209G and V1290L mutations. However, transfection experiments using porcine aortic endothelial (PAE) cells demonstrated that no single mutation or combination of two or three mutations caused HGF-independent constitutive activation. Conversely, the expressed amount of receptor protein had a pivotal role in the basal kinase activity. With respect to downstream signaling molecules of HGFR in ACHN or VMRC-RCW, the Ras-MAPK pathway was downregulated, whereas phosphoinositide 3-kinase (PI3-kinase) was not further activated by HGF-treatment in VMRC-RCW cells. The PI3-kinase inhibitors, wortmannin and LY294002 strongly inhibited spontaneous migration of VMRC-RCW. One transfected PAE cell line with massive overexpression of HGFR demonstrated scattered morphology and increased PI3-kinase activity in association with increased motility, which was partially inhibited by LY294002. Taken together, our results indicate that the overexpression of HGFR causes increase in cellular motility and PI3-kinase shows the important contribution on the increased motility of renal carcinoma cells.

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References

  • Antonyak MA, Moscatello DK, Wong AJ . 1998 J. Biol. Chem. 273: 2817–2822

  • Bardelli A, Pugliese L, Comoglio PM . 1997 Biochim. Biophys. Acta. 1333: M41–M51

  • Birchmeier C, Gherardi E . 1998 Trend. Cell Biol. 8: 404–410

  • Chappuis-Flament S, Pasini A, De Vita G, Segouffin-Cariou C, Fusco A, Attie T, Lenoir GM, Santoro M, Billaud M . 1998 Oncogene 17: 2851–2861

  • Comoglio PM, Boccaccio C . 1996 Genes Cell 1: 347–354

  • Cooper CS, Park M, Blair DG, Tainsky MA, Huebner K, Croce CM, Vande Woude GF . 1984 Nature 311: 29–33

  • Cutrupi S, Baldanzi G, Gramaglia D, Maffe A, Schaap D, Giraudo E, van Blitterwijk WJ, Bussolino F, Comoglio PM, Graziani A . 2000 EMBO J. 19: 4614–4622

  • Ferracini R, Longati P, Naldini L, Vigna E, Comoglio PM . 1991 J. Biol. Chem. 266: 19558–19564

  • Fruman DA, Meyers RE, Cantley LC . 1998 Annu. Rev. Biochem. 67: 481–550

  • Gherardi E, Gray J, Stoker M, Peryman M, Furlong R . 1989 Proc. Natl. Acad. Sci. USA 86: 5844–5848

  • Hanks SK, Quinn AM, Hunter T . 1988 Science 241: 42–52

  • Hartmann G, Weidner KM, Schwarz H, Birchmeier W . 1994 J. Biol. Chem. 269: 21936–21939

  • Herrera R . 1998 J. Cell. Sci. 111: 1039–1049

  • Holt KH, Olson L, Moye-Rowley WS, Pessin JE . 1994 Mol. Cell. Biol. 14: 42–49

  • Huang SS, Huang JS . 1988 J. Biol. Chem. 263: 12608–12618

  • Hubbard SR, Mohammadi M, Schlessinger J . 1998 J. Biol. Chem. 273: 11987–11990

  • Hubbard SR, Wei L, Ellis L, Hendrickson WA . 1994 Nature 372: 746–754

  • Igawa T, Kanda S, Kanetake H, Saito Y, Ichihara A, Tomita Y, Nakamura T . 1991 Biochem. Biophys. Res. Commun. 174: 831–838

  • Inoue G, Cheatham B, Kahn CR . 1996 J. Biol. Chem. 271: 28206–28211

  • Jeffers M, Rong S, Vande Woude GF . 1996 J. Mol. Med. 74: 505–513

  • 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

  • Kan M, Zhang GH, Zarnegar R, Michalopoulos G, Myoken Y, McKeehan WL, Stevens JL . 1991 Biochem. Biophys. Res. Commun. 174: 331–337

  • Kanda S, Hodgkin MN, Woodfield RJ, Wakelam MJO, Thomas G, Claesson-Welsh L . 1997 J. Biol. Chem. 272: 23347–23353

  • Kanda S, Lerner EC, Tsuda S, Shono T, Kanetake H, Smithgall TE . 2000 J. Biol. Chem. 275: 10105–10111

  • Kawaida K, Matsumoto K, Shimazu H, Nakamura T . 1994 Proc. Natl. Acad. Sci. USA 91: 4357–4361

  • Keating MT, Williams LT . 1988 Science 239: 914–916

  • Klippel A, Escobedo JA, Fantl WJ, Williams LT . 1992 Mol. Cell. Biol. 12: 1451–1459

  • Kodama A, Matozaki T, Fukuhara A, Kikyo M, Ichihashi M, Takai Y . 2000 Mol. Biol. Cell 11: 2565–2575

  • Lee RCH, Walters JA, Reyland ME, Anderson SM . 1999 J. Biol. Chem. 274: 10024–10034

  • Levine MD, Liotta LA, Stracke ML . 1995 EXS 74: 157–179

  • Longati P, Bardelli A, Ponzetto C, Naldini L, Comoglio PM . 1994 Oncogene 9: 49–57

  • Matsumoto K, Nakamura T . 1997 Biochem. Biophys. Res. Commun. 239: 639–644

  • Medico E, Mongiovi AM, Huff J, Jelinek M-A, Follenzi A, Gaudino G, Parsons JT, Comoglio PM . 1996 Mol. Biol. Cell 7: 495–504

  • Michieli P, Basilico C, Pennachietti S, Maffe A, Tamagnone L, Giordano S, Bardelli A, Comoglio PM . 1999 Oncogene 18: 5221–5231

  • Miyazawa K, Shimomura T, Kitamura A, Kondo J, Morimoto Y, Kitamura N . 1993 J. Biol. Chem. 268: 10024–10028

  • Miyazawa K, Tsubouchi H, Naka K, Takahashi K, Okigaki M, Arakaki N, Nakayama H, Hirono S, Sakiyama O, Takahashi K, Gohda E, Daikuhara Y, Kitamura N . 1989 Biochem. Biophys. Res. Commun. 163: 967–973

  • Mizejewski GJ . 1999 Proc. Soc. Exp. Biol. Med. 222: 124–138

  • Montesano R, Matsumoto K, Nakamura T, Orchi L . 1991 Cell 67: 901–908

  • Moscatello DK, Holgado-Madruga M, Emlet DR, Montgomery RB, Wong AJ . 1998 J. Biol. Chem. 273: 200–206

  • Moscatello DK, Montgomery RB, Sundareshan P, McDanel H, Wong MY, Wong AJ . 1996 Oncogene 13: 85–96

  • Nagata N, Worobec AS, Oh CK, Chowdhury BA, Tannenbaum S, Suzuki Y, Metcalfe DD . 1995 Proc. Natl. Acad. Sci. USA 92: 10560–10564

  • Naka D, Ishii T, Yoshiyama Y, Miyazawa K, Hara H, Hishida T, Kitamura N . 1992 J. Biol. Chem. 267: 20114–20119

  • Nakamura T, Nishizawa T, Hagiya M, Seki T, Shimonishi M, Sugimura A, Tashiro K, Shimizu S . 1989 Nature 342: 440–443

  • Nakopoulou L, Vouriakou C, Papaliodi E, Lazaris AC, Stefanaski K, Michalopoulos G . 1997 Pathol. Res. Pract. 193: 299–304

  • Naldini L, Tamgnone L, Vigna E, Sachs M, Hartmann G, Birchmeier W, Daikuhara Y, Tsubouchi H, Blasi F, Comoglio PM . 1992 EMBO J. 11: 4825–4833

  • Natali PG, Prat M, Nicotra MR, Bigotti A, Olivero M, Comoglio PM, Di Renzo MF . 1996 Int. J. Cancer 69: 212–217

  • Neilson KM, Friesel R . 1996 J. Biol. Chem. 271: 25049–25057

  • Nishimura N, Kanda S, Yogi Y, Kawamura M, Nakamura M, Hyakutake H, Kanetake H, Saito Y . 1992 Int. J. Cancer 52: 105–109

  • Park M, Dean M, Cooper CS, Schmidt M, O'Brien SJ, Blair DG, Vande Woude GF . 1986 Cell 45: 895–904

  • Park WS, Dong SM, Kim SY, Na EY, Shin MS, Pi JH, Kim BJ, Bae JH, Hong YK, Lee KS, Lee SH, Yoo NJ, Jang JJ, Pack S, Zhuang Z, Schnidt L, Zbar B, Lee JY . 1999 Cancer Res. 59: 307–310

  • Pawson T, Scott JD . 1997 Science 278: 2075–2080

  • Piao X, Bernstein A . 1996 Blood 87: 3117–3123

  • Ponzetto C, Bardelli A, Zhen Z, Maina F, dalla Zonca P, Giordano S, Graziani A, Panayotou G, Comoglio PM . 1994 Cell 77: 261–271

  • Rahimi N, Hung W, Tremblay E, Saulnier R, Elliott B . 1998 J. Biol. Chem. 273: 33714–33721

  • Ridley AJ, Comoglio PM, Hall A . 1995 Mol. Cell. Biol. 15: 1110–1122

  • Robertson SC, Tynan JA, Donoghue DJ . 2000 Trend. Genet. 16: 265–271

  • Rodrigues GA, Park M . 1994 Curr. Opin. Genetics Develop. 4: 15–24

  • Royal I, Park M . 1995 J. Biol. Chem. 270: 27780–27787

  • Rusciano D, Lorenzoni P, Burger MM . 1996 J. Biol. Chem. 271: 20763–20769

  • Schmidt L, Duh F-M, Chen F, Kishida T, Glenn G, Choyke P, Scherer SW, Zhuang Z, Lubensky I, Dean M, Allikmets R, Chidambaran A, Bergerheim UR, Feltis JT, Casadevall C, Zamarron A, Bernues M, Richard S, Lips CMJ, Walther MM, Tsui L-C, Geil L, Orcutt ML, Stackhouse T, Lipan J, Slife L, Brauch H, Decker J, Niehans G, Hughson MD, Moch H, Storkel S, Lerman MI, Linehan WM, Zbar B . 1997 Nature Genet. 16: 68–73

  • Schmidt L, Junker K, Nakaigawa N, Kinjerski T, Weirich G, Miller M, Lubensky I, Neumann HPH, Brauch H, Decker J, Vocke C, Brown JA, Jenkins R, Richard S, Bergerheim U, Gerrard B, Dean M, Linehan WM, Zbar B . 1999 Oncogene 18: 2343–2350

  • Schmidt L, Junker K, Weirich G, Glenn G, Choyke P, Lubensky I, Zhuang Z, Jeffers M, Vande Woude G, Neumann H, Walther M, Linehan WM, Zbar B . 1998 Cancer Res. 58: 1719–1722

  • Stein RC, Waterfield MD . 2000 Mol. Med. Today 6: 347–357

  • Takaishi K, Sasaki T, Kato M, Yamochi W, Kuroda S, Nakamura T, Takeichi M, Takai Y . 1994 Oncogene 9: 273–279

  • Tamagnone L, Comoglio PM . 1997 Cytokine Growth Factor Rev. 8: 129–142

  • Tanimura S, Chatani Y, Hoshino R, Sato M, Watanabe S, Kataoka T, Nakamura T, Kohno M . 1998 Oncogene 17: 57–65

  • van Weering DH, de Rooij J, Marte B, Downward J, Bos JL, Burgering BM . 1998 Mol. Cell. Biol. 18: 1802–1811

  • Voldborg BR, Damstrup L, Spang-Thomsen M, Poulsen HS . 1997 Annals Oncol. 8: 1197–1206

  • Webster MK, Donoghue DJ . 1996 EMBO J. 15: 520–527

  • Weidner K, DiCesare S, Sachs M, Brinkmann V, Behrens J, Birchmeier W . 1996 Nature 384: 173–176

  • Weiner DB, Liu J, Cohen JA, Williams WV, Greene MI . 1989 Nature 339: 230–231

  • Weiss A, Schlessinger J . 1998 Cell 94: 277–280

  • Wells A . 2000 Adv. Cancer Res. 78: 31–101

  • Wennstrom S, Siegban A, Yokote K, Arvidsson AK, Heldin C-H, Mori S, Claesson-Welsh L . 1994 Oncogene 234: 434–441

  • Wymann MP, Pirola L . 1998 Biochim. Biophys. Acta 1436: 127–150

  • Zarnegar R, Michalopoulos GK . 1995 J. Cell. Biol. 129: 1177–1180

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Acknowledgements

We are grateful to Dr Carl-Henrik Heldin for the generous gift of PAE cells. We acknowledge Dr Keiji Miyazawa for the helpful suggestions, and we gratefully acknowledge the outstanding assistance of Mr Takumi Shimogama and Miss Miki Yoshimoto in our laboratory and members of the Nagasaki University Radioisotope Center. This work was partly supported by the Grant-in-Aid from the Japanese Society for the Promotion of Science.

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Authors and Affiliations

  1. Department of Urology, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan

    Takao Nakamura, Shigeru Kanda, Kanenori Maeda & Hiroshi Kanetake

  2. Department of Molecular Microbiology and Immunology, Division of Cytokine Signaling, Nagasaki University Graduate School of Medicine, 4-12-1 Sakamoto, Nagasaki, 852-8523, Japan

    Takao Nakamura, Kazuo Yamamoto, Tomoko Kohno, Kanenori Maeda & Toshifumi Matsuyama

  3. Division of Endothelial Cell Biology, Nagasaki University Graduate School of Medicine, 4-12-1 Sakamoto, Nagasaki, 852-8501, Japan

    Shigeru Kanda

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Nakamura, T., Kanda, S., Yamamoto, K. et al. Increase in hepatocyte growth factor receptor tyrosine kinase activity in renal carcinoma cells is associated with increased motility partly through phosphoinositide 3-kinase activation. Oncogene 20, 7610–7623 (2001). https://doi.org/10.1038/sj.onc.1204975

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