Abstract
The urokinase plasminogen activator receptor (uPAR) focuses extracellular protease activity to the cell surface, modulates cell adhesion and activates intracellular signal transduction pathways. In a range of cancers uPAR expression often has a negative correlation with prognosis. Here we show that uPAR transcription is stimulated by V12 H-Ras, the effector loop mutant V12 H-Ras G37 and constitutively-active RalA 72L. RalA-dependent transcription required the presence of the ATF2-like AP1-site at −70 bp and the c-Jun binding motif at −184 bp in the uPAR promoter. Consistent with this, both Gal4-c-Jun- and Gal4-ATF2-fusion proteins were activated by RalA signalling through phosphorylation of their activation domains at Ser63 and Ser73 of c-Jun or Thr69 and Thr71 of ATF2. A transdominant inhibitory mutant of c-Jun N-terminal kinase (JNK) failed to inhibit uPAR transcription demonstrating that JNK activation is not a prerequisite for RalA-dependent uPAR transcription. A dominant negative inhibitor of c-Src effectively inhibited RalA-dependent uPAR transcription identifying it as a downstream effector in the RalA signalling pathway. These data provide evidence for the existence of a novel signalling pathway that links RalA to the activation of uPAR transcription via a c-Src intermediate and activation of AP1.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Aguirre-Ghiso JA, Alonso DF, Farias EF, Gomez DE, de Kier Joffe' EB . 1999a Eur. J. Biochem. 263: 295–304
Aguirre-Ghiso JA, Frankel P, Farias EF, Lu Z, Jiang H, Olsen A, Feig LA, de Kier Joffe' EB, Foster DA . 1999b Oncogene 18: 4718–4725
Aguirre-Ghiso JA, Kovalski K, Ossowski L . 1999c J. Cell Biol. 147: 89–104
Allgayer H, Wang H, Shirasawa S, Sasazuki T, Boyd D . 1999 Br. J. Cancer 80: 1884–1891
Andreasen PA, Kjoller L, Christensen L, Duffy MJ . 1997 Int. J. Cancer 72: 1–22
Andreasen PA, Egulend R, Petersen HH . 2000 Cell Mol. Life Sci. 57: 25–40
Bos JL . 1989 Cancer Res. 49: 4682–4689
Bos JL . 1997 Biochem et Biophys Acta. 1333: M19–M31
Bos JL . 1998 EMBO J. 17: 6776–6782
de Bruyn KMT, de Rooij J, Wolthuis RMF, Rehmann H, Wesenbeek J, Cool RH, Wittinghofer AH, Bos JL . 2000 J. Biol. Chem. 275: 29761–29766
de Ruiter ND, Wolthuis RMF, van Dam H, Burgering BMT, Bos JL . 2000 Mol. Cell Biol. 20: 8480–8488
Dignam JD, Lebovitz RM, Roeder RG . 1983 Nucl. Acids Res. 11: 1475–1489
Dumler I, Weis A, Mayboroda OA, Maasch C, Jerke U, Haller H, Gulba DC . 1998 J. Biol. Chem. 273: 315–321
Frost JA, Steen H, Shapiro P, Lewis T, Ahn N, Shaw PE, Cobb MH . 1997 EMBO J. 16: 6426–6438
Goi T, Shipitsin M, Lu Z, Foster DA, Klinz SG, Feig LA . 2000 EMBO J. 19: 623–630
Hai T, Curran T . 1991 Proc. Natl. Acad. Sci. USA 88: 3720–3724
Hofer F, Berdeaux R, Martin GS . 1998 Curr. Biol. 8: 839–842
Hunter T . 1997 Cell 88: 333–346
Jankun J, Maher VM, McCormick JJ . 1991 Cancer Res. 51: 1221–1226
Janulis M, Silberman S, Ambegaokar A, Gutkind JS, Shultz RM . 1999 J. Biol. Chem. 274: 801–813
Johnson RS, Spiegelman BM, Hanahan D, Wisdom R . 1996 Mol. Cell Biol. 16: 4504–4511
Karin M, Liu Z-G, Zandi E . 1997 Curr. Opin. Cell Biol. 9: 240–245
Karin M . 1995 J. Biol. Chem. 270: 16483–16486
Kauffmann-Zeh A, Rodriguez-Viciana P, Ulrich E, Gilbert C, Coffer P, Downward J, Evan G . 1997 Nature 385: 544–548
Kindzelskii AL, Laska ZO, Todd RF, Petty HR . 1996 J. Immunol. 156: 297–309
Kindzelskii AL, Eszes MM, Todd RF, Petty HR . 1997 Biophys. J. 73: 1777–1784
Kops GJ, de Ruiter ND, Vries-Smits AM, Powell DR, Bos JL, Burgering BM . 1999 Nature 398: 630–634
Koshelnick Y, Ehart M, Hufnagl P, Heinrich PC, Binder BR . 1997 J. Biol. Chem. 272: 28563–28567
Koshelnick Y, Ehart M, Stockinger H, Binder BR . 1999 Thromb. Haemostas. 82: 305–311
Lengyel E, Stepp E, Gum R, Boyd D . 1995 J. Biol. Chem. 270: 23007–23012
Ma Y-C, Huang J, Ali S, Lowry W, Huang X-Y . 2000 Cell 102: 635–646
Medema RH, Kops GJ, Bos JL, Burgering BM . 2000 Nature 404: 782–787
Murai H, Ikeda M, Kishida S, Ishida O, Okazaki-Kishida M, Matsuura Y, Kikuchi A . 1997 J. Biol. Chem. 272: 10483–10490
Muller SM, Okan E, Jones P . 2000 Biochem. Biophys. Res. Com. 270: 892–898
Nguyen DH, Catling AD, Webb DJ, Sankovic M, Walker LA, Somylo AV, Weber MJ, Gonias SL . 1999 J. Cell Biol. 146: 149–164
Okazaki M, Kishida S, Hinoi T, Hasegawa T, Tamada M, Kataoka T, Kikuchi A . 1997 Oncogene 14: 515–521
Rodriguez-Viciana P, Warne PH, Khwaja A, Marte BM, Pappin D, Das P, Waterfield MD, Ridley A, Downward J . 1997 Cell 89: 457–467
Sadowski I, Ptashne M . 1989 Nucl. Acid Res. 17: 7539
Sambrook J, Fritsch EF, Maniatis T . 1989 Molecular Cloning: A Laboratory Manual, 2nd edn., Cold Spring Harbour Press: Cold Spring Harbour, N.Y
Shetty S, Kumar A, Idell S . 1997 Mol. Cell Biol. 17: 1075–1083
Shields JM, Pruitt K, McFall A, Shaub A, Der CJ . 2000 Trends Cell. Biol. 10: 147–154
Smeal T, Binetruy B, Mercola DA, Birrer M, Karin M . 1991 Nature 354: 494–496
Soravia E, Grebe A, De luca P, Helin K, Suh TT, Degan JL, Blasi F . 1995 Blood 86: 624–635
Tang H, Kerins DM, Hao Q, Inagami T, Vaughan DE . 1998 J. Biol. Chem. 273: 18268–18272
Urano T, Emkey R, Feig LA . 1996 EMBO J. 15: 810–816
Waltz DA, Natkin LR, Fijita RM, Wei Y, Chapman HA . 1997 J. Clin Invest. 100: 58–67
Webb CP, Van Aelst L, Wigler MH, Vande Woude GF . 1998 Proc. Natl. Acad. Sci. USA 95: 8773–8778
Westermarck J, Kähäri VM . 1999 FASEB J. 8: 781–792
Wei Y, Waltz DA, Rao N, Drummond RJ, Rosenburg S, Chapman HA . 1994 J. Biol. Chem. 269: 32380–32388
Wei Y, Lukashev M, Simon DI, Bodary SC, Rosenberg S, Doyle MV, Chapman HA . 1996 Science 273: 1551–1555
Webb CP, Van Aelst L, Wigler MH, Vande Woude GF . 1998 Proc. Natl. Acad. Sci. USA 95: 8773–8778
White MA, Nicolette C, Minden A, Polverino A, Van Aelst L, Karin M, Wigler MH . 1995 Cell 80: 533–541
Wolthuis RM, de Ruiter ND, Cool RH, Bos JL . 1997 EMBO J. 16: 6748–6761
Wolthius RMF, Zwartkruis F, Moen TC, Bos JL . 1998a Curr. Biol. 8: 471–474
Wolthuis RMF, Franke B, van Triest M, Bauer B, Cool RH, Camonis JH, Akkerman JW, Bos JL . 1998b Mol. Cell Biol. 18: 2486–2491
Xue W, Mizukami I, Todd III RF, Petty HR . 1997 Cancer Res. 57: 1682–1689
Yamamoto T, Taya S, Kaibuchi K . 1999 J. Biochem. 126: 799–803
Yang J-J, Kang J-S, Krauss RS . 1998 Mol. Cell Biol. 18: 2586–2595
Acknowledgements
The authors would like to thank Dr J Downward, Dr H Gille and Dr P Angel for their donations of plasmid constructs. The work was funded in part by grants from the European Social Fund to P Jones and the Wellcome Trust UK to PE Shaw.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Okan, E., Drewett, V., Shaw, P. et al. The small-GTPase RalA activates transcription of the urokinase plasminogen activator receptor (uPAR) gene via an AP1-dependent mechanism. Oncogene 20, 1816–1824 (2001). https://doi.org/10.1038/sj.onc.1204260
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1204260
Keywords
This article is cited by
-
Suppression of lung cancer progression by isoliquiritigenin through its metabolite 2, 4, 2’, 4’-Tetrahydroxychalcone
Journal of Experimental & Clinical Cancer Research (2018)
-
The calcineurin–NFAT pathway allows for urokinase receptor-mediated beta3 integrin signaling to cause podocyte injury
Journal of Molecular Medicine (2012)