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Expression of RALT, a feedback inhibitor of ErbB receptors, is subjected to an integrated transcriptional and post-translational control

Oncogene volume 21, pages 6530–6539 (2002)Cite this article

Abstract

Over-expression studies have demonstrated that RALT (receptor associated late transducer) is a feedback inhibitor of ErbB-2 mitogenic and transforming signals. In growth-arrested cells, expression of endogenous RALT is induced by mitogenic stimuli, is high throughout mid to late G1 and returns to baseline as cells move into S phase. Here, we show that physiological levels of RALT effectively suppress ErbB-2 mitogenic signals. We also investigate the regulatory mechanisms that preside to the control of RALT expression. We demonstrate that pharmacological ablation of extracellular signal-regulated kinase (ERK) activation leads to blockade of RALT expression, unlike genetic and/or pharmacological interference with the activities of PKC, Src family kinases, p38 SAPK and PI-3K. Tamoxifen-dependent activation of an inducible Raf : ER chimera was sufficient to induce RALT expression. Thus, activation of the Ras–Raf–ERK pathway is necessary and sufficient to drive RALT expression. The RALT protein is labile and was found to accumulate robustly upon pharmacological inhibition of the proteasome. We were able to detect ubiquitin-conjugated RALT species in living cells, suggesting that ubiquitinylation targets RALT for proteasome-dependent degradation. Such an integrated transcriptional and post-translational control is likely to provide RALT with the ability to fluctuate timely in order to tune ErbB signals.

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References

  • Alessi DR, Cuenda A, Cohen P, Dudley DT, Saltiel AR . 1995 J. Biol. Chem. 270: 27489–27494

  • Alexander WS, Starr R, Fenner JE, Scott CL, Handman E, Sprigg NS, Corbin JE, Cornish AL, Darwiche R, Owczarek CM, Kay TW, Nicola NA, Hertzog PJ, Metcalf D, Hilton DJ . 1999 Cell 98: 597–608

  • Blagosklonny MV, An WG, Melillo G, Nguyen P, Trepel JB, Neckers LM . 1999 Oncogene 18: 6460–6468

  • Chen C, Okayama H . 1987 Mol. Cell Biol. 7: 2745–2752

  • Chiariello M, Gomez E, Gutkind JS . 2000 Biochem. J. 349: 869–876

  • Davies SP, Reddy H, Caivano M, Cohen P . 2000 Biochem. J. 351: 95–105

  • Douglas DN, Fink HS, Ridgway ND, Cook HW, Byers DM . 1999 Biochim. Biophys. Acta 1448: 439–449

  • Fazioli F, Kim UH, Rhee SG, Molloy CJ, Segatto O, Di Fiore PP . 1991 Mol. Cell Biol. 11: 2040–2048

  • Fenteany G, Standaert RF, Lane WS, Choi S, Corey EJ, Schreiber SL . 1995 Science 268: 726–731

  • Fiorentino L, Pertica C, Fiorini M, Talora C, Crescenzi M, Castellani L, Alema S, Benedetti P, Segatto O . 2000 Mol. Cell Biol. 20: 7735–7750

  • Fiorini M, Alimandi M, Fiorentino L, Sala G, Segatto O . 2001 FEBS Lett. 490: 132–141

  • Flanagan AM, Lader CS . 1998 Curr. Opin. Hematol. 5: 181–185

  • Freeman M . 2000 Nature 408: 313–319

  • Gallo R, Provenzano C, Carbone R, Di Fiore PP, Castellani L, Falcone G, Alema S . 1997 Oncogene 15: 1929–1936

  • Ghiglione C, Perrimon N, Perkins LA . 1999 Dev. Biol. 205: 181–193

  • Greenwood S, Struhl G . 1997 Development 124: 4879–4886

  • Gross I, Bassit B, Benezra M, Licht JD . 2001 J. Biol. Chem. 276: 46460–46468

  • Hackel PO, Gishizky M, Ullrich A . 2001 Biol. Chem. 382: 1649–1662

  • Harari D, Yarden Y . 2000 Oncogene 19: 6102–6114

  • Hochstrasser M . 1996 Annu. Rev. Genet. 30: 405–439

  • Huggins GS, Chin MT, Sibinga NE, Lee SL, Haber E, Lee ME . 1999 J. Biol. Chem. 274: 28690–28696

  • Hughes EA, Ortmann B, Surman M, Cresswell P . 1996 J. Exp. Med. 183: 1569–1578

  • Impagnatiello MA, Weitzer S, Gannon G, Compagni A, Cotten M, Christofori G . 2001 J. Cell Biol. 152: 1087–1098

  • Jones SM, Kazlauskas A . 2001 FEBS Lett. 490: 110–116

  • Krebs DL, Hilton DJ . 2001 Stem Cells 19: 378–387

  • Latella L, Sacco A, Pajalunga D, Tiainen M, Macera D, D'Angelo M, Felici A, Sacchi A, Crescenzi M . 2001 Mol. Cell Biol. 21: 5631–5643

  • Lee KL, Makkinje A, Ch'Ang LY, Kenney FT . 1989 Arch. Biochem. Biophys. 269: 106–113

  • Loda M, Cukor B, Tam SW, Lavin P, Fiorentino M, Draetta GF, Jessup JM, Pagano M . 1997 Nat. Med. 3: 231–234

  • Luttrell DK, Luttrell LM, Parsons SJ . 1988 Mol. Cell Biol. 8: 497–501

  • Makkinje A, Quinn DA, Chen A, Cadilla CL, Force T, Bonventre JV, Kyriakis JM . 2000 J. Biol. Chem. 275: 17838–17847

  • Marine JC, McKay C, Wang D, Topham DJ, Parganas E, Nakajima H, Pendeville H, Yasukawa H, Sasaki A, Yoshimura A, Ihle JN . 1999a Cell 98: 617–627

  • Marine JC, Topham DJ, McKay C, Wang D, Parganas E, Stravopodis D, Yoshimura A, Ihle JN . 1999b Cell 98: 609–616

  • Marshall CJ . 1995 Cell 80: 179–185

  • Marte BM, Graus-Porta D, Jeschke M, Fabbro D, Hynes NE, Taverna D . 1995a Oncogene 10: 167–175

  • Marte BM, Jeschke M, Graus-Porta D, Taverna D, Hofer P, Groner B, Yarden Y, Hynes NE . 1995b Mol. Endocrinol. 9: 14–23

  • McMahon M, Woods D . 2001 Biochim. Biophys. Acta 1471: M63–M71

  • Moghal N, Sternberg PW . 1999 Curr. Opin. Cell Biol. 11: 190–196

  • Mulcahy LS, Smith MR, Stacey DW . 1985 Nature 313: 241–243

  • Muthuswamy SK, Muller WJ . 1995 Oncogene 11: 1801–1810

  • Myung J, Kim KB, Crews CM . 2001 Med. Res. Rev. 21: 245–273

  • Nagao M, Kaziro Y, Itoh H . 1999 Oncogene 18: 4425–4434

  • Oberg C, Li J, Pauley A, Wolf E, Gurney M, Lendahl U . 2001 J. Biol. Chem. 276: 35847–35853

  • Ozaki K, Kadomoto R, Asato K, Tanimura S, Itoh N, Kohno M . 2001 Biochem. Biophys. Res. Commun. 285: 1084–1088

  • Pages G, Lenormand P, L'Allemain G, Chambard JC, Meloche S, Pouyssegur J . 1993 Proc. Natl. Acad. Sci. USA 90: 8319–8323

  • Pai LM, Barcelo G, Schupbach T . 2000 Cell 103: 51–61

  • Palombella VJ, Rando OJ, Goldberg AL, Maniatis T . 1994 Cell 78: 773–785

  • Pear WS, Nolan GP, Scott ML, Baltimore D . 1993 Proc. Natl. Acad. Sci. USA 90: 8392–8396

  • Perrimon N, McMahon AP . 1999 Cell 97: 13–16

  • Peschard P, Fournier TM, Lamorte L, Naujokas MA, Band H, Langdon WY, Park M . 2001 Mol. Cell 8: 995–1004

  • Rechsteiner M, Rogers SW . 1996 Trends Biochem. Sci. 21: 267–271

  • Robinson MJ, Cobb MH . 1997 Curr. Opin. Cell Biol. 9: 180–186

  • Rosette C, Karin M . 1996 Science 274: 1194–1197

  • Rountree MR, Bachman KE, Herman JG, Baylin SB . 2001 Oncogene 20: 3156–3165

  • Salama SR, Hendricks KB, Thorner J . 1994 Mol. Cell Biol. 14: 7953–7966

  • Samuels ML, Weber MJ, Bishop JM, McMahon M . 1993 Mol. Cell Biol. 13: 6241–6252

  • Sasaki A, Taketomi T, Wakioka T, Kato R, Yoshimura A . 2001 J. Biol. Chem. 276: 36804–36808

  • Schafer C, Ross SE, Bragado MJ, Groblewski GE, Ernst SA, Williams JA . 1998 J. Biol. Chem. 273: 24173–24180

  • Schlessinger J . 2000 Cell 103: 211–225

  • Simon MA . 2000 Cell 103: 13–15

  • Spataro V, Norbury C, Harris AL . 1998 Br. J. Cancer 77: 448–455

  • Vlahos CJ, Matter WF, Hui KY, Brown RF . 1994 J. Biol. Chem. 269: 5241–5248

  • Wallace AD, Cidlowski JA . 2001 J. Biol. Chem. 276: 42714–42721

  • Waterman H, Yarden Y . 2001 FEBS Lett. 490: 142–152

  • Wick M, Burger C, Funk M, Muller R . 1995 Exp. Cell Res. 219: 527–535

  • Woods D, Parry D, Cherwinski H, Bosch E, Lees E, McMahon M . 1997 Mol. Cell Biol. 17: 5598–5611

  • Xu J, Attisano L . 2000 Proc. Natl. Acad. Sci. USA 97: 4820–4825

  • Yarden Y, Sliwkowski MX . 2001 Nat. Rev. Mol. Cell Biol. 2: 127–137

  • Yoon CH, Lee J, Jongeward GD, Sternberg PW . 1995 Science 269: 1102–1105

  • Yoshikawa H, Matsubara K, Qian GS, Jackson P, Groopman JD, Manning JE, Harris CC, Herman JG . 2001 Nat. Genet. 28: 29–35

  • Zhu J, Woods D, McMahon M, Bishop JM . 1998 Genes Dev. 12: 2997–3007

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Acknowledgements

This paper is dedicated to the cherished memory of our friend and colleague Franco Tatò. We are indebted to B Berk, D Bohmann, N Canu, M Crescenzi, CJ Marshall, M McMahon, J Han, L Parada and H Paterson for providing reagents. We thank C Full and R Fraioli for expert technical assistance. M Fiorini is the recipient of an AIRC post-doctoral fellowship. O Segatto is supported by AIRC; S Alemà acknowledges the support of AIRC and CNR-PF-Biotecnologie.

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Authors and Affiliations

  1. Laboratory of Immunology, Istituto Regina Elena, Rome, 00156, Italy

    Monia Fiorini, Gianluca Sala & Oreste Segatto

  2. Istituto di Biologia Cellulare, C.N.R., Monterotondo, 00016, Scalo, Italy

    Costanza Ballarò, Germana Falcone & Stefano Alemà

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  1. Monia Fiorini
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Fiorini, M., Ballarò, C., Sala, G. et al. Expression of RALT, a feedback inhibitor of ErbB receptors, is subjected to an integrated transcriptional and post-translational control. Oncogene 21, 6530–6539 (2002). https://doi.org/10.1038/sj.onc.1205823

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