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  • Original Paper
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Feedback inhibition by RALT controls signal output by the ErbB network

Oncogene volume 22, pages 4221–4234 (2003)Cite this article

Abstract

The ErbB-2 interacting protein receptor-associated late transducer (RALT) was previously identified as a feedback inhibitor of ErbB-2 mitogenic signals. We now report that RALT binds to ligand-activated epidermal growth factor receptor (EGFR), ErbB-4 and ErbB-2.ErbB-3 dimers. When ectopically expressed in 32D cells reconstituted with the above ErbB receptor tyrosine kinases (RTKs) RALT behaved as a pan-ErbB inhibitor. Importantly, when tested in either cell proliferation assays or biochemical experiments measuring activation of ERK and AKT, RALT affected the signalling activity of distinct ErbB dimers with different relative potencies. RALT ΔEBR, a mutant unable to bind to ErbB RTKs, did not inhibit ErbB-dependent activation of ERK and AKT, consistent with RALT exerting its suppressive activity towards these pathways at a receptor-proximal level. Remarkably, RALT ΔEBR retained the ability to suppress largely the proliferative activity of ErbB-2.ErbB-3 dimers over a wide range of ligand concentrations, indicating that RALT can intercept ErbB-2.ErbB-3 mitogenic signals also at a receptor-distal level. A suppressive function of RALT ΔEBR towards the mitogenic activity of EGFR and ErbB-4 was detected at low levels of receptor occupancy, but was completely overcome by saturating concentrations of ligand. We propose that quantitative and qualitative aspects of RALT signalling concur in defining identity, strength and duration of signals generated by the ErbB network.

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References

  • Alimandi M, Romano A, Curia MC, Muraro R, Fedi P, Aaronson SA, Di Fiore PP and Kraus MH . (1995). Oncogene, 10, 1813–1821.

  • Alimandi M, Wang LM, Bottaro D, Lee CC, Kuo A, Frankel M, Fedi P, Tang C, Lippman M and Pierce JH . (1997). EMBO J., 16, 5608–5617.

  • Carraway III KL, Sliwkowski MX, Akita R, Platko JV, Guy PM, Nuijens A, Diamonti AJ, Vandlen RL, Cantley LC and Cerione RA . (1994). J. Biol. Chem., 269, 14303–14306.

  • Carraway III KL, Weber JL, Unger MJ, Ledesma J, Yu N, Gassmann M and Lai C . (1997). Nature, 387, 512–516.

  • Cook SJ, Aziz N and McMahon M . (1999). Mol. Cell. Biol., 19, 330–341.

  • Di Fiore PP, Segatto O, Taylor WG, Aaronson SA and Pierce JH . (1990). Science, 248, 79–83.

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

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

  • Fiorini M, Ballaro C, Sala G, Falcone G, Alema S and Segatto O . (2002). Oncogene, 21, 6530–6539.

  • Freeman M . (2000). Nature, 408, 313–319.

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

  • Graus-Porta D, Beerli RR, Daly JM and Hynes NE . (1997). EMBO J., 16, 1647–1655.

  • Graus-Porta D, Beerli RR and Hynes NE . (1995). Mol. Cell. Biol., 15, 1182–1191.

  • Guy PM, Platko JV, Cantley LC, Cerione RA and Carraway III KL . (1994). Proc. Natl. Acad. Sci. USA, 91, 8132–8136.

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

  • Hazzalin CA and Mahadevan LC . (2002). Nat. Rev. Mol. Cell. Biol., 3, 30–40.

  • Jones SM and Kazlauskas A . (2001). FEBS Lett., 490, 110–116.

  • Karunagaran D, Tzahar E, Beerli RR, Chen X, Graus-Porta D, Ratzkin BJ, Seger R, Hynes NE and Yarden Y . (1996). EMBO J., 15, 254–264.

  • Kops GJ, Medema RH, Glassford J, Essers MA, Dijkers PF, Coffer PJ, Lam EW and Burgering BM . (2002). Mol. Cell. Biol., 22, 2025–2036.

  • Lawlor MA and Alessi DR . (2001). J. Cell Sci., 114, 2903–2910.

  • Lee KF, Simon H, Chen H, Bates B, Hung MC and Hauser C . (1995). Nature, 378, 394–398.

  • Levkowitz G, Waterman H, Zamir E, Kam Z, Oved S, Langdon WY, Beguinot L, Geiger B and Yarden Y . (1998). Genes Dev., 12, 3663–3674.

  • Lonardo F, Di Marco E, King CR, Pierce JH, Segatto O, Aaronson SA and Di Fiore PP . (1990). New Biol., 2, 992–1003.

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

  • Marshall CJ . (1995). Cell, 80, 179–185.

  • Murphy LO, Smith S, Chen RH, Fingar DC and Blenis J . (2002). Nat. Cell Biol., 4, 556–564.

  • Neve RM, Holbro T and Hynes NE . (2002). Oncogene, 21, 4567–4576.

  • Olayioye MA, Beuvink I, Horsch K, Daly JM and Hynes NE . (1999). J. Biol. Chem., 274, 17209–17218.

  • Olayioye MA, Graus-Porta D, Beerli RR, Rohrer J, Gay B and Hynes NE . (1998). Mol. Cell. Biol., 18, 5042–5051.

  • Olayioye MA, Neve RM, Lane HA and Hynes NE . (2000). EMBO J., 19, 3159–3167.

  • Perrimon N and McMahon AP . (1999). Cell, 97, 13–16.

  • Pinkas-Kramarski R, Soussan L, Waterman H, Levkowitz G, Alroy I, Klapper L, Lavi S, Seger R, Ratzkin BJ, Sela M and Yarden Y . (1996). EMBO J., 15, 2452–2467.

  • Pruitt K and Der CJ . (2001). Cancer Lett., 171, 1–10.

  • Riese DJ and Stern DF . (1998). Bioessays, 20, 41–48.

  • Riese DJ, van Raaij TM, Plowman GD, Andrews GC and Stern DF . (1995). Mol. Cell. Biol., 15, 5770–5776.

  • Shin I, Yakes FM, Rojo F, Shin NY, Bakin AV, Baselga J and Arteaga CL . (2002). Nat. Med., 8, 1145–1152.

  • Simpson F, Hussain NK, Qualmann B, Kelly RB, Kay BK, McPherson PS and Schmid SL . (1999). Nat. Cell Biol., 1, 119–124.

  • Tang CK, Goldstein DJ, Payne J, Czubayko F, Alimandi M, Wang LM, Pierce JH and Lippman ME . (1998). Cancer Res., 58, 3415–3422.

  • Viglietto G, Motti ML, Bruni P, Melillo RM, D'Alessio A, Califano D, Vinci F, Chiappetta G, Tsichlis P, Bellacosa A, Fusco A and Santoro M . (2002). Nat. Med., 8, 1136–1144.

  • Wallasch C, Weiss FU, Niederfellner G, Jallal B, Issing W and Ullrich A . (1995). EMBO J., 14, 4267–4275.

  • Waterman H and Yarden Y . (2001). FEBS Lett., 490, 142–152.

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

  • Zhou BP, Liao Y, Xia W, Spohn B, Lee MH and Hung MC . (2001a). Nat. Cell Biol., 3, 245–252.

  • Zhou BP, Liao Y, Xia W, Zou Y, Spohn B and Hung MC . (2001b). Nat. Cell Biol., 3, 973–982.

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Acknowledgements

S Anastasi dedicates this work to the loving memory of his mother. We thank Y Yarden and J Sap for reagents and C Full for tissue culture work. MF is the recipient of an AIRC fellowship. This work was supported by grants from: EC (5th program) and AIRC to OS, AIRC and CNR PF- Biotecnologie to SA, AIRC to MA.

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Author notes

  1. Loredana Fiorentino

    Present address: The Burnham Institute, 10901 N Torrey Pines Rd, La Jolla, CA, 92037, USA

  2. Sergio Anastasi and Loredana Fiorentino: These two authors contributed equally to this work

Authors and Affiliations

  1. Regina Elena Cancer Institute, Via Delle Messi d'Oro, 156, Rome, 00158, Italy

    Sergio Anastasi, Loredana Fiorentino, Monia Fiorini, Rocco Fraioli, Gianluca Sala & Oreste Segatto

  2. University of Cassino, Cassino, Italy

    L Castellani

  3. INFM Sez. B, University of Rome Tor Vergata, Rome, Italy

    L Castellani

  4. Istituto di Biologia Cellulare, CNR Monterotondo 00016, Italy

    Stefano Alemà

  5. Department of Experimental Medicine, University of Rome La Sapienza, Viale Regina Elena 324, Rome, 00161, Italy

    Maurizio Alimandi

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  1. Sergio Anastasi
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Correspondence to Oreste Segatto.

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Anastasi, S., Fiorentino, L., Fiorini, M. et al. Feedback inhibition by RALT controls signal output by the ErbB network. Oncogene 22, 4221–4234 (2003). https://doi.org/10.1038/sj.onc.1206516

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