Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Key role of Shc signaling in the transforming pathway triggered by Ret/ptc2 oncoprotein

Oncogene volume 20, pages 3475–3485 (2001)Cite this article

Abstract

The RET/PTC oncogenes, generated by chromosomal rearrangements in papillary thyroid carcinomas, are constitutively activated versions of protoRET, a gene encoding two protein isoforms of a transmembrane tyrosine kinase receptor. By using Ret/ptc2 short isoform (iso9), we have previously demonstrated that Tyr586 (Tyr1062 of protoRet) is the docking site for both the PTB and the SH2 domains of Shc. To determine the relevance of this interaction for the transforming activity of Ret/ptc oncogenes, we have generated and characterized novel Ret/ptc mutants unable to activate Shc: Ret/ptc2 long isoform (iso51)-Y586F and both isoforms of Ret/ptc2-N583A. These mutants neither activate Shc nor transform NIH3T3 cells. Since Tyr1062 shows features of a multifunctional docking site, we have used a Shc mutant (Shc Y317F) to directly assess Shc role. We have demonstrated that in our cell system Shc Y317F behaves like a dominant interfering mutant on the activation of the Grb2-Sos pathway by endogenous Shc triggered by Ret/ptc2. A strong reduction of the transforming activity of Ret/ptc2 in presence of this mutant was also demonstrated. Our data suggest that Shc activation play a key role in the transforming pathways triggered by Ret/ptc oncoproteins. Moreover, we have shown that coexpression of the Shc-Y317F mutant with Ret/ptc2 specifically causes apoptosis, and that the surviving cells lose the long-term expression of one of the two genes.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  • Alberti L, Borrello MG, Ghizzoni S, Torriti F, Rizzetti MG, Pierotti MA . 1998 Oncogene 17: 1079–1087

  • Arighi E, Alberti L, Torriti F, Ghizzoni S, Rizzetti MG, Pelicci G, Pasini B, Bongarzone I, Piutti C, Pierotti MA, Borrello MG . 1997 Oncogene 14: 773–782

  • Asai N, Murakami H, Iwashita T, Takahashi M . 1996 J. Biol. Chem. 271: 17644–17649

  • Besset V, Scott RP, Ibanez CF . 2000 J. Biol. Chem. 275: 39159–39166

  • Bongarzone I, Monzini N, Borrello MG, Carcano C, Ferraresi G, Arighi E, Mondellini P, Della Porta G, Pierotti MA . 1993 Mol. Cell. Biol. 13: 358–366

  • Bongarzone I, Pierotti MA, Monzini N, Mondellini P, Manenti G, Donghi R, Pilotti S, Grieco M, Santoro M, Fusco A, Vecchio G, Della Porta G . 1989 Oncogene 4: 1457–1462

  • Bordeaux MC, Forcet C, Granger L, Corset V, Bidaud C, Billaud M, Bredesen DE, Edery P, Mehlen P . 2000 EMBO J. 19: 4056–4063

  • Borrello MG, Pelicci G, Arighi E, De Filippis L, Greco A, Bongarzone I, Rizzetti MG, Pelicci PG, Pierotti MA . 1994 Oncogene 9: 1661–1668

  • Borrello MG, Alberti L, Arighi E, Bongarzone I, Battistini C, Bardelli A, Pasini B, Piutti C, Rizzetti MG, Mondellini P, Radice MT, Pierotti MA . 1996 Mol. Cell. Biol. 16: 2151–2163

  • Creedon DJ, Tansey MG, Baloh RH, Osborne PA, Lampe PA, Fahrner TJ, Heuckeroth RO, Milbrandt J, Johnson Jr EM . 1997 Proc. Natl. Acad. Sci. USA 94: 7018–7023

  • Durbec P, Marcos-Gutierrez CV, KilKenny C, Grigoriou M, Wartiowaara K, Suvanto P, Smith D, Ponder B, Costantini F, Saarma M, Sariola H, Pachnis V . 1996 Nature 381: 789–793

  • Durick K, Yao VJ, Borrello MG, Bongarzone I, Pierotti MA, Taylor SS . 1995 J. Biol. Chem. 270: 24642–24645

  • Durick K, Wu RY, Gill GN, Taylor SS . 1996 J. Biol. Chem. 271: 12691–12694

  • Durick K, Gill GN, Taylor SS . 1998 Mol. Cell. Biol. 18: 2298–2308

  • Fambrough D, McClure K, Kazlauskas A, Lander ES . 1999 Cell 97: 727–741

  • Fischer AH, Bond JA, Taysavang P, Battles OE, Wynford-Thomas D . 1998 Am. J. Pathol. 153: 1443–1450

  • Fixman ED, Naujokas MA, Rodrigues GA, Moran MF, Park M . 1995 Oncogene 10: 237–249

  • Gotoh N, Toyoda M, Shibuya M . 1997 Mol. Cell. Biol. 17: 1824–1831

  • Guo M, Hay BA . 1999 Curr. Opin. Cell. Biol. 11: 745–752

  • Hayashi H, Ichihara M, Iwashita T, Murakami H, Shimono Y, Kawai K, Kurokawa K, Murakumo Y, Imai T . 2000 Oncogene 14: 4469–4475

  • Hennige AM, Lammers R, Arlt D, Hoppner W, Strack V, Niederfellner G, Seif FJ, Haring H, Kellerer M . 2000 Mol. Cell. Endocrinol. 167: 69–76

  • Hill RJ, Zozulya S, Lu YL, Hollenbach PW, Joyce-Shaikh B, Bogenberger J, Gishizky ML . 1996 Cell Growth Diff. 7: 1125–1134

  • Ishizaka Y, Ochiai M, Tahira T, Sugimura T, Nagao M . 1989 Oncogene 4: 789–794

  • Kavanaugh WM, Williams LJ . 1994 Science 266: 1862–1865

  • Liu X, Vega QC, Decker RA, Pandey A, Worby CA, Dixon JE . 1996 J. Biol. Chem. 271: 5309–5312

  • Lorenzo MJ, Gish GD, Houghton C, Stonehouse TJ, Pawson T, Ponder BAJ, Smith DP . 1997 Oncogene 14: 763–771

  • Lowenstein EJ, Daly RJ, Batzer AG, Li W, Margolis B, Lammers R, Ullrich A, Skolnik EY, Bar-Sagi D, Schlessinger J . 1992 Cell 70: 431–442

  • Migliaccio E, Giorgio M, Mele S, Pelicci G, Reboldi P, Pandolfi PP, Lanfrancone L, Pelicci PG . 1999 Nature 402: 309–313

  • Milbrandt J, de Sauvage FJ, Fahrner TJ, Baloh RH, Leitner ML, Tansey MG, Lampe PA, Heuckeroth RO, Kotzbauer PT, Simburger KS, Golden JP, Davies JA, Vejsada R, Kato AC, Hynes M, Sherman D, Nishimura M, Wang LC, Vandlen R, Moffat B, Klein RD, Poulsen K, Gray C, Garces A, Henderson CE, Phillips HS, Johnson Jr EM . 1998 Neuron 20: 245–253

  • Pandey A, Duan H, Di Fiore PP, Dixit VM . 1995 J. Biol. Chem. 270: 21461–21463

  • Pandey A, Liu X, Dixon JE, Di Fiore PP, Dixit VM . 1996 J. Biol. Chem. 271: 10607–10610

  • Pasini B, Borrello MG, Greco A, Bongarzone I, Luo Y, Mondellini P, Alberti L, Miranda C, Arighi E, Bocciardi R, Seri M, Barone V, Romeo G, Pierotti MA . 1995 Nature Genet. 10: 35–40

  • Pasini B, Ceccherini I, Romeo G . 1996 Trends Genet. 12: 138–144

  • Pelicci G, Lanfrancone L, Grignani F, McGlade J, Cavallo F, Forni G, Nicoletti I, Pawson T, Pelicci PG . 1992 Cell 70: 93–104

  • Pelicci G, Lanfrancone L, Salcini AE, Romano A, Mele S, Borrello MG, Segatto O, Di Fiore PP, Pelicci PG . 1995 Oncogene 11: 899–907

  • Pierotti MA, Bongarzone I, Borrello MG, Greco A, Pilotti S, Sozzi G . 1996 Genes Chrom. Cancer 16: 1–14

  • Porter AC, Vaillancourt RR . 1998 Oncogene 17: 1343–1352

  • Santoro M, Wong WT, Aroca P, Santos E, Matoskova B, Grieco M, Fusco A, Di Fiore PP . 1994 Mol. Cell. Biol. 14: 663–675

  • Schlessinger J . 1993 Trends Biochem. Sci. 18: 273–275

  • Segouffin-Cariou C, Billaud M . 2000 J. Biol. Chem. 275: 356–3576

  • Songyang Z, Carraway III KL, Eck MJ, Harrison SC, Feldman RA, Mohammadi M, Schlessinger J, Hubbard SR, Smith DP, Eng C, Lorenzo MJ, Ponder BAJ, Mayer BJ, Cantley LC . 1995 Nature 373: 536–539

  • Songyang Z, Shoelson SE, McGlade J, Olivier P, Pawson T, Bustelo XR, Barbacid M, Sabe H, Hanafusa H, Yi T . 1994 Mol. Cell. Biol. 14: 2777–2785

  • Takahashi M, Buma Y, Iwamoto T, Inaguma Y, Ikeda H, Hiai H . 1988 Oncogene 3: 571–578

  • Takahashi M, Ritz J, Cooper GM . 1985 Cell 42: 581–588

  • Thomas D, Bradshaw RA . 1997 J. Biol. Chem. 272: 22293–22299

  • Trub T, Choi WE, Wolf G, Ottinger E, Chen YJ, Weiss M, Shoelson SE . 1995 J. Biol. Chem. 270: 18205–18208

  • Trupp M, Arenas E, Fainzilber M, Nilsson AS, Sieber BA, Grigoriou M, KilKenny C, Salazar-Grueso E, Pachnis V, Arumae U . 1996 Nature 381: 785–788

  • Trupp M, Scott R, Whittemore SR, Ibanez CF . 1999 J. Biol. Chem. 274: 20885–20894

  • Valius M, Bazenet C, Kazlauskas A . 1993 Mol. Cell. Biol. 13: 133–143

  • van Weering DHJ, Bos JL . 1997 J. Biol. Chem. 272: 249–254

Download references

Acknowledgements

We are grateful to Angela Greco and Domenico Delia for helpful discussions. We thank Maria Grazia Rizzetti for excellent technical assistance and Cristina Mazzadi for secretarial assistance. This study was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC), by Italy/USA A81A10 and by the CNR special project 900522.PF49. E Mercalli is a recipient of an AIRC fellowship.

Author information

Authors and Affiliations

  1. Department of Experimental Oncology, Research Unit #3, Istituto Nazionale Tumori, Via G. Venezian, 1, Milan, 20133, Italy

    Elena Mercalli, Simona Ghizzoni, Elena Arighi, Luisella Alberti, Romina Sangregorio, Maria T Radice, Marco A Pierotti & Maria Grazia Borrello

  2. SUGEN, 230 East Grand Ave, South San Francisco, 94080, California, CA, USA

    Mikhail L Gishizky

Authors
  1. Elena Mercalli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Simona Ghizzoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Elena Arighi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Luisella Alberti
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Romina Sangregorio
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Maria T Radice
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mikhail L Gishizky
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Marco A Pierotti
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Maria Grazia Borrello
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mercalli, E., Ghizzoni, S., Arighi, E. et al. Key role of Shc signaling in the transforming pathway triggered by Ret/ptc2 oncoprotein. Oncogene 20, 3475–3485 (2001). https://doi.org/10.1038/sj.onc.1204462

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1204462

Keywords

This article is cited by

Search

Advanced search

Quick links