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:

ETV6-NTRK3 transformation requires insulin-like growth factor 1 receptor signaling and is associated with constitutive IRS-1 tyrosine phosphorylation

Oncogene volume 21, pages 5684–5695 (2002)Cite this article

Abstract

Congenital fibrosarcoma (CFS) and cellular mesoblastic nephroma (CMN) are pediatric spindle cell malignancies that share two specific cytogenetic abnormalities: trisomy of chromosome 11 and a t(12;15)(p13;q25) translocation. The t(12;15) rearrangement creates a transcriptionally active fusion gene that encodes a chimeric oncoprotein, ETV6-NTRK3 (EN). EN transforms NIH3T3 fibroblasts through constitutive activation of both the Ras-mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol-3′kinase (PI3K)-Akt pathway. However, the role of trisomy 11 in CFS and CMN remains unknown. In this study we demonstrate elevated expression of the chromosome 11p15.5 insulin-like growth factor 2 gene (IGF2) in CFS and CMN tumors. Moreover, we present evidence that an intact IGF signaling axis is essential for in vitro EN-mediated transformation. EN only very weakly transformed so-called R-murine fibroblasts derived from mice with a targeted disruption of the IGF1 receptor gene (IGFRI), but transformation activity was fully restored in R− cells engineered to re-express IGFRI (R+ cells). We also observed that the major IGFRI substrate, insulin-receptor substrate-1 (IRS-1), was constitutively tyrosine phosphorylated and could be co-immunoprecipitated with EN in either R− or R+ cells expressing the EN oncoprotein. IRS-1 association with Grb2 and PI3K p85, which link IGFRI to the Ras-MAPK and PI3K-Akt pathways, respectively, was enhanced in both cell types in the presence of EN. However, activation of the Ras-MAPK and PI3K-Akt pathways was markedly attenuated in EN-expressing R− cells compared to EN-transformed R+ cells. This suggests that IRS-1 may be functioning as an adaptor in EN signal transduction, but that a link to EN transformation pathways requires the presence of IGFRI. Our findings indicate that an intact IGF signaling axis is essential for EN transformation, and are consistent with a role for trisomy 11 in augmenting this pathway in EN expressing tumors.

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
Figure 9
Figure 10

Similar content being viewed by others

References

  • Baker J, Liu JP, Robertson EJ, Efstratiadis A . 1993 Cell 75: 73–82

  • Baserga R . 1995 Cancer Res. 55: 249–252

  • Baserga R . 1999 Exp. Cell. Res. 253: 1–6

  • Baserga R . 2000 Oncogene 19: 5574–5581

  • Bernstein R, Zeltzer PM, Lin F, Carpenter PM . 1994 Cancer Genet. Cytogenet. 78: 82–86

  • 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

  • Bourgeois JM, Knezevich SR, Mathers JA, Sorensen PHB . 2000 Amer. J. Surg. Path. 24: 937–946

  • Burgaud JL, Resnicoff M, Baserga R . 1995 Biochem. Biophys. Res. Commun. 214: 475–481

  • Coppola D, Ferber A, Miura M, Sell C, D'Ambrosio C, Rubin R, Baserga R . 1994 Mol. Cell. Biol. 14: 4588–4595

  • D'Ambrosio C, Ferber A, Resnicoff M, Baserga R . 1996 Cancer Res. 56: 4013–4020

  • D'Ambrosio C, Keller SR, Morrione A, Lienhard GE, Baserga R, Surmacz E . 1995 Cell Growth Differ. 6: 557–562

  • Dal Cin P, Lipcsei G, Hermand G, Boniver J, Van den Berghe H . 1998 Cancer Genet. Cytogenet. 103: 68–70

  • Downward J . 1996 Cancer Surv. 27: 87–100

  • Dudek H, Datta SR, Franke TF, Birnbaum MJ, Yao R, Cooper GM, Segal RA, Kaplan DR, Greenberg ME . 1997 Science 275: 661–665

  • Dunn SE, Ehrlich M, Sharp NJ, Reiss K, Solomon G, Hawkins R, Baserga R, Barrett JC . 1998 Cancer Res. 58: 3353–3361

  • Fei ZL, D'Ambrosio C, Li S, Surmacz E, Baserga R . 1995 Mol. Cell. Biol. 15: 4232–4239

  • Fisher C . 1996 Eur. J. Cancer 32A: 2094–2100

  • Franke TF, Kaplan DR, Cantley LC . 1997a Cell 88: 435–437

  • Franke TF, Kaplan DR, Cantley LC, Toker A . 1997b Science 275: 665–668

  • Giovannone B, Scaldaferri ML, Federici M, Porzio O, Lauro D, Fusco A, Sbraccia P, Borboni P, Lauro R, Sesti G . 2000 Diabetes Metab. Res. Rev. 16: 434–441

  • Hoff III HB, Tresini M, Li S, Sell C . 1998 Exp. Cell Res. 238: 359–370

  • Hongo A, D'Ambrosio C, Miura M, Morrione A, Baserga R . 1996 Oncogene 12: 1231–1238

  • Joneson T, Bar-Sagi D . 1997 J. Mol. Med. 75: 587–593

  • Kaneko Y, Homma C, Maseki N, Sakurai M, Hata J-i . 1991 Cancer Res. 51: 5937–5942

  • Knezevich SR, Garnett MJ, Pysher TJ, Beckwith JB, Grundy PE, Sorensen PH . 1998a Cancer Res. 58: 5046–5048

  • Knezevich SR, McFadden DE, Tao W, Lim JF, Sorensen PH . 1998b Nat. Genet. 18: 184–187

  • Kriauciunas KM, Myers Jr MG, Kahn CR . 2000 Mol. Cell. Biol. 20: 6849–6859

  • LeRoith D, Werner H, Beitner-Johnson D, Roberts Jr CT . 1995 Endocr. Rev. 16: 143–163

  • Liu JP, Baker J, Perkins AS, Robertson EJ, Efstratiadis A . 1993 Cell 75: 59–72

  • Mascarello JT, Cajulis TR, Krous HF, Carpenter PM . 1994 Cancer Genet. Cytogenet. 77: 50–54

  • Miknyoczki SJ, Lang D, Huang L, Klein-Szanto AJ, Dionne CA, Ruggeri BA . 1999 Int. J. Cancer 81: 417–427

  • Miranda C, Greco A, Miele C, Pierotti MA, Van Obberghen E . 2001 J. Cell. Physiol. 186: 35–46

  • Morrione A, DeAngelis T, Baserga R . 1995 J. Virol. 69: 5300–5303

  • Myers Jr MG, White MF . 1996 Annu. Rev. Pharmacol. Toxicol. 36: 615–658

  • Neuenschwander S, Roberts Jr CT, LeRoith D . 1995 Endocrinology 136: 4298–4303

  • O'Connor R, Kauffmann-Zeh A, Liu Y, Lehar S, Evan GI, Baserga R, Blattler WA . 1997 Mol. Cell. Biol. 17: 427–435

  • O'Malley DP, Mierau GW, Beckwith JB, Weeks DA . 1996 Ultrastruct. Pathol. 20: 417–427

  • Obermeier A, Lammers R, Wiesmuller KH, Jung G, Schlessinger J, Ullrich A . 1993 J. Biol. Chem. 268: 22963–22966

  • Pahlman S, Hoehner JC . 1996 Mol. Med. Today 2: 432–438

  • Pass HI, Mew DJ, Carbone M, Matthews WA, Donington JS, Baserga R, Walker CL, Resnicoff M, Steinberg SM . 1996 Cancer Res. 56: 4044–4048

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

  • Polychronakos C, Giannoukakis N, Deal CL . 1995 Dev. Genet. 17: 253–262

  • Ponten J . 1971 Virol. Monogr. 8: 1–253

  • Prager D, Li HL, Asa S, Melmed S . 1994 Proc. Natl. Acad. Sci. USA 91: 2181–2185

  • Razzini G, Ingrosso A, Brancaccio A, Sciacchitano S, Esposito DL, Falasca M . 2000 Mol. Endocrinol. 14: 823–836

  • Reinach FC, MacLeod AR . 1986 Nature 322: 648–650

  • Reiss K, D'Ambrosio C, Tu X, Tu C, Baserga R . 1998 Clin. Cancer Res. 4: 2647–2655

  • Resnicoff M, Coppola D, Sell C, Rubin R, Ferrone S, Baserga R . 1994a Cancer Res. 54: 4848–4850

  • Resnicoff M, Sell C, Rubini M, Coppola D, Ambrose D, Baserga R, Rubin R . 1994b Cancer Res. 54: 2218–2222

  • Reuther GW, Lambert QT, Caligiuri MA, Der CJ . 2000 Mol. Cell. Biol. 20: 8655–8666

  • Rubin BP, Chen CJ, Morgan TW, Xiao S, Grier HE, Kozakewich HP, Perez-Atayde AR, Fletcher JA . 1998 Am. J. Pathol. 153: 1451–1458

  • Sambrook J, Fritch EF, Maniatis T . 1989 Molecular cloning: a laboratory manual 2nd edn Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press

    Google Scholar 

  • Schofield DE, Fletcher JA, Grier HE, Yunis EJ . 1994 Am. J. Surg. Pathol. 18: 14–24

  • Schofield DE, Yunis EJ, Fletcher JA . 1993 Am. J. Pathol. 143: 714–724

  • Sell C, Dumenil G, Deveaud C, Miura M, Coppola D, DeAngelis T, Rubin R, Efstratiadis A, Baserga R . 1994 Mol. Cell. Biol. 14: 3604–3612

  • Sell C, Rubini M, Rubin R, Liu JP, Efstratiadis A, Baserga R . 1993 Proc. Natl. Acad. Sci. USA 90: 11217–11221

  • Sharifah NA, Yun K, McLay J . 1995 Diagn. Mol. Pathol. 4: 279–285

  • Steller MA, Zou Z, Schiller JT, Baserga R . 1996 Cancer Res. 56: 5087–5091

  • Surmacz E, Sell C, Swantek J, Kato H, Roberts Jr CT, LeRoith D, Baserga R . 1995 Exp. Cell Res. 218: 370–380

  • Tognon C, Garnett M, Kenward E, Kay R, Morrison K, Sorensen PHB . 2001 Cancer Research 61: 8909–8916

  • Toretsky JA, Helman LJ . 1996 J. Endocrinol. 149: 367–372

  • Toretsky JA, Kalebic T, Blakesley V, LeRoith D, Helman LJ . 1997 J. Biol. Chem. 272: 30822–30827

  • Valentinis B, Morrione A, Taylor SJ, Baserga R . 1997 Mol. Cell. Biol. 17: 3744–3754

  • Wai DH, Knezevich SR, Lucas T, Jansen B, Kay RJ, Sorensen PHB . 2000 Oncogene 19: 906–915

  • Wang W, Kumar P, Epstein J, Helman L, Moore JV, Kumar S . 1998 Cancer Res. 58: 4426–4433

  • Weeraratna AT, Arnold JT, George DJ, DeMarzo A, Isaacs JT . 2000 Prostate 45: 140–148

  • Werner H . 1998 Mol. Cell Endocrinol. 141: 1–5

  • Wieland I, Arden KC, Michels D, Klein-Hitpass L, Bohm M, Viars CS, Weidle UH . 1999 Oncogene 18: 4530–4537

  • Yamada M, Ohnishi H, Sano S, Nakatani A, Ikeuchi T, Hatanaka H . 1997 J. Biol. Chem. 272: 30334–30339

  • Yenush L, Zanella C, Uchida T, Bernal D, White MF . 1998 Mol. Cell. Biol. 18: 6784–6794

Download references

Acknowledgements

The authors wish to thank Dr Renato Baserga for supplying R− cells and Drs Michael Cox and Rob Kay for helpful discussions. This work was supported by funds from the Canadian Institutes for Health Research (to PHB Sorensen) and by funds from the Johal Program in Pediatric Oncology Basic and Translational Research at the BC Research Institute for Children's and Women's Health.

Author information

Authors and Affiliations

  1. Department of Pathology, BC Research Institute for Children's and Women's Health, and the University of British Columbia, Vancouver, BC V5Z 4H4, Canada

    Kevin B Morrison, Cristina E Tognon, Mathew J Garnett & Poul H B Sorensen

  2. Department of Pediatrics, BC Research Institute for Children's and Women's Health, and the University of British Columbia, Vancouver, BC V5Z 4H4, Canada

    Kevin B Morrison, Cristina E Tognon, Mathew J Garnett & Poul H B Sorensen

  3. Department of Pediatrics, Ste-Justine Hospital Research Center, Montreal, H3T 1C5, Quebec, Canada

    Cheri Deal

Authors
  1. Kevin B Morrison
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cristina E Tognon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mathew J Garnett
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Cheri Deal
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Poul H B Sorensen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Poul H B Sorensen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Morrison, K., Tognon, C., Garnett, M. et al. ETV6-NTRK3 transformation requires insulin-like growth factor 1 receptor signaling and is associated with constitutive IRS-1 tyrosine phosphorylation. Oncogene 21, 5684–5695 (2002). https://doi.org/10.1038/sj.onc.1205669

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1205669

Keywords

This article is cited by

Search

Advanced search

Quick links