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The RFG oligomerization domain mediates kinase activation and re-localization of the RET/PTC3 oncoprotein to the plasma membrane

Oncogene volume 20, pages 599–608 (2001)Cite this article

Abstract

The RET/PTC3 oncogene arises from the fusion between the N-terminal encoding domain of the RFG gene and the tyrosine kinase encoding domain of RET receptor. RET/PTC3 is very frequent in papillary thyroid carcinomas, especially in children exposed to the Chernobyl accident. We have studied the functional consequences of the RFG–RET fusion. Here we show that the N-terminal coiled-coil domain of RGF mediates oligomerization and activation of the kinase and of the transforming capability of RET/PTC3. In addition, the RFG coiled-coil domain mediates a physical association between RET/PTC3 and RGF proteins, rendering RFG a bona fide substrate of RET/PTC3 kinase. Finally, we show that the coiled-coil domain of RGF is essential for the distribution of the RET/PTC3 protein at the membrane/particulate cell compartment level, where also most of the RFG protein is localized. We propose that fusion to the RFG coiled-coil domain provides RET kinase with a scaffold that mediates oligomerization and re-localization of the RET/PTC3 protein, a process that may be crucial for the signalling of this specific RET/PTC variant.

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References

  • Airaksinen MS, Titievsky A and Saarma M. . 1999 Mol. Cell. Neurosci. 13: 313–325.

  • Bongarzone I, Butti MG, Coronelli S, Borrello MG, Santoro M, Mondellini P, Pilotti S, Fusco A, Della Porta G and Pierotti MA. . 1994 Cancer Res. 54: 2979–2985.

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

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

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

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

  • Fazioli F, Minichiello L, Matoskova B, Wong WT and Di Fiore PP. . 1993 Mol. Cell. Biol. 13: 5814–5828.

  • Grieco M, Santoro M, Berlingieri MT, Melillo RM, Donghi R, Bongarzone I, Pierotti MA, Della Porta G, Fusco A and Vecchio G. . 1990 Cell 60: 557–563.

  • Hayashi H, Ichihara M, Iwashita T, Murakami H, Shimono Y, Kawai K, Kurokawa K, Murakumo Y, Imai T, Funahashi H, Nakao A and Takahashi M. . 2000 Oncogene 19: 4469–4475.

  • Heinlein CA, Ting HJ, Yeh S and Chang C. . 1999 J. Biol. Chem. 274: 16147–16152.

  • Huang LF, Durick K, Weiner JA, Chun J and Taylor SS. . 1997a Proc. Natl. Acad. Sci. USA 94: 11184-11189.

  • Huang LJ, Durick K, Weiner JA, Chun J and Taylor SS. . 1997b J. Biol. Chem. 272: 8057–8064.

  • Jhiang SM, Sagartz JE, Tong Q, Parker-Thornburg J, Capen CC, Cho JY, Xing S and Ledent C. . 1996 Endocrinology 137: 375–378.

  • Klugbauer S, Demidchik EP, Lengfelder E and Rabes HM. . 1998a Cancer Res. 58: 198–203.

  • Klugbauer S, Demidchik EP, Lengfelder E and Rabes HM. . 1998b Oncogene 16: 671–675.

  • Klugbauer S and Rabes HM. . 1999 Oncogene 18: 4388–4393.

  • Nakata T, Kitamura Y, Shimizu K, Tanaka S, Fujimori M, Yokoyama S, Ito K and Emi M. . 1999 Genes Chrom. Cancer 25: 97–103.

  • Nikiforov YE, Rowland JM, Bove KE, Monforte-Munoz H and Fagin JA. . 1997 Cancer Res. 57: 1690–1694.

  • Nikoforova MN, Stringer JR, Blough R, Medvedovic M, Fagin JA and Nikiforov YE. . 2000 Science 290: 138–141.

  • Pawson T and Scott JD. . 1997 Science 278: 2075–2080.

  • Pierotti MA, Vigneri P and Bongarzone I. . 1998 Rec. Res. Cancer Res. 154: 237–247.

  • Powell Jr DJ, Russell J, Nibu K, Li G, Rhee E, Liao M, Goldstein M, Keane WM, Santoro M, Fusco A and Rothstein JL. . 1998 Cancer Res. 58: 5523–5528.

  • Rodrigues GA and Park M. . 1994 Curr. Opin. Genet. Dev. 4: 15–24.

  • Salassidis K, Bruch J, Zitzelsberger H, Lengfelder E, Kellerer AM and Bauchinger M. . 2000 Cancer Res. 60: 2786–2789.

  • Santoro M, Melillo RM, Grieco M, Berlingieri MT, Vecchio G and Fusco A. . 1993 Cell Growth Differ. 4: 77–84.

  • Santoro M, Dathan NA, Berlingieri MT, Bongarzone I, Paulin C, Grieco M, Pierotti MA, Vecchio G and Fusco A. . 1994 Oncogene 9: 509–516.

  • Santoro M, Chiappetta G, Cerrato A, Salvatore D, Zhang L, Manzo G, Picone A, Portella G, Santelli G, Vecchio G and Fusco A. . 1996 Oncogene 12: 1821–1826.

  • Sugg SL, Ezzat S, Rosen IB, Freeman JL and Asa SL. . 1998 J. Clin. Endocrinol. Metab. 83: 4116–4122.

  • Thomas GA, Bunnell H, Cook HA, Williams ED, Nerovnya A, Cherstvoy ED, Tronko ND, Bogdanova TI, Chiappetta G, Viglietto G, Pentimalli F, Salvatore G, Fusco A, Santoro M and Vecchio G. . 1999 J. Clin. Endocrinol. Metab. 84: 4232–4238.

  • Tong Q, Xing S and Jhiang SM. . 1997 J. Biol. Chem. 272: 9043–9047.

  • Treuter E, Albrektsen T, Johansson L, Leers J and Gustafsson JA. . 1998 Mol. Endocrinol. 12: 864–881.

  • Viglietto G, Chiappetta G, Martinez-Tello FJ, Fukunaga FH, Tallini G, Rigopoulou D, Visconti R, Mastro A, Santoro M and Fusco A. . 1995 Oncogene 11: 1207–1210.

  • Yeh S and Chang C. . 1996 Proc. Natl. Acad. Sci. USA 93: 5517–5521.

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Acknowledgements

We are grateful to O Segatto for the 293T cells, S Gutkind for the pCEFL-HA vector, and PP Di Fiore for the anti-eps15 antibody. We thank F Carlomagno for the two-hybrid assay and critical reading of the manuscript, F Sferratore for technical assistance and Jean Ann Gilder for editing the text. This study was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC), by EC grants BMH4-CT96-0814 and FIS5 1999 00032 and by the Progetto Biotecnologie ‘5%’ of the Consiglio Nazionale delle Ricerche (CNR). MV Barone and GM Pierantoni were recipients of fellowships of the Italian Foundation for Cancer Research (FIRC). The paper was written while G Vecchio was a Scholar-in-Residence at the Fogarty International Center for Advanced Study in the Health Sciences, National Institutes of Health, Bethesda.

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Authors and Affiliations

  1. c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, Centro di Endocrinologia ed Oncologia Sperimentale del CNR, Facoltà di Medicina e Chirurgia, Università di Napoli ‘Federico II’ via S. Pansini 5, Naples, 80131, Italy

    Carmen Monaco, Roberta Visconti, Maria Vittoria Barone, Giovanna Maria Pierantoni, Maria Terasa Berlingieri, Giancarlo Vecchio & Massimo Santoro

  2. Department of Organic and Biological Chemistry, Università di Napoli ‘Federico II’, Via Mezzocannone 16, Naples, 80134, Italy

    Claudia De Lorenzo

  3. Fondazione Senatore Pascale, via M. Semmola, Naples, 80131, Italy

    Alba Mineo

  4. Dipartimento di Medicina Sperimentale e Clinica, Facoltà di Medicina e Chirurgia, Università di Catanzaro, via T. Campanella 5, Catanzaro, 88100, Italy

    Alfredo Fusco

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  1. Carmen Monaco
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  2. Roberta Visconti
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  3. Maria Vittoria Barone
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  5. Maria Terasa Berlingieri
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  6. Claudia De Lorenzo
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  7. Alba Mineo
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  8. Giancarlo Vecchio
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Monaco, C., Visconti, R., Barone, M. et al. The RFG oligomerization domain mediates kinase activation and re-localization of the RET/PTC3 oncoprotein to the plasma membrane. Oncogene 20, 599–608 (2001). https://doi.org/10.1038/sj.onc.1204127

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