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  • Original Paper
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RAI(ShcC/N-Shc)-dependent recruitment of GAB1 to RET oncoproteins potentiates PI3-K signalling in thyroid tumors

Oncogene volume 24, pages 6303–6313 (2005)Cite this article

Abstract

RAI, also named ShcC/N-Shc, one of the members of the Shc proteins family, is a substrate of the RET receptor tyrosine kinase. Here, we show that RAI forms a protein complex with both RET/MEN2A and RET/PTC oncoproteins. By coimmunoprecipitation, we found that RAI associates with the Grb2-associated binder1 (GAB1) adapter. This association is constitutive, but, in the presence of RET oncoproteins, both RAI and GAB1 are tyrosine-phosphorylated, and the stoichiometry of this interaction remarkably increases. Consequently, the p85 regulatory subunit of phosphatidylinositol-3 kinase (PI-3K) is recruited to the complex, and its downstream effector Akt is activated. We show that human thyroid cancer cell lines derived from papillary or medullary thyroid carcinoma (PTC or MTC) carrying, respectively, RET/PTC and RET/MEN2A oncoproteins express RAI proteins. We also show that human PTC samples express higher levels of RAI, when compared to normal thyroid tissue. In thyroid cells expressing RET/PTC1, ectopic expression of RAI protects cells from apoptosis; on the other hand, the silencing of endogenous RAI by small inhibitory duplex RNAs in a PTC cell line that expresses endogenous RET/PTC1, increases the rate of spontaneous apoptosis. These data suggest that RAI is a critical substrate for RET oncoproteins in thyroid carcinomas.

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References

  • Basolo F, Giannini R, Toniolo A, Casalone R, Nikiforova M, Pacini F, Elisei R, Miccoli P, Berti P, Faviana P, Fiore L, Monaco C, Pierantoni GM, Fedele M, Nikiforov YE, Santoro M and Fusco A . (2002). Int. J. Cancer, 97, 608–614.

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

  • Carlomagno F, Vitagliano D, Guida T, Napolitano M, Vecchio G, Fusco A, Gazit A, Levitzki A and Santoro M . (2001). Cancer Res., 62, 1077–1082.

  • Castellone MD, Cirafici AM, De Vita G, De Falco V, Malorni L, Tallini G, Fagin JA, Fusco A, Melillo RM and Santoro M . (2003). Oncogene, 22, 246–255.

  • Cattaneo E and Pelicci PG . (1998). Trends Neurosci., 21, 476–481.

  • Celetti A, Cerrato A, Merolla F, Vitagliano D, Vecchio G and Grieco M . (2004). Oncogene, 23, 109–121.

  • Cerutti J, Trapasso F, Battaglia C, Zhang L, Martelli ML, Berlingieri MT, Fagin J, Santoro M and Fusco A . (1996). Clin. Cancer Res., 2, 119–126.

  • Conti L, Sipione S, Magrassi L, Bonfanti L, Rigamonti D, Pettirossi V, Peschanski M, Haddad B, Pelicci P, Milanesi G, Pelicci G and Cattaneo E . (2001). Nat. Neurosci., 4, 579–586.

  • Cooley LD, Elder FF, Knuth A and Gagel RF . (1995). Cancer Genet Cytogenet., 80, 138–149.

  • Curcio F, Ambesi-Impiombato FS, Perrella G and Coon HG . (1994). Proc. Natl. Acad. Sci. USA, 91, 9004–9008.

  • Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K and Tuschl T . (2001). Nature, 411, 494–498.

  • Ganju P, O’Bryan JP, Der C, Winter J and James IF . (1998). Eur. J. Neurosci., 10, 1995–2008.

  • Gu H and Neel BG . (2003). Trends Cell Biol., 13, 122–130.

  • 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.

  • Hingorani SR, Jacobetz MA, Robertson GP, Herlyn M and Tuveson DA . (2003). Cancer Res., 63, 5198–5202.

  • Jin ZG, Wong C, Wu J and Berk BC . (2005). J. Biol. Chem., 280, 12305–12309.

  • Lewitzky M, Kardinal C, Gehring NH, Schmidt EK, Konkol B, Eulitz M, Birchmeier W, Schaeper U and Feller SM . (2001). Oncogene, 20, 1052–1062.

  • Liu HY and Meakin SO . (2002). J. Biol. Chem., 277, 26046–26056.

  • Lock LS, Royal I, Naujokas MA and Park M . (2000). J. Biol. Chem., 275, 31536–31545.

  • Luzi L, Confalonieri S, Di Fiore PP and Pelicci PG . (2000). Curr. Opin. Genet. Dev., 10, 668–674.

  • Maeda K, Murakami H, Yoshida R, Ichihara M, Abe A, Hirai M, Murohara T and Takahashi M . (2004). Biochem. Biophys. Res. Commun., 323, 345–354.

  • Miyake I, Hakomori Y, Shinohara A, Gamou T, Saito M, Iwamatsu A and Sakai R . (2002). Oncogene, 21, 5823–5834.

  • Nakamura T, Komiya M, Gotoh N, Koizumi S, Shibuya M and Mori N . (2002). Oncogene, 21, 22–31.

  • Nakamura T, Muraoka S, Sanokawa R and Mori N . (1998). J. Biol. Chem., 273, 6960–6967.

  • Nakazawa T, Nakano I, Sato M, Nakamura T, Tamai M and Mori N . (2002). J. Neurosci. Res., 68, 668–680.

  • Nakamura T, Sanokawa R, Sasaki Y, Ayusawa D, Oishi M and Mori N . (1996). Oncogene, 13, 1111–1121.

  • Nikiforov YE . (2002). Endocr. Pathol., 13, 3–16.

  • O’Bryan JP, Lambert QT and Der CJ . (1998). J. Biol. Chem., 273, 20431–20437.

  • O’Bryan JP, Songyang Z, Cantley L, Der CJ and Pawson T . (1996). Proc. Natl. Acad. Sci. USA, 93, 2729–2734.

  • Ohta K, Endo T, Haraguchi K, Hershman JM and Onaya T . (2001). J. Clin. Endocrinol. Metab., 86, 2170–2177.

  • Pelicci G, Dente L, De Giuseppe A, Verducci-Galletti B, Giuli S, Mele S, Vetriani C, Giorgio M, Pandolfi PP, Cesareni G and Pelicci PG . (1996). Oncogene, 13, 633–641.

  • Pelicci G, Troglio F, Bodini A, Melillo RM, Pettirossi V, Coda L, De Giuseppe A, Santoro M and Pelicci PG . (2002). Mol. Cell. Biol., 22, 7351–7363.

  • Pierotti MA . (2001). Cancer Lett., 166, 1–7.

  • Ravichandran KS . (2001). Oncogene, 20, 6322–6330.

  • Sakai R, Henderson JT, O’Bryan JP, Elia AJ, Saxton TM and Pawson T . (2000). Neuron, 28, 819–833.

  • Santoro M, Carlomagno F, Melillo RM and Fusco A . (2004). Cell Mol. Life Sci., 61, 2954–2964.

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

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

  • Schaeper U, Gehring NH, Fuchs KP, Sachs M, Kempkes B and Birchmeier W . (2000). J. Cell Biol., 149, 1419–1432.

  • Segouffin-Cariou C and Billaud M . (2000). J. Biol. Chem., 275, 3568–3576.

  • Tanabe K, Kiryu-Seo S, Nakamura T, Mori N, Tsujino H, Ochi T and Kiyama H . (1998). Brain Res. Mol. Brain Res., 53, 291–296.

  • Tuschl T, Zamore PD, Lehmann R, Bartel DP and Sharp PA . (1999). Genes Dev., 13, 3191–3197.

  • 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.

  • Wang J, Knauf JA, Basu S, Puxeddu E, Kuroda H, Santoro M, Fusco A and Fagin JA . (2003). Mol. Endocrinol., 17, 1425–1436.

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Acknowledgements

We thank Francesco Curcio for P5 cells, JM Hershman for BHP cells, and S Giordano and P Gual for GAB1 plasmids. We are also grateful to Fulvio Basolo, who provided us the human tumor samples. This work was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC), by the Ministero Italiano per l’Universita’, Istruzione e Ricerca Scientifica (MIUR), by the BIOGEM s.c.a.r.l. (Biologia e Genetica Molecolare nel Mezzogiorno d’Italia) and by the Centro Regionale di Competenza GEAR (Genomic for Applied Research). VG was a fellow of the Centro Regionale di Competenza GEAR.

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  1. Valentina De Falco and Valentina Guarino: These authors contributed equally to this study

Authors and Affiliations

  1. c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, Istituto di Endocrinologia ed Oncologia Sperimentale del CNR ‘G. Salvatore’, Via S. Pansini 5, Naples, 80131, Italy

    Valentina De Falco, Valentina Guarino, Luca Malorni, Anna Maria Cirafici, Massimo Santoro & Rosa Marina Melillo

  2. Department of Experimental Oncology, European Institute of Oncology, Milan, Italy

    Flavia Troglio, Marco Erreni & Giuliana Pelicci

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  1. Valentina De Falco
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Correspondence to Rosa Marina Melillo.

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De Falco, V., Guarino, V., Malorni, L. et al. RAI(ShcC/N-Shc)-dependent recruitment of GAB1 to RET oncoproteins potentiates PI3-K signalling in thyroid tumors. Oncogene 24, 6303–6313 (2005). https://doi.org/10.1038/sj.onc.1208776

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