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Differential requirement of Tyr1062 multidocking site by RET isoforms to promote neural cell scattering and epithelial cell branching

Oncogene volume 23, pages 7297–7309 (2004)Cite this article

Abstract

The receptor tyrosine kinase RET is alternatively spliced to yield two main isoforms, RET9 and RET51, which differ in their carboxyl terminal. Activated RET induces different biological responses such as morphological transformation, neurite outgrowth, proliferation, cell migration and branching. The two isoforms have been suggested to have separate intracellular signaling pathways and different roles in mouse development. Here we show that both isoforms are able to induce cell scattering of SK-N-MC neuroepithelioma cell line and branching tubule formation in MDCK cell line. However, the Y1062F mutation, which abrogates the transforming activity of both activated RET isoforms in NIH3T3 cells, does not abolish scattering and branching morphogenesis of RET51, whereas impairs these biological effects of RET9. The GDNF-induced biological effects of RET51 are inhibited by the simultaneous abrogation of both Tyr1062 and Tyr1096 docking sites. Thus, Tyr1096 may substitute the functions of Tyr1062. GRB2 is the only known adaptor protein binding to Tyr1096. Dominant-negative GRB2 expressed in MDCK cells together with RET9 or RET51 significantly reduces branching. Therefore, GRB2 is necessary for RET-mediated branching of MDCK cells.

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References

  • Airaksinen MS and Saarma M . (2002). Nat. Rev. Neurosci., 3, 383–394.

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

  • Alberti L, Carniti C, Miranda C, Roccato E and Pierotti MA . (2003). J. Cell. Physiol., 195, 168–186.

  • Andreozzi F, Melillo RM, Carlomagno F, Oriente F, Miele C, Fiory F, Santopietro S, Castellone MD, Beguinot F, Santoro M and Formisano P . (2003). Oncogene, 22, 2942–2949.

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

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

  • Baloh RH, Tansey MG, Golden JP, Creedon DJ, Heuckeroth RO, Keck CL, Zimonjic DB, Popescu NC, Johnson Jr EM and Milbrandt J . (1997). Neuron, 18, 793–802.

  • Baloh RH, Enomoto H, Johnson Jr EM and Milbrandt J . (2000). Curr. Opin. Neurobiol., 10, 103–110.

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

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

  • Borrello MG, Mercalli E, Perego C, Degl'Innocenti D., Ghizzoni S, Arighi E, Eroini B, Rizzetti MG and Pierotti MA . (2002). Biochem. Biophys. Res. Commun., 296, 515–522.

  • Borrello MG, Smith DP, Pasini B, Bongarzone I, Greco A, Lorenzo MJ, Arighi E, Miranda C, Eng C, Alberti L, Bocciardi R, Mondellini P, Scopsi L, Romeo G, Ponder BAJ and Pierotti MA . (1995). Oncogene, 11, 2419–2427.

  • Carter MT, Yome JL, Marcil MN, Martin CA, Vanhorne JB and Mulligan LM . (2001). Cytogenet. Cell. Genet., 95, 169–176.

  • Coulpier M, Anders J and Ibanez CF . (2002). J. Biol. Chem., 277, 1991–1999.

  • de Graaff E, Srinivas S, Kilkenny C, D'Agati V, Mankoo BS, Costantini F and Pachnis V . (2001). Genes Dev., 15, 2433–2444.

  • De Vita G, Melillo RM, Carlomagno F, Visconti R, Castellone MD, Bellacosa A, Billaud M, Fusco A, Tsichlis PN and Santoro M . (2000). Cancer Res., 60, 3727–3731.

  • Durbec PL, Larsson-Blomberg LB, Schuchardt A, Costantini F and Pachnis V . (1996). Development, 122, 349–358.

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

  • Fukuda T, Kiuchi K and Takahashi M . (2002). J. Biol. Chem., 277, 19114–19121.

  • Grimm J, Sachs M, Britsch S, Di Cesare S, Schwarz-Romond T, Alitalo K and Birchmeier W . (2001). J. Cell Biol., 154, 345–354.

  • 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.

  • Hayashi Y, Iwato M, Arakawa Y, Fujisawa H, Thoma Y, Hasegawa M, Tachibana O and Yamashita J . (2001). J. Neurooncol., 55, 51–58.

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

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

  • Iwahashi N, Murakami H, Nimura Y and Takahashi M . (2002). Biochem. Biophys. Res. Commun., 294, 642–649.

  • Iwashita T, Kurokawa K, Qiao S, Murakami H, Asai N, Kawai K, Hashimoto M, Watanabe T, Ichihara M and Takahashi M . (2001). Gastroenterology, 121, 24–33.

  • Jhiang SM . (2000). Oncogene, 19, 5590–5597.

  • Jing S, Yu Y, Fang M, Hu Z, Holst PL, Boone T, Delaney J, Schultz H, Zhou R and Fox GM . (1997). J. Biol. Chem., 272, 33111–33117.

  • Kawamoto Y, Takeda K, Okuno Y, Yamakawa Y, Ito Y, Taguchi R, Kato M, Suzuki H, Takahashi M and Nakashima I . (2004). J. Biol. Chem. (Jan 6 Epub ahead of print).

  • Kurokawa K, Iwashita T, Murakami H, Hayashi H, Kawai K and Takahashi M . (2001). Oncogene, 20, 1929–1938.

  • Lanzi C, Cassinelli G, Pensa T, Cassinis M, Gambetta RA, Borrello MG, Menta E, Pierotti MA and Zunino F . (2000). Int. J. Cancer, 85, 384–390.

  • Lee DC, Chan KW and Chan SY . (2002). Oncogene, 21, 5582–5592.

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

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

  • Melillo RM, Carlomagno F, De Vita G, Formisano P, Vecchio G, Fusco A, Billaud M and Santoro M . (2001). Oncogene, 20, 209–218.

  • Mercalli E, Ghizzoni S, Arighi E, Alberti L, Sangregorio R, Radice MT, Gishizky ML, Pierotti MA and Borrello MG . (2001). Oncogene, 20, 3475–3485.

  • Mograbi B, Bocciardi R, Bourget I, Busca R, Rochet N, Farahi-Far D, Juhel T and Rossi B . (2001a). J. Biol. Chem., 276, 45307–45319.

  • Mograbi B, Bocciardi R, Bourget I, Juhel T, Farahi-Far D, Romeo G, Ceccherini I and Rossi B . (2001b). Mol. Cell. Biol., 21, 6719–6730.

  • Pachnis V, Mankoo B and Costantini F . (1993). Development, 119, 1005–1017.

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

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

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

  • Pierotti MA, Bongarzone I, Borrello MG, Greco A, Pilotti S and Sozzi G . (1996). Genes Chromosomes Cancer, 16, 1–14.

  • Sanicola M, Hession C, Worley D, Carmillo P, Ehrenfels C, Walus L, Robinson S, Jaworski G, Wei H, Tizard R, Whitty A, Pepinsky RB and Cate RL . (1997). Proc. Natl. Acad. Sci. USA, 94, 6238–6243.

  • Schedl A and Hastie ND . (2000). Curr. Opin. Genet. Dev., 10, 543–549.

  • Schuchardt A, D'Agati V, Larsson-Blomberg L, Costantini F and Pachnis V . (1994). Nature, 367, 380–383.

  • Schuchardt A, D'Agati V, Pachnis V and Costantini F . (1996). Development, 122, 1919–1929.

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

  • Srinivas S, Wu Z, Chen CM, D'Agati V and Costantini F . (1999). Development, 126, 1375–1386.

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

  • Takahashi M, Ritz J and Cooper GM . (1985). Cell, 42, 581–588.

  • Tanaka M, Gupta R and Mayer BJ . (1995). Mol. Cell. Biol., 15, 6829–6837.

  • Tang MJ, Worley D, Sanicola M and Dressler GR . (1998). J. Cell Biol., 142, 1337–1345.

  • Taraviras S and Pachnis V . (1999). Curr. Opin. Genet. Dev., 9, 321–327.

  • Trupp M, Raynoschek C, Belluardo N and Ibanez CF . (1998). Mol. Cell. Neurosci., 11, 47–63.

  • Tsui-Pierchala BA, Ahrens RC, Crowder RJ, Milbrandt J and Johnson Jr EM . (2002). J. Biol. Chem., 277, 34618–34625.

  • Tsuzuki T, Takahashi M, Asai N, Iwashita T, Matsuyama M and Asai J . (1995). Oncogene, 10, 191–198.

  • van Puijenbroek AA, van Weering DH, van den Brink CE, Bos JL, van der Saag PT, de Laat SW and den Hertog J . (1997). Oncogene, 14, 1147–1157.

  • van Weering DH and Bos JL . (1997). J. Biol. Chem., 272, 249–254.

  • van Weering DH, Medema JP, van Puijenbroek A, Burgering BM, Baas PD and Bos JL . (1995). Oncogene, 11, 2207–2214.

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Acknowledgements

We gratefully acknowledge Mordechai Anafi and Bruce J Mayer for the GRB2 constructs, Darrin P Smith for RET-MEN2A mutant constructs and Cinzia Lanzi for RPI1 inhibitor. We thank Miss Maria Teresa Radice for excellent technical assistance and Miss Cristina Mazzadi for secretarial help. This study was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC) and Consiglio Nazionale Ricerche (CNR).

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Authors and Affiliations

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

    Debora Degl'Innocenti, Elena Arighi, Romina Sangregorio, Luisella Alberti, Maria Grazia Rizzetti, Marco A Pierotti & Maria Grazia Borrello

  2. Developmental Biology, Institute of Biomedicine, Biomedicum Helsinki, P.O. Box 63, FIN-0014 University of Helsinki, Finland

    Elena Arighi, Anna Popsueva & Hannu Sariola

  3. HUCH-Diagnostics Department of Pathology, P.O. Box 400, FIN-00290 Helsinki University Central Hospital, Finland

    Hannu Sariola

  4. FIRC Institute of Molecular Oncology (IFOM), Via Adamello, Milan, 16 20139, Italy

    Cristina Ferrario & Marco A Pierotti

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  1. Debora Degl'Innocenti
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Correspondence to Marco A Pierotti or Maria Grazia Borrello.

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Degl'Innocenti, D., Arighi, E., Popsueva, A. et al. Differential requirement of Tyr1062 multidocking site by RET isoforms to promote neural cell scattering and epithelial cell branching. Oncogene 23, 7297–7309 (2004). https://doi.org/10.1038/sj.onc.1207862

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