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RET and neuroendocrine tumors

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Abstract

The RET proto-oncogene encodes a receptor tyrosine kinase that is a main component of the signaling pathway activated by the glial cell line-derived neurotrophic factor family ligands. Gene targeting studies revealed that signaling through RET plays a crucial role in neuronal and renal organogenesis. It is well-known that germline mutations in RET lead to the human inherited diseases, multiple endocrine neoplasia type 2 (MEN 2) and Hirschsprung’s disease, and that somatic rearrangements of RET cause papillary thyroid carcinoma. Due to marked advances in understanding of the molecular mechanisms of the development of MEN 2, a consensus on MEN 2 management associated with RET status is being reached and currently put into general use as a guideline. In this review, we summarize progress in the study of RET from bench to bedside, focusing on pathophysiology of neuroendocrine tumors.

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References

  1. Takahashi M, Ritz J, Cooper GM (1985) Activation of a novel human transforming gene, ret, by DNA rearrangement. Cell 42:581–588

    PubMed  CAS  Google Scholar 

  2. Takahashi M, Cooper GM (1987) ret transforming gene encodes a fusion protein homologous to tyrosine kinases. Mol Cell Biol 7:1378–1385

    PubMed  CAS  Google Scholar 

  3. Takahashi M, Inaguma Y, Hiai H, Hirose F (1988) Developmentally regulated expression of a human “finger”-containing gene encoded by the 5′ half of the ret transforming gene. Mol Cell Biol 8:1853–1856

    PubMed  CAS  Google Scholar 

  4. Pachnis V, Mankoo B, Costantini F (1993) Expression of the c-ret proto-oncogene during mouse embryogenesis. Development 119:1005–1017

    PubMed  CAS  Google Scholar 

  5. Avantaggiato V, Dathan NA, Grieco M, Fabien N, Lazzaro D, Fusco A, Simeone A, Santoro M (1994) Developmental expression of the RET protooncogene. Cell Growth Differ 5:305–311

    PubMed  CAS  Google Scholar 

  6. Tsuzuki T, Takahashi M, Asai N, Iwashita T, Matsuyama M, Asai J (1995) Spatial and temporal expression of the ret proto-oncogene product in embryonic, infant and adult rat tissues. Oncogene 10:191–198

    PubMed  CAS  Google Scholar 

  7. Schuchardt A, D’Agati V, Larsson-Blomberg L, Costantini F, Pachnis V (1994) Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret. Nature 367:380–383

    PubMed  CAS  Google Scholar 

  8. Durbec PL, Larsson-Blomberg LB, Schuchardt A, Costantini F, Pachnis V (1996) Common origin and developmental dependence on c-ret of subsets of enteric and sympathetic neuroblasts. Development 122:349–358

    PubMed  CAS  Google Scholar 

  9. Taraviras S, Marcos-Gutierrez CV, Durbec P, Jani H, Grigoriou M, Sukumaran M, Wang LC, Hynes M, Raisman G, Pachnis V (1999) Signalling by the RET receptor tyrosine kinase and its role in the development of the mammalian enteric nervous system. Development 126:2785–2797

    PubMed  CAS  Google Scholar 

  10. Grieco M, Santoro M, Berlingieri MT, Melillo RM, Donghi R, Bongarzone I, Pierotti MA, Della Porta G, Fusco A, Vecchio G (1990) PTC is a novel rearranged form of the ret proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas. Cell 60:557–563

    PubMed  CAS  Google Scholar 

  11. Mulligan LM, Kwok JB, Healey CS, Elsdon MJ, Eng C, Gardner E, Love DR, Mole SE, Moore JK, Papi L, Ponder MA, Telenius H, Tunnacliffe A, Ponder BJ (1993) Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 363:458–460

    PubMed  CAS  Google Scholar 

  12. Donis-Keller H, Dou S, Chi D, Carlson KM, Toshima K, Lairmore TC, Howe JR, Moley JF, Goodfellow P, Wells SA Jr (1993) Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet 2:851–856

    PubMed  CAS  Google Scholar 

  13. Hofstra RM, Landsvater RM, Ceccherini I, Stulp RP, Stelwagen T, Luo Y, Pasini B, Hoppener JW, van Amstel HK, Romeo G, Lips CJ, Buys CH (1994) A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature 367:375–376

    PubMed  CAS  Google Scholar 

  14. Carlson KM, Dou S, Chi D, Scavarda N, Toshima K, Jackson CE, Wells SA Jr, Goodfellow PJ, Donis-Keller H (1994) Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B. Proc Natl Acad Sci USA 91:1579–1583

    PubMed  CAS  Google Scholar 

  15. Romeo G, Ronchetto P, Luo Y, Barone V, Seri M, Ceccherini I, Pasini B, Bocciardi R, Lerone M, Kaariainen H, Martucciello G (1994) Point mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschsprung’s disease. Nature 367:377–378

    PubMed  CAS  Google Scholar 

  16. Edery P, Lyonnet S, Mulligan LM, Pelet A, Dow E, Abel L, Holder S, Nihoul-Fekete C, Ponder BA, Munnich A (1994) Mutations of the RET proto-oncogene in Hirschsprung’s disease. Nature 367:378–380

    PubMed  CAS  Google Scholar 

  17. Ishizaka Y, Itoh F, Tahira T, Ikeda I, Sugimura T, Tucker J, Fertitta A, Carrano AV, Nagao M (1989) Human ret proto-oncogene mapped to chromosome 10q11.2. Oncogene 4:1519–1521

    PubMed  CAS  Google Scholar 

  18. Pasini B, Hofstra RM, Yin L, Bocciardi R, Santamaria G, Grootscholten PM, Ceccherini I, Patrone G, Priolo M, Buys CH, Romeo G (1995) The physical map of the human RET proto-oncogene. Oncogene 11:1737–1743

    PubMed  CAS  Google Scholar 

  19. Takahashi M, Buma Y, Iwamoto T, Inaguma Y, Ikeda H, Hiai H (1988) Cloning and expression of the ret proto-oncogene encoding a tyrosine kinase with two potential transmembrane domains. Oncogene 3:571–578

    PubMed  CAS  Google Scholar 

  20. Takahashi M, Buma Y, Hiai H (1989) Isolation of ret proto-oncogene cDNA with an amino-terminal signal sequence. Oncogene 4:805–806

    PubMed  CAS  Google Scholar 

  21. Iwamoto T, Taniguchi M, Asai N, Ohkusu K, Nakashima I, Takahashi M (1993) cDNA cloning of mouse ret proto-oncogene and its sequence similarity to the cadherin superfamily. Oncogene 8:1087–1091

    PubMed  CAS  Google Scholar 

  22. Tahira T, Ishizaka Y, Itoh F, Sugimura T, Nagao M (1990) Characterization of ret proto-oncogene mRNAs encoding two isoforms of the protein product in a human neuroblastoma cell line. Oncogene 5:97–102

    PubMed  CAS  Google Scholar 

  23. Myers SM, Eng C, Ponder BA, Mulligan LM (1995) Characterization of RET proto-oncogene 3’ splicing variants and polyadenylation sites: a novel C-terminus for RET. Oncogene 11:2039–2045

    PubMed  CAS  Google Scholar 

  24. Trupp M, Belluardo N, Funakoshi H, Ibanez CF (1997) Complementary and overlapping expression of glial cell line-derived neurotrophic factor (GDNF), c-ret proto-oncogene, and GDNF receptor-alpha indicates multiple mechanisms of trophic actions in the adult rat CNS. J Neurosci 17:3554–3567

    PubMed  CAS  Google Scholar 

  25. Enomoto H, Crawford PA, Gorodinsky A, Heuckeroth RO, Johnson EM Jr, Milbrandt J (2001) RET signaling is essential for migration, axonal growth and axon guidance of developing sympathetic neurons. Development 128:3963–3974

    PubMed  CAS  Google Scholar 

  26. Nagao M, Ishizaka Y, Nakagawara A, Kohno K, Kuwano M, Tahira T, Itoh F, Ikeda I, Sugimura T (1990) Expression of ret proto-oncogene in human neuroblastomas. Jpn J Cancer Res 81:309–312

    PubMed  CAS  Google Scholar 

  27. Ikeda I, Ishizaka Y, Tahira T, Suzuki T, Onda M, Sugimura T, Nagao M (1990) Specific expression of the ret proto-oncogene in human neuroblastoma cell lines. Oncogene 5:1291–1296

    PubMed  CAS  Google Scholar 

  28. Santoro M, Rosati R, Grieco M, Berlingieri MT, D’Amato GL, de Franciscis V, Fusco A (1990) The ret proto-oncogene is consistently expressed in human pheochromocytomas and thyroid medullary carcinomas. Oncogene 5:1595–1598

    PubMed  CAS  Google Scholar 

  29. Takahashi M, Buma Y, Taniguchi M (1991) Identification of the ret proto-oncogene products in neuroblastoma and leukemia cells. Oncogene 6:297–301

    PubMed  CAS  Google Scholar 

  30. de Graaff E, Srinivas S, Kilkenny C, D’Agati V, Mankoo BS, Costantini F, Pachnis V (2001) Differential activities of the RET tyrosine kinase receptor isoforms during mammalian embryogenesis. Genes Dev 15:2433–2444

    PubMed  CAS  Google Scholar 

  31. Tsui-Pierchala BA, Ahrens RC, Crowder RJ, Milbrandt J, Johnson EM Jr (2002) The long and short isoforms of Ret function as independent signaling complexes. J Biol Chem 277:34618–34625

    PubMed  CAS  Google Scholar 

  32. Lee DC, Chan KW, Chan SY (2002) RET receptor tyrosine kinase isoforms in kidney function and disease. Oncogene 21:5582–5592

    PubMed  CAS  Google Scholar 

  33. Lin LF, Doherty DH, Lile JD, Bektesh S, Collins F (1993) GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science 260:1130–1132

    PubMed  CAS  Google Scholar 

  34. Trupp M, Arenas E, Fainzilber M, Nilsson AS, Sieber BA, Grigoriou M, Kilkenny C, Salazar-Grueso E, Pachnis V, Arumae U (1996) Functional receptor for GDNF encoded by the c-ret proto-oncogene. Nature 381:785–789

    PubMed  CAS  Google Scholar 

  35. Treanor JJ, Goodman L, de Sauvage F, Stone DM, Poulsen KT, Beck CD, Gray C, Armanini MP, Pollock RA, Hefti F, Phillips HS, Goddard A, Moore MW, Buj-Bello A, Davies AM, Asai N, Takahashi M, Vandlen R, Henderson CE, Rosenthal A (1996) Characterization of a multicomponent receptor for GDNF. Nature 382:80–83

    PubMed  CAS  Google Scholar 

  36. Kotzbauer PT, Lampe PA, Heuckeroth RO, Golden JP, Creedon DJ, Johnson EM Jr, Milbrandt J (1996) Neurturin, a relative of glial-cell-line-derived neurotrophic factor. Nature 384:467–470

    PubMed  CAS  Google Scholar 

  37. 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 EM Jr (1998) Persephin, a novel neurotrophic factor related to GDNF and neurturin. Neuron 20:245–253

    PubMed  CAS  Google Scholar 

  38. Baloh RH, Tansey MG, Lampe PA, Fahrner TJ, Enomoto H, Simburger KS, Leitner ML, Araki T, Johnson EM Jr, Milbrandt J (1998) Artemin, a novel member of the GDNF ligand family, supports peripheral and central neurons and signals through the GFRalpha3-RET receptor complex. Neuron 21:1291–1302

    PubMed  CAS  Google Scholar 

  39. Jing S, Wen D, Yu Y, Holst PL, Luo Y, Fang M, Tamir R, Antonio L, Hu Z, Cupples R, Louis JC, Hu S, Altrock BW, Fox GM (1996) GDNF-induced activation of the ret protein tyrosine kinase is mediated by GDNFR-alpha, a novel receptor for GDNF. Cell 85:1113–1124

    PubMed  CAS  Google Scholar 

  40. Klein RD, Sherman D, Ho WH, Stone D, Bennett GL, Moffat B, Vandlen R, Simmons L, Gu Q, Hongo JA, Devaux B, Poulsen K, Armanini M, Nozaki C, Asai N, Goddard A, Phillips H, Henderson CE, Takahashi M, Rosenthal A (1997) A GPI-linked protein that interacts with Ret to form a candidate neurturin receptor. Nature 387:717–721

    PubMed  CAS  Google Scholar 

  41. Buj-Bello A, Adu J, Pinon LG, Horton A, Thompson J, Rosenthal A, Chinchetru M, Buchman VL, Davies AM (1997) Neurturin responsiveness requires a GPI-linked receptor and the Ret receptor tyrosine kinase. Nature 387:721–724

    PubMed  CAS  Google Scholar 

  42. Jing S, Yu Y, Fang M, Hu Z, Holst PL, Boone T, Delaney J, Schultz H, Zhou R, Fox GM (1997) GFRalpha-2 and GFRalpha-3 are two new receptors for ligands of the GDNF family. J Biol Chem 272:33111–33117

    PubMed  CAS  Google Scholar 

  43. Worby CA, Vega QC, Chao HH, Seasholtz AF, Thompson RC, Dixon JE (1998) Identification and characterization of GFRalpha-3, a novel Co-receptor belonging to the glial cell line-derived neurotrophic receptor family. J Biol Chem 273:3502–3508

    PubMed  CAS  Google Scholar 

  44. Thompson J, Doxakis E, Pinon LG, Strachan P, Buj-Bello A, Wyatt S, Buchman VL, Davies AM (1998) GFRalpha-4, a new GDNF family receptor. Mol Cell Neurosci 11:117–126

    PubMed  CAS  Google Scholar 

  45. Enokido Y, de Sauvage F, Hongo JA, Ninkina N, Rosenthal A, Buchman VL, Davies AM (1998) GFR alpha-4 and the tyrosine kinase Ret form a functional receptor complex for persephin. Curr Biol 8:1019–1022

    PubMed  CAS  Google Scholar 

  46. Sanchez MP, Silos-Santiago I, Frisen J, He B, Lira SA, Barbacid M (1996) Renal agenesis and the absence of enteric neurons in mice lacking GDNF. Nature 382:70–73

    PubMed  CAS  Google Scholar 

  47. Pichel JG, Shen L, Sheng HZ, Granholm AC, Drago J, Grinberg A, Lee EJ, Huang SP, Saarma M, Hoffer BJ, Sariola H, Westphal H (1996) Defects in enteric innervation and kidney development in mice lacking GDNF. Nature 382:73–76

    PubMed  CAS  Google Scholar 

  48. Moore MW, Klein RD, Farinas I, Sauer H, Armanini M, Phillips H, Reichardt LF, Ryan AM, Carver-Moore K, Rosenthal A (1996) Renal and neuronal abnormalities in mice lacking GDNF. Nature 382:76–79

    PubMed  CAS  Google Scholar 

  49. Cacalano G, Farinas I, Wang LC, Hagler K, Forgie A, Moore M, Armanini M, Phillips H, Ryan AM, Reichardt LF, Hynes M, Davies A, Rosenthal A (1998) GFRalpha1 is an essential receptor component for GDNF in the developing nervous system and kidney. Neuron 21:53–62

    PubMed  CAS  Google Scholar 

  50. Enomoto H, Araki T, Jackman A, Heuckeroth RO, Snider WD, Johnson EM Jr, Milbrandt J (1998) GFR alpha1-deficient mice have deficits in the enteric nervous system and kidneys. Neuron 21:317–324

    PubMed  CAS  Google Scholar 

  51. Heuckeroth RO, Enomoto H, Grider JR, Golden JP, Hanke JA, Jackman A, Molliver DC, Bardgett ME, Snider WD, Johnson EM Jr, Milbrandt J (1999) Gene targeting reveals a critical role for neurturin in the development and maintenance of enteric, sensory, and parasympathetic neurons. Neuron 22:253–263

    PubMed  CAS  Google Scholar 

  52. Rossi J, Luukko K, Poteryaev D, Laurikainen A, Sun YF, Laakso T, Eerikainen S, Tuominen R, Lakso M, Rauvala H, Arumae U, Pasternack M, Saarma M, Airaksinen MS (1999) Retarded growth and deficits in the enteric and parasympathetic nervous system in mice lacking GFR alpha2, a functional neurturin receptor. Neuron 22:243–252

    PubMed  CAS  Google Scholar 

  53. Honma Y, Araki T, Gianino S, Bruce A, Heuckeroth R, Johnson E, Milbrandt J (2002) Artemin is a vascular-derived neurotropic factor for developing sympathetic neurons. Neuron 35:267–282

    PubMed  CAS  Google Scholar 

  54. Nishino J, Mochida K, Ohfuji Y, Shimazaki T, Meno C, Ohishi S, Matsuda Y, Fujii H, Saijoh Y, Hamada H (1999) GFR alpha3, a component of the artemin receptor, is required for migration and survival of the superior cervical ganglion. Neuron 23:725–736

    PubMed  CAS  Google Scholar 

  55. Tomac AC, Agulnick AD, Haughey N, Chang CF, Zhang Y, Backman C, Morales M, Mattson MP, Wang Y, Westphal H, Hoffer BJ (2002) Effects of cerebral ischemia in mice deficient in Persephin. Proc Natl Acad Sci USA 99:9521–9526

    PubMed  CAS  Google Scholar 

  56. Lindfors PH, Lindahl M, Rossi J, Saarma M, Airaksinen MS (2006) Ablation of persephin receptor glial cell line-derived neurotrophic factor family receptor alpha4 impairs thyroid calcitonin production in young mice. Endocrinology 147:2237–2244

    PubMed  CAS  Google Scholar 

  57. Liu X, Vega QC, Decker RA, Pandey A, Worby CA, Dixon JE (1996) Oncogenic RET receptors display different autophosphorylation sites and substrate binding specificities. J Biol Chem 271:5309–5312

    PubMed  CAS  Google Scholar 

  58. Kawamoto Y, Takeda K, Okuno Y, Yamakawa Y, Ito Y, Taguchi R, Kato M, Suzuki H, Takahashi M, Nakashima I (2004) Identification of RET autophosphorylation sites by mass spectrometry. J Biol Chem 279:14213–14224

    PubMed  CAS  Google Scholar 

  59. Ichihara M, Murakumo Y, Takahashi M (2004) RET and neuroendocrine tumors. Cancer Lett 204:197–211

    PubMed  CAS  Google Scholar 

  60. Kodama Y, Asai N, Kawai K, Jijiwa M, Murakumo Y, Ichihara M, Takahashi M (2005) The RET proto-oncogene: a molecular therapeutic target in thyroid cancer. Cancer Sci 96:143–148

    PubMed  CAS  Google Scholar 

  61. Arighi E, Borrello MG, Sariola H (2005) RET tyrosine kinase signaling in development and cancer. Cytokine Growth Factor Rev 16:441–467

    PubMed  CAS  Google Scholar 

  62. Grimm J, Sachs M, Britsch S, Di Cesare S, Schwarz-Romond T, Alitalo K, Birchmeier W (2001) Novel p62 dok family members, dok-4 and dok-5, are substrates of the c-Ret receptor tyrosine kinase and mediate neuronal differentiation. J Cell Biol 154:345–354

    PubMed  CAS  Google Scholar 

  63. Uchida M, Enomoto A, Fukuda T, Kurokawa K, Maeda K, Kodama Y, Asai N, Hasegawa T, Shimono Y, Jijiwa M, Ichihara M, Murakumo Y, Takahashi M (2006) Dok-4 regulates GDNF-dependent neurite outgrowth through downstream activation of Rap1 and mitogen-activated protein kinase. J Cell Sci 119:3067–3077

    PubMed  CAS  Google Scholar 

  64. Crowder RJ, Enomoto H, Yang M, Johnson EM Jr, Milbrandt J (2004) Dok-6, a Novel p62 Dok family member, promotes Ret-mediated neurite outgrowth. J Biol Chem 279:42072–42081

    PubMed  CAS  Google Scholar 

  65. Jijiwa M, Fukuda T, Kawai K, Nakamura A, Kurokawa K, Murakumo Y, Ichihara M, Takahashi M (2004) A targeting mutation of tyrosine 1062 in Ret causes a marked decrease of enteric neurons and renal hypoplasia. Mol Cell Biol 24:8026–8036

    PubMed  CAS  Google Scholar 

  66. Wong A, Bogni S, Kotka P, de Graaff E, D’Agati V, Costantini F, Pachnis V (2005) Phosphotyrosine 1062 is critical for the in vivo activity of the Ret9 receptor tyrosine kinase isoform. Mol Cell Biol 25:9661–9673

    PubMed  CAS  Google Scholar 

  67. Encinas M, Tansey MG, Tsui-Pierchala BA, Comella JX, Milbrandt J, Johnson EM Jr (2001) c-Src is required for glial cell line-derived neurotrophic factor (GDNF) family ligand-mediated neuronal survival via a phosphatidylinositol-3 kinase (PI-3K)-dependent pathway. J Neurosci 21:1464–1472

    PubMed  CAS  Google Scholar 

  68. Encinas M, Crowder RJ, Milbrandt J, Johnson EM Jr (2004) Tyrosine 981, a novel ret autophosphorylation site, binds c-Src to mediate neuronal survival. J Biol Chem 279:18262–18269.

    PubMed  CAS  Google Scholar 

  69. Zhang Y, Zhu W, Wang YG, Liu XJ, Jiao L, Liu X, Zhang ZH, Lu CL, He C (2006) Interaction of SH2-Bbeta with RET is involved in signaling of GDNF-induced neurite outgrowth. J Cell Sci 119:1666–1676

    PubMed  CAS  Google Scholar 

  70. 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) The full oncogenic activity of Ret/ptc2 depends on tyrosine 539, a docking site for phospholipase Cgamma. Mol Cell Biol 16:2151–2163

    PubMed  CAS  Google Scholar 

  71. Alberti L, Borrello MG, Ghizzoni S, Torriti F, Rizzetti MG, Pierotti MA (1998) Grb2 binding to the different isoforms of Ret tyrosine kinase. Oncogene 17:1079–1087

    PubMed  CAS  Google Scholar 

  72. Fukuda T, Kiuchi K, Takahashi M (2002) Novel mechanism of regulation of Rac activity and lamellipodia formation by RET tyrosine kinase. J Biol Chem 277:19114–19121

    PubMed  CAS  Google Scholar 

  73. Schuringa JJ, Wojtachnio K, Hagens W, Vellenga E, Buys CH, Hofstra R, Kruijer W (2001) MEN2A-RET-induced cellular transformation by activation of STAT3. Oncogene 20:5350–5358

    PubMed  CAS  Google Scholar 

  74. Schuetz G, Rosario M, Grimm J, Boeckers TM, Gundelfinger ED, Birchmeier W (2004) The neuronal scaffold protein Shank3 mediates signaling and biological function of the receptor tyrosine kinase Ret in epithelial cells. J Cell Biol 167:945–952

    PubMed  CAS  Google Scholar 

  75. Tansey MG, Baloh RH, Milbrandt J, Johnson EM Jr (2000) GFRalpha-mediated localization of RET to lipid rafts is required for effective downstream signaling, differentiation, and neuronal survival. Neuron 25:611–623

    PubMed  CAS  Google Scholar 

  76. Paratcha G, Ledda F, Baars L, Coulpier M, Besset V, Anders J, Scott R, Ibanez CF (2001) Released GFRalpha1 potentiates downstream signaling, neuronal survival, and differentiation via a novel mechanism of recruitment of c-Ret to lipid rafts. Neuron 29:171–184

    PubMed  CAS  Google Scholar 

  77. Pierchala BA, Milbrandt J, Johnson EM Jr (2006) Glial cell line-derived neurotrophic factor-dependent recruitment of Ret into lipid rafts enhances signaling by partitioning Ret from proteasome-dependent degradation. J Neurosci 26:2777–2787

    PubMed  CAS  Google Scholar 

  78. Richardson DS, Lai AZ, Mulligan LM (2006) RET ligand-induced internalization and its consequences for downstream signaling. Oncogene 25:3206–3211

    PubMed  CAS  Google Scholar 

  79. Eng C (1999) RET proto-oncogene in the development of human cancer. J Clin Oncol 17:380–393

    PubMed  CAS  Google Scholar 

  80. Mulligan LM, Marsh DJ, Robinson BG, Schuffenecker I, Zedenius J, Lips CJ, Gagel RF, Takai SI, Noll WW, Fink M et al (1995) Genotype-phenotype correlation in multiple endocrine neoplasia type 2: report of the International RET Mutation Consortium. J Intern Med. 238:343–346

    PubMed  CAS  Google Scholar 

  81. Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF, van Amstel HK, Lips CJ, Nishisho I, Takai SI, Marsh DJ, Robinson BG, Frank-Raue K, Raue F, Xue F, Noll WW, Romei C, Pacini F, Fink M, Niederle B, Zedenius J, Nordenskjold M, Komminoth P, Hendy GN, Mulligan LM et al (1996) The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA 276:1575–1579

    PubMed  CAS  Google Scholar 

  82. Asai N, Iwashita T, Matsuyama M, Takahashi M (1995) Mechanism of activation of the ret proto-oncogene by multiple endocrine neoplasia 2A mutations. Mol Cell Biol 15:1613–1619

    PubMed  CAS  Google Scholar 

  83. Santoro M, Carlomagno F, Romano A, Bottaro DP, Dathan NA, Grieco M, Fusco A, Vecchio G, Matoskova B, Kraus MH, Di Fiore PP (1995) Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science 267:381–383

    PubMed  CAS  Google Scholar 

  84. 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 BA, Pierotti MA (1995) RET activation by germline MEN2A and MEN2B mutations. Oncogene 11:2419–2427

    PubMed  CAS  Google Scholar 

  85. Iwashita T, Asai N, Murakami H, Matsuyama M, Takahashi M (1996) Identification of tyrosine residues that are essential for transforming activity of the ret proto-oncogene with MEN2A or MEN2B mutation. Oncogene 12:481–487

    PubMed  CAS  Google Scholar 

  86. Rossel M, Pasini A, Chappuis S, Geneste O, Fournier L, Schuffenecker I, Takahashi M, van Grunsven LA, Urdiales JL, Rudkin BB, Lenoir GM, Billaud M (1997) Distinct biological properties of two RET isoforms activated by MEN 2A and MEN 2B mutations. Oncogene 14:265–275

    PubMed  CAS  Google Scholar 

  87. Ito S, Iwashita T, Asai N, Murakami H, Iwata Y, Sobue G, Takahashi M (1997) Biological properties of Ret with cysteine mutations correlate with multiple endocrine neoplasia type 2A, familial medullary thyroid carcinoma, and Hirschsprung’s disease phenotype. Cancer Res 57:2870–2872

    PubMed  CAS  Google Scholar 

  88. Pasini A, Geneste O, Legrand P, Schlumberger M, Rossel M, Fournier L, Rudkin BB, Schuffenecker I, Lenoir GM, Billaud M (1997) Oncogenic activation of RET by two distinct FMTC mutations affecting the tyrosine kinase domain. Oncogene 15:393–402

    PubMed  CAS  Google Scholar 

  89. Iwashita T, Kato M, Murakami H, Asai N, Ishiguro Y, Ito S, Iwata Y, Kawai K, Asai M, Kurokawa K, Kajita H, Takahashi M (1999) Biological and biochemical properties of Ret with kinase domain mutations identified in multiple endocrine neoplasia type 2B and familial medullary thyroid carcinoma. Oncogene 18:3919–3922

    PubMed  CAS  Google Scholar 

  90. Murakami H, Iwashita T, Asai N, Shimono Y, Iwata Y, Kawai K, Takahashi M (1999) Enhanced phosphatidylinositol 3-kinase activity and high phosphorylation state of its downstream signalling molecules mediated by ret with the MEN 2B mutation. Biochem Biophys Res Commun 262:68–75

    PubMed  CAS  Google Scholar 

  91. Murakami H, Yamamura Y, Shimono Y, Kawai K, Kurokawa K, Takahashi M (2002) Role of Dok1 in cell signaling mediated by RET tyrosine kinase. J Biol Chem 277:32781–32790

    PubMed  CAS  Google Scholar 

  92. Marshall GM, Peaston AE, Hocker JE, Smith SA, Hansford LM, Tobias V, Norris MD, Haber M, Smith DP, Lorenzo MJ, Ponder BA, Hancock JF (1997) Expression of multiple endocrine neoplasia 2B RET in neuroblastoma cells alters cell adhesion in vitro, enhances metastatic behavior in vivo, and activates Jun kinase. Cancer Res 57:5399–5405

    PubMed  CAS  Google Scholar 

  93. Songyang Z, Carraway KL 3rd, Eck MJ, Harrison SC, Feldman RA, Mohammadi M, Schlessinger J, Hubbard SR, Smith DP, Eng C, Lorenzo MJ, Ponder BA, Mayer BJ, Cantley LC (1995) Catalytic specificity of protein-tyrosine kinases is critical for selective signalling. Nature 373:536–539

    PubMed  CAS  Google Scholar 

  94. Bocciardi R, Mograbi B, Pasini B, Borrello MG, Pierotti MA, Bourget I, Fischer S, Romeo G, Rossi B (1997) The multiple endocrine neoplasia type 2B point mutation switches the specificity of the Ret tyrosine kinase towards cellular substrates that are susceptible to interact with Crk and Nck. Oncogene 15:2257–2265

    PubMed  CAS  Google Scholar 

  95. Salvatore D, Melillo RM, Monaco C, Visconti R, Fenzi G, Vecchio G, Fusco A, Santoro M (2001) Increased in vivo phosphorylation of ret tyrosine 1062 is a potential pathogenetic mechanism of multiple endocrine neoplasia type 2B. Cancer Res 61:1426–1431

    PubMed  CAS  Google Scholar 

  96. Mise N, Drosten M, Racek T, Tannapfel A, Putzer BM (2006) Evaluation of potential mechanisms underlying genotype-phenotype correlations in multiple endocrine neoplasia type 2. Oncogene (in press)

  97. Scheid MP, Woodgett JR (2001) PKB/AKT: functional insights from genetic models. Nat Rev Mol Cell Biol 2:760–768

    PubMed  CAS  Google Scholar 

  98. Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2:489–2501

    PubMed  CAS  Google Scholar 

  99. Enomoto A, Murakami H, Asai N, Morone N, Watanabe T, Kawai K, Murakumo Y, Usukura J, Kaibuchi K, Takahashi M (2005) Akt/PKB regulates actin organization and cell motility via Girdin/APE. Dev Cell 9:389–402

    PubMed  CAS  Google Scholar 

  100. Watanabe T, Ichihara M, Hashimoto M, Shimono K, Shimoyama Y, Nagasaka T, Murakumo Y, Murakami H, Sugiura H, Iwata H, Ishiguro N, Takahashi M (2002) Characterization of gene expression induced by RET with MEN2A or MEN2B mutation. Am J Pathol 161:249–256

    PubMed  CAS  Google Scholar 

  101. Jain S, Watson MA, DeBenedetti MK, Hiraki Y, Moley JF, Milbrandt J (2004) Expression profiles provide insights into early malignant potential and skeletal abnormalities in multiple endocrine neoplasia type 2B syndrome tumors. Cancer Res 64:3907–3913

    PubMed  CAS  Google Scholar 

  102. Nilsson O, Tisell LE, Jansson S, Ahlman H, Gimm O, Eng C (1999) Adrenal and extra-adrenal pheochromocytomas in a family with germline RET V804L mutation. JAMA 281:1587–1588

    PubMed  CAS  Google Scholar 

  103. Gimm O, Niederle BE, Weber T, Bockhorn M, Ukkat J, Brauckhoff M, Thanh PN, Frilling A, Klar E, Niederle B, Dralle H (2002) RET proto-oncogene mutations affecting codon 790/791: A mild form of multiple endocrine neoplasia type 2A syndrome? Surgery 132:952–959

    PubMed  Google Scholar 

  104. Dvorakova S, Vaclavikova E, Duskova J, Vlcek P, Ryska A, Bendlova B (2005) Exon 5 of the RET proto-oncogene: a newly detected risk exon for familial medullary thyroid carcinoma, a novel germ-line mutation Gly321Arg. J Endocrinol Invest 28:905–909

    PubMed  CAS  Google Scholar 

  105. Bae SJ, Kim DJ, Kim JY, Park SY, Choi SH, Song YD, Ki CS, Chung JH (2006) A Rare Extracellular D631Y Germl ine Mutation of the RET Proto-Oncogene in Two Korean Families with Multiple Endocrine Neoplasia 2A. Thyroid 16:609–614

    PubMed  CAS  Google Scholar 

  106. de Groot JW, Links TP, Plukker JT, Lips CJ, Hofstra RM (2006) RET as a Diagnostic and Therapeutic Target in Sporadic and Hereditary Endocrine Tumors. Endocr Rev (in press)

  107. Jindrichova S, Kodet R, Krskova L, Vlcek P, Bendlova B (2003) The newly detected mutations in the RET proto-oncogene in exon 16 as a cause of sporadic medullary thyroid carcinoma. J Mol Med 81:819–823

    PubMed  CAS  Google Scholar 

  108. Goodfellow PJ, Wells SA Jr (1995) RET gene and its implications for cancer. J Natl Cancer Inst 87:1515–1523

    PubMed  CAS  Google Scholar 

  109. Sherman SI (2003) Thyroid carcinoma. Lancet 361:501–511

    PubMed  Google Scholar 

  110. Hofstra RM, Landsvater RM, Ceccherini I, Stulp RP, Stelwagen T, Luo Y, Pasini B, Hoppener JW, van Amstel HK, Romeo G, Lips CJ, Buys CH (1994) A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature 367:375–376

    PubMed  CAS  Google Scholar 

  111. Eng C, Smith DP, Mulligan LM, Nagai MA, Healey CS, Ponder MA, Gardner E, Scheumann GF, Jackson CE, Tunnacliffe A, Ponder BA (1994) Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours. Hum Mol Genet 3:237–241

    PubMed  CAS  Google Scholar 

  112. Eng C, Mulligan LM, Smith DP, Healey CS, Frilling A, Raue F, Neumann HP, Pfragner R, Behmel A, Lorenzo MJ et al (1995) Mutation of the RET protooncogene in sporadic medullary thyroid carcinoma. Genes Chromosomes Cancer 12:209–212

    PubMed  CAS  Google Scholar 

  113. Marsh DJ, Learoyd DL, Andrew SD, Krishnan L, Pojer R, Richardson AL, Delbridge L, Eng C, Robinson BG (1996) Somatic mutations in the RET proto-oncogene in sporadic medullary thyroid carcinoma. Clin Endocrinol (Oxf) 44:249–257

    CAS  Google Scholar 

  114. Romei C, Elisei R, Pinchera A, Ceccherini I, Molinaro E, Mancusi F, Martino E, Romeo G, Pacini F (1996) Somatic mutations of the ret protooncogene in sporadic medullary thyroid carcinoma are not restricted to exon 16 and are associated with tumor recurrence. J Clin Endocrinol Metab 81:1619–1622

    PubMed  CAS  Google Scholar 

  115. Uchino S, Noguchi S, Yamashita H, Sato M, Adachi M, Yamashita H, Watanabe S, Ohshima A, Mitsuyama S, Iwashita T, Takahashi M (1999) Somatic mutations in RET exons 12 and 15 in sporadic medullary thyroid carcinomas: different spectrum of mutations in sporadic type from hereditary type. Jpn J Cancer Res 90:1231–1237

    PubMed  CAS  Google Scholar 

  116. Jindrichova S, Kodet R, Krskova L, Vlcek P, Bendlova B (2003) The newly detected mutations in the RET proto-oncogene in exon 16 as a cause of sporadic medullary thyroid carcinoma. J Mol Med 81:819–823

    PubMed  CAS  Google Scholar 

  117. Dvorakova S, Vaclavikova E, Sykorova V, Duskova J, Vlcek P, Ryska A, Novak Z, Bendlova B (2006) New multiple somatic mutations in the RET proto-oncogene associated with a sporadic medullary thyroid carcinoma. Thyroid 16:311–316

    PubMed  CAS  Google Scholar 

  118. Zedenius J, Larsson C, Bergholm U, Bovee J, Svensson A, Hallengren B, Grimelius L, Backdahl M, Weber G, Wallin G (1995) Mutations of codon 918 in the RET proto-oncogene correlate to poor prognosis in sporadic medullary thyroid carcinomas. J Clin Endocrinol Metab 80:3088–3090

    PubMed  CAS  Google Scholar 

  119. Zedenius J, Wallin G, Hamberger B, Nordenskjold M, Weber G, Larsson C (1994) Somatic and MEN 2A de novo mutations identified in the RET proto-oncogene by screening of sporadic MTC:s. Hum Mol Genet 3:1259–1262

    PubMed  CAS  Google Scholar 

  120. Komminoth P, Kunz EK, Matias-Guiu X, Hiort O, Christiansen G, Colomer A, Roth J, Heitz PU (1995) Analysis of RET protooncogene point mutations distinguishes heritable from nonheritable medullary thyroid carcinomas. Cancer 76:479–489

    PubMed  CAS  Google Scholar 

  121. Scurini C, Quadro L, Fattoruso O, Verga U, Libroia A, Lupoli G, Cascone E, Marzano L, Paracchi S, Busnardo B, Girelli ME, Bellastella A, Colantuoni V (1998) Germline and somatic mutations of the RET proto-oncogene in apparently sporadic medullary thyroid carcinomas. Mol Cell Endocrinol 137:51–57

    PubMed  CAS  Google Scholar 

  122. Shirahama S, Ogura K, Takami H, Ito K, Tohsen T, Miyauchi A, Nakamura Y (1998) Mutational analysis of the RET proto-oncogene in 71 Japanese patients with medullary thyroid carcinoma. J Hum Genet 43:101–106

    PubMed  CAS  Google Scholar 

  123. Huang CN, Wu SL, Chang TC, Huang SH, Chang TJ (1998) RET protooncogene mutations in patients with apparently sporadic medullary thyroid carcinoma. J Formos Med Assoc 97:541–546

    PubMed  CAS  Google Scholar 

  124. Koper JW, Lamberts SW (2000) Sporadic endocrine tumours and their relationship to the hereditary endocrine neoplasia syndromes. Eur J Clin Invest 30:493–500

    PubMed  CAS  Google Scholar 

  125. Wiench M, Wygoda Z, Gubala E, Wloch J, Lisowska K, Krassowski J, Scieglinska D, Fiszer-Kierzkowska A, Lange D, Kula D, Zeman M, Roskosz J, Kukulska A, Krawczyk Z, Jarzab B (2001) Estimation of risk of inherited medullary thyroid carcinoma in apparent sporadic patients. J Clin Oncol 19:1374–1380

    PubMed  CAS  Google Scholar 

  126. Pacak K, Linehan WM, Eisenhofer G, Walther MM, Goldstein DS (2001) Recent advances in genetics, diagnosis, localization, and treatment of pheochromocytoma. Ann Intern Med 134:315–329

    PubMed  CAS  Google Scholar 

  127. Neumann HP, Bausch B, McWhinney SR, Bender BU, Gimm O, Franke G, Schipper J, Klisch J, Altehoefer C, Zerres K, Januszewicz A, Eng C, Smith WM, Munk R, Manz T, Glaesker S, Apel TW, Treier M, Reineke M, Walz MK, Hoang-Vu C, Brauckhoff M, Klein-Franke A, Klose P, Schmidt H, Maier-Woelfle M, Peczkowska M, Szmigielski C, Eng C; Freiburg-Warsaw-Columbus Pheochromocytoma Study Group (2002) Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 346:1459–1466

    PubMed  CAS  Google Scholar 

  128. Bryant J, Farmer J, Kessler LJ, Townsend RR, Nathanson KL (2003) Pheochromocytoma: the expanding genetic differential diagnosis. J Natl Cancer Inst 95:1196–1204

    PubMed  CAS  Google Scholar 

  129. Lenders JW, Eisenhofer G, Mannelli M, Pacak K (2005) Phaeochromocytoma. Lancet 366:665–675

    PubMed  Google Scholar 

  130. Baysal BE, Ferrell RE, Willett-Brozick JE, Lawrence EC, Myssiorek D, Bosch A, Van Der Mey A, Taschner PE, Rubinstein WS, Myers EN, Richard CW 3rd, Cornelisse CJ, Devilee P, Devlin B (2000) Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 287:848–851

    PubMed  CAS  Google Scholar 

  131. Niemann S, Muller U (2000) Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat Genet 26:268–270

    PubMed  CAS  Google Scholar 

  132. Astuti D, Latif F, Dallol A, Dahia PL, Douglas F, George E, Skoldberg F, Husebye ES, Eng C, Maher ER (2001) Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet 69:49–54

    PubMed  CAS  Google Scholar 

  133. Beldjord C, Desclaux-Arramond F, Raffin-Sanson M, Corvol JC, De Keyzer Y, Luton JP, Plouin PF, Bertagna X (1995) The RET protooncogene in sporadic pheochromocytomas: frequent MEN 2-like mutations and new molecular defects. J Clin Endocrinol Metab 80:2063–2068

    PubMed  CAS  Google Scholar 

  134. Lindor NM, Honchel R, Khosla S, Thibodeau SN (1995) Mutations in the RET protooncogene in sporadic pheochromocytomas. J Clin Endocrinol Metab 80:627–629

    PubMed  CAS  Google Scholar 

  135. Yoshimoto K, Tanaka C, Hamaguchi S, Kimura T, Iwahana H, Miyauchi A, Itakura M (1995) Tumor-specific mutations in the tyrosine kinase domain of the RET proto-oncogene in pheochromocytomas of sporadic type. Endocr J 42:265–270

    PubMed  CAS  Google Scholar 

  136. Kondo T, Ezzat S, Asa SL (2006) Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nat Rev Cancer 6:292–306

    PubMed  CAS  Google Scholar 

  137. Pierotti MA, Bongarzone I, Borello MG, Greco A, Pilotti S, Sozzi G (1996) Cytogenetics and molecular genetics of carcinomas arising from thyroid epithelial follicular cells. Genes Chromosomes Cancer 16:1–14

    PubMed  CAS  Google Scholar 

  138. Jhiang SM (2000) The RET proto-oncogene in human cancers. Oncogene 19:5590–5597

    PubMed  CAS  Google Scholar 

  139. Tallini G, Asa SL (2001) RET oncogene activation in papillary thyroid carcinoma. Adv Anat Pathol 8:345–354

    PubMed  CAS  Google Scholar 

  140. Tallini G, Santoro M, Helie M, Carlomagno F, Salvatore G, Chiappetta G, Carcangiu ML, Fusco A (1998) RET/PTC oncogene activation defines a subset of papillary thyroid carcinomas lacking evidence of progression to poorly differentiated or undifferentiated tumor phenotypes. Clin Cancer Res 4:287–294

    PubMed  CAS  Google Scholar 

  141. Sugg SL, Ezzat S, Zheng L, Freeman JL, Rosen IB, Asa SL (1999) Oncogene profile of papillary thyroid carcinoma. Surgery 125:46–52

    PubMed  CAS  Google Scholar 

  142. Musholt TJ, Musholt PB, Khaladj N, Schulz D, Scheumann GF, Klempnauer J (2000) Prognostic significance of RET and NTRK1 rearrangements in sporadic papillary thyroid carcinoma. Surgery 128:984–993

    PubMed  CAS  Google Scholar 

  143. Nakazawa T, Kondo T, Kobayashi Y, Takamura N, Murata S, Kameyama K, Muramatsu A, Ito K, Kobayashi M, Katoh R (2005) RET gene rearrangements (RET/PTC1 and RET/PTC3) in papillary thyroid carcinomas from an iodine-rich country (Japan). Cancer 104:943–951

    PubMed  CAS  Google Scholar 

  144. Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE, Fagin JA (2003) High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer Res 63:1454–1457

    PubMed  CAS  Google Scholar 

  145. Xu X, Quiros RM, Gattuso P, Ain KB, Prinz RA (2003) High prevalence of BRAF gene mutation in papillary thyroid carcinomas and thyroid tumor cell lines. Cancer Res 63:4561–4567

    PubMed  CAS  Google Scholar 

  146. Puxeddu E, Moretti S, Elisei R, Romei C, Pascucci R, Martinelli M, Marino C, Avenia N, Rossi ED, Fadda G, Cavaliere A, Ribacchi R, Falorni A, Pontecorvi A, Pacini F, Pinchera A, Santeusanio F (2004) BRAF(V599E) mutation is the leading genetic event in adult sporadic papillary thyroid carcinomas. J Clin Endocrinol Metab 89:2414–2420

    PubMed  CAS  Google Scholar 

  147. Xing M (2005) BRAF mutation in thyroid cancer. Endocr Relat Cancer 12:245–262

    PubMed  CAS  Google Scholar 

  148. Melillo RM, Castellone MD, Guarino V, De Falco V, Cirafici AM, Salvatore G, Caiazzo F, Basolo F, Giannini R, Kruhoffer M, Orntoft T, Fusco A, Santoro M (2005) The RET/PTC-RAS-BRAF linear signaling cascade mediates the motile and mitogenic phenotype of thyroid cancer cells. J Clin Invest 115:1068–1081

    PubMed  CAS  Google Scholar 

  149. Mitsutake N, Miyagishi M, Mitsutake S, Akeno N, Mesa C Jr, Knauf JA, Zhang L, Taira K, Fagin JA (2006) BRAF mediates RET/PTC-induced mitogen-activated protein kinase activation in thyroid cells: functional support for requirement of the RET/PTC-RAS-BRAF pathway in papillary thyroid carcinogenesis. Endocrinology 147:1014–1019

    PubMed  CAS  Google Scholar 

  150. Lips CJ (1998) Clinical management of the multiple endocrine neoplasia syndromes: results of a computerized opinion poll at the Sixth International Workshop on Multiple Endocrine Neoplasia and von Hippel-Lindau disease. J Intern Med 243:589–594

    PubMed  CAS  Google Scholar 

  151. Berndt I, Reuter M, Saller B, Frank-Raue K, Groth P, Grussendorf M, Raue F, Ritter MM, Hoppner W (1998) A new hot spot for mutations in the ret protooncogene causing familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2A. J Clin Endocrinol Metab 83:770–774

    PubMed  CAS  Google Scholar 

  152. Niccoli-Sire P, Murat A, Rohmer V, Franc S, Chabrier G, Baldet L, Maes B, Savagner F, Giraud S, Bezieau S, Kottler ML, Morange S, Conte-Devolx B; French Calcitonin Tumors Group (GETC) (2001) Familial medullary thyroid carcinoma with noncysteine ret mutations: phenotype-genotype relationship in a large series of patients. J Clin Endocrinol Metab 86:3746–3753

    PubMed  CAS  Google Scholar 

  153. Brandi ML, Gagel RF, Angeli A, Bilezikian JP, Beck-Peccoz P, Bordi C, Conte-Devolx B, Falchetti A, Gheri RG, Libroia A, Lips CJ, Lombardi G, Mannelli M, Pacini F, Ponder BA, Raue F, Skogseid B, Tamburrano G, Thakker RV, Thompson NW, Tomassetti P, Tonelli F, Wells SA Jr, Marx SJ (2001) Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 86:5658–5671

    PubMed  CAS  Google Scholar 

  154. Skinner MA, Moley JA, Dilley WG, Owzar K, Debenedetti MK, Wells SA Jr (2005) Prophylactic thyroidectomy in multiple endocrine neoplasia type 2A. N Engl J Med 353:1105–1113

    PubMed  CAS  Google Scholar 

  155. Learoyd DL, Gosnell J, Elston MS, Saurine TJ, Richardson AL, Delbridge LW, Aglen JV, Robinson BG (2005) Experience of prophylactic thyroidectomy in multiple endocrine neoplasia type 2A kindreds with RET codon 804 mutations. Clin Endocrinol (Oxf) 63:636–641

    CAS  Google Scholar 

  156. Heizmann O, Haecker FM, Zumsteg U, Muller B, Oberholzer M, Oertli D (2006) Presymptomatic thyroidectomy in multiple endocrine neoplasia 2a. Eur J Surg Oncol 32:98–102

    PubMed  CAS  Google Scholar 

  157. Gosnell JE, Sywak MS, Sidhu SB, Gough IR, Learoyd DL, Robinson BG, Delbridge LW (2006) New era: prophylactic surgery for patients with multiple endocrine neoplasia-2a. ANZ J Surg 76:586–590

    PubMed  Google Scholar 

  158. Piolat C, Dyon JF, Sturm N, Pinson S, Bost M, Jouk PS, Plantaz D, Chabre O (2006) Very early prophylactic thyroid surgery for infants with a mutation of the RET proto-oncogene at codon 634: evaluation of the implementation of international guidelines for MEN type 2 in a single centre. Clin Endocrinol (Oxf) 65:118–124

    CAS  Google Scholar 

  159. Frank-Raue K, Buhr H, Dralle H, Klar E, Senninger N, Weber T, Rondot S, Hoppner W, Raue F (2006) Long-term outcome in 46 gene carriers of hereditary medullary thyroid carcinoma after prophylactic thyroidectomy: impact of individual RET genotype. Eur J Endocrinol 155:229–236

    PubMed  CAS  Google Scholar 

  160. Schuffenecker I, Virally-Monod M, Brohet R, Goldgar D, Conte-Devolx B, Leclerc L, Chabre O, Boneu A, Caron J, Houdent C, Modigliani E, Rohmer V, Schlumberger M, Eng C, Guillausseau PJ, Lenoir GM (1998) Risk and penetrance of primary hyperparathyroidism in multiple endocrine neoplasia type 2A families with mutations at codon 634 of the RET proto-oncogene. Groupe D’etude des Tumeurs a Calcitonine. J Clin Endocrinol Metab 83:487–491

    PubMed  CAS  Google Scholar 

  161. O’Riordain DS, O’Brien T, Grant CS, Weaver A, Gharib H, van Heerden JA (1993) Surgical management of primary hyperparathyroidism in multiple endocrine neoplasia types 1 and 2. Surgery 114:1031–1037

    PubMed  CAS  Google Scholar 

  162. Raue F, Kraimps JL, Dralle H, Cougard P, Proye C, Frilling A, Limbert E, Llenas LF, Niederle B (1995) Primary hyperparathyroidism in multiple endocrine neoplasia type 2A. J Intern Med 238:369–373

    PubMed  CAS  Google Scholar 

  163. Wu LT, Averbuch SD, Ball DW, de Bustros A, Baylin SB, McGuire WP 3rd (1994) Treatment of advanced medullary thyroid carcinoma with a combination of cyclophosphamide, vincristine, and dacarbazine. Cancer 73:432–436

    PubMed  CAS  Google Scholar 

  164. Nocera M, Baudin E, Pellegriti G, Cailleux AF, Mechelany-Corone C, Schlumberger M (2000) Treatment of advanced medullary thyroid cancer with an alternating combination of doxorubicin-streptozocin and 5 FU-dacarbazine. Groupe d’Etude des Tumeurs a Calcitonine (GETC). Br J Cancer 83:715–718

    PubMed  CAS  Google Scholar 

  165. Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J (2000) Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science 289:1938–1942

    PubMed  CAS  Google Scholar 

  166. Heinrich MC, Griffith DJ, Druker BJ, Wait CL, Ott KA, Zigler AJ (2000) Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood 96:925–932

    PubMed  CAS  Google Scholar 

  167. Cohen MS, Hussain HB, Moley JF (2002) Inhibition of medullary thyroid carcinoma cell proliferation and RET phosphorylation by tyrosine kinase inhibitors. Surgery 132:960–966

    PubMed  Google Scholar 

  168. de Groot JW, Plaza Menacho I, Schepers H, Drenth-Diephuis LJ, Osinga J, Plukker JT, Links TP, Eggen BJ, Hofstra RM (2006) Cellular effects of imatinib on medullary thyroid cancer cells harboring multiple endocrine neoplasia Type 2A and 2B associated RET mutations. Surgery 139:806–814

    PubMed  CAS  Google Scholar 

  169. Atkins M, Jones CA, Kirkpatrick P (2006) Sunitinib maleate. Nat Rev Drug Discov 5:279–280

    PubMed  CAS  Google Scholar 

  170. Kim DW, Jo YS, Jung HS, Chung HK, Song JH, Park KC, Park SH, Hwang JH, Rha SY, Kweon GR, Lee SJ, Jo KW, Shong M (2006) An orally administered multi-target tyrosine kinase inhibitor, SU11248, is a novel potent inhibitor of thyroid oncogenic RET/PTC kinases. J Clin Endocrinol Metab (in press)

  171. Carlomagno F, Anaganti S, Guida T, Salvatore G, Troncone G, Wilhelm SM, Santoro M (2006) BAY 43-9006 inhibition of oncogenic RET mutants. J Natl Cancer Inst 98:326–334

    PubMed  CAS  Google Scholar 

  172. Carlomagno F, Vitagliano D, Guida T, Ciardiello F, Tortora G, Vecchio G, Ryan AJ, Fontanini G, Fusco A, Santoro M (2002) ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases. Cancer Res 62:7284–7290

    PubMed  CAS  Google Scholar 

  173. Carlomagno F, Santoro M (2004) Identification of RET kinase inhibitors as potential new treatment for sporadic and inherited thyroid cancer. J Chemother 16(Suppl 4):49–51

    PubMed  CAS  Google Scholar 

  174. Cuccuru G, Lanzi C, Cassinelli G, Pratesi G, Tortoreto M, Petrangolini G, Seregni E, Martinetti A, Laccabue D, Zanchi C, Zunino F (2004) Cellular effects and antitumor activity of RET inhibitor RPI-1 on MEN2A-associated medullary thyroid carcinoma. J Natl Cancer Inst 96:1006–1014

    PubMed  CAS  Google Scholar 

  175. Petrangolini G, Cuccuru G, Lanzi C, Tortoreto M, Belluco S, Pratesi G, Cassinelli G, Zunino F (2006) Apoptotic cell death induction and angiogenesis inhibition in large established medullary thyroid carcinoma xenografts by Ret inhibitor RPI-1. Biochem Pharmacol 72:405–414

    PubMed  CAS  Google Scholar 

  176. Carlomagno F, Vitagliano D, Guida T, Napolitano M, Vecchio G, Fusco A, Gazit A, Levitzki A, Santoro M (2002) The kinase inhibitor PP1 blocks tumorigenesis induced by RET oncogenes. Cancer Res 62:1077–1082

    PubMed  CAS  Google Scholar 

  177. Carlomagno F, Vitagliano D, Guida T, Basolo F, Castellone MD, Melillo RM, Fusco A, Santoro M (2003) Efficient inhibition of RET/papillary thyroid carcinoma oncogenic kinases by 4-amino-5-(4-chloro-phenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2). J Clin Endocrinol Metab 88:1897–1902

    PubMed  CAS  Google Scholar 

  178. Strock CJ, Park JI, Rosen M, Dionne C, Ruggeri B, Jones-Bolin S, Denmeade SR, Ball DW, Nelkin BD (2003) CEP-701 and CEP-751 inhibit constitutively activated RET tyrosine kinase activity and block medullary thyroid carcinoma cell growth. Cancer Res 63:5559–5563

    PubMed  CAS  Google Scholar 

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  1. Department of Pathology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan

    Yoshiki Murakumo, Mayumi Jijiwa, Naoya Asai, Masatoshi Ichihara & Masahide Takahashi

  2. Division of Molecular Pathology, Center for Neurological Disease and Cancer, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan

    Masahide Takahashi

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  1. Yoshiki Murakumo
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Correspondence to Yoshiki Murakumo.

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Murakumo, Y., Jijiwa, M., Asai, N. et al. RET and neuroendocrine tumors. Pituitary 9, 179–192 (2006). https://doi.org/10.1007/s11102-006-0263-4

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