Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

RET Tyrosine Kinase Receptor

  • Maria Domenica Castellone
  • Mikko O. Laukkanen
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101648

Synonyms

 CDHF12;  CDHR16;  HSCR1;  MTC1;  MEN2;  PTC

Historical Background

RET (REarranged during Transfection) proto-oncogene, which locates on chromosome 10q11.2, encodes for a tyrosine kinase receptor that binds ligands of the GDNF (Glial-Derived Neurotrophic Factor) family (Maniè et al. 2001). It was first isolated in 1985 by Takahashi and coworkers (Takahashi et al. 1985) and later found rearranged in human thyroid papillary carcinoma (PTC) as a chimeric gene generated by fusion of RET tyrosine kinase with 5′ terminal region of a new gene called CCDC6, located on the same chromosome 10 (Grieco et al. 1990). RET is physiologically involved in the development of the central and peripheral nervous system, kidney, male germ cells, and thyroid calcitonin-secreting parafollicular C cells. In humans, loss-of-function mutations of RET cause congenital aganglionosis of the colon and impaired enteric nervous system formation, known as Hirschsprung’s disease, whereas RET gain-of-function...

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References

  1. Ballerini P, Struski S, Cresson C, Prade N, Toujani S, Deswarte C, Dobbelstein S, Petit A, Lapillonne H, Gautier EF, Demur C, Lippert E, Pages P, Mansat-De Mas V, Donadieu J, Huguet F, Dastugue N, Broccardo C, Perot C, Delabesse E. RET fusion genes are associated with chronic myelomonocytic leukemia and enhance monocytic differentiation. Leukemia. 2012;26:2384–9.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Castellone MD, Santoro M. Dysregulated RET signaling in thyroid cancer. Endocrinol Metab Clin N Am. 2008;37:363–74.CrossRefGoogle Scholar
  3. Flavin R, Jackl G, Finn S, Smyth P, Ring M, O’Regan E, Cahill S, Unger K, Denning K, Jinghuan L, Aherne S, Tallini G, Gaffney E, O’Leary JJ, Zitzelsberger H, Sheils O. RET/PTC rearrangement occurring in primary peritoneal carcinoma. Int J Surg Pathol. 2009;17:187–97.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Gattelli A, Nalvarte I, Boulay A, Roloff TC, Schreiber M, Carragher N, Macleod KK, Schlederer M, Lienhard S, Kenner L, Torres-Arzayus MI, Hynes NE. Ret inhibition decreases growth and metastatic potential of estrogen receptor positive breast cancer cells. EMBO Mol Med. 2013;5:1335–50.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Grieco M, Santoro M, Berlingieri MT, Melillo RM, Donghi R, Bongarzone I, Pierotti MA, Della Porta G, Fusco A, Vecchio G. PTC is a novel rearranged form of the ret proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas. Cell. 1990;60:557–63.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Guerra A, Di Crescenzo V, Garzi A, Cinelli M, Carlomagno C, Tonacchera M, Zeppa P, Vitale M. Genetic mutations in the treatment of anaplastic thyroid cancer: a systematic review. BMC Surg. 2013;13:S44.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Kawamoto Y, Takeda K, Okuno Y, Yamakawa Y, Ito Y, Taguchi R, Kato M, Suzuki H, Takahashi M, Nakashima I. Identification of RET autophosphorylation sites by mass spectrometry. J Biol Chem. 2004;279:14213–24.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Kohno T, Ichikawa H, Totoki Y, Yasuda K, Hiramoto M, Nammo T, Sakamoto H, Tsuta K, Furuta K, Shimada Y, Iwakawa R, Ogiwara H, Oike T, Enari M, Schetter AJ, Okayama H, Haugen A, Skaug V, Chiku S, Yamanaka I, Arai Y, Watanabe S, Sekine I, Ogawa S, Harris CC, Tsuda H, Yoshida T, Yokota J, Shibata T. KIF5B-RET fusions in lung adenocarcinoma. Nat Med. 2012;18:375–7.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Kondo T, Ezzat S, Asa SL. Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nat Rev Cancer. 2006;6:292–306.CrossRefPubMedGoogle Scholar
  10. Maniè S, Santoro M, Fusco A, Billaud M. The RET receptor: function in development and dysfunction in congenital malformation. Trends Genet. 2001;17:580–9.PubMedPubMedCentralCrossRefGoogle Scholar
  11. Nikiforov YE. RET/PTC rearrangement in thyroid tumors. Endocr Pathol. 2002;13:3–16.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Santoro M, Melillo RM, Carlomagno F, Fusco A, Vecchio G. Molecular mechanisms of RET activation in human cancer. Ann N Y Acad Sci. 2002;963:116–21.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Santoro M, Carlomagno F, Melillo RM, Fusco A. Dysfunction of the RET receptor in human cancer. Cell Mol Life Sci. 2004;61:2954–64.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Santoro M, Carlomagno F. Drug insight: small-molecule inhibitors of protein kinases in the treatment of thyroid cancer. Nat Clin Pract Endocrinol Metab. 2006;2:42–52.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Schlumberger M, Sherman SI. Clinical trials for progressive differentiated thyroid cancer: patient selection, study design, and recent advances. Thyroid. 2009;19:1393–400.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Takahashi M, Ritz J, Cooper GM. Activation of a novel human transforming gene, ret, by DNA rearrangement. Cell. 1985;42:581–8.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Thomas GA, Bunnell H, Cook HA, Williams ED, Nerovnya A, et al. High prevalence of RET/PTC rearrangements in Ukrainian and Belarussian post-Chernobyl thyroid papillary carcinomas: a strong correlation between RET/PTC3 and the solid-follicular variant. J Clin Endocrinol Metab. 1999;84:4232–8.PubMedPubMedCentralGoogle Scholar
  18. Wells Jr SA, Robinson BG, Gagel RF, Dralle H, Fagin JA, Santoro M, Baudin E, Elisei R, Jarzab B, Vasselli JR, Read J, Langmuir P, Ryan AJ, Schlumberger MJ. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012;30:134–41.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Wiesner T, He J, Yelensky R, Esteve-Puig R, Botton T, Yeh I, Lipson D, Otto G, Brennan K, Murali R, Garrido M, Miller VA, Ross JS, Berger MF, Sparatta A, Palmedo G, Cerroni L, Busam KJ, Kutzner H, Cronin MT, Stephens PJ, Bastian BC. Kinase fusions are frequent in Spitz tumours and spitzoid melanomas. Nat Commun. 2014;5:3116.PubMedPubMedCentralCrossRefGoogle Scholar
  20. Williams D. Twenty years’ experience with post-Chernobyl thyroid cancer. Best Pract Res Clin Endocrinol Metab. 2008;22:1061–73.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Maria Domenica Castellone
    • 1
  • Mikko O. Laukkanen
    • 2
  1. 1.Institute of Experimental Endocrinology and Oncology (IEOS), CNRNaplesItaly
  2. 2.IRCCS SDNNaplesItaly