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Gene Review

RET  -  ret proto-oncogene

Homo sapiens

Synonyms: CDHF12, CDHR16, HSCR1, MEN2A, MEN2B, ...
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Disease relevance of RET


Psychiatry related information on RET


High impact information on RET

  • These results uncover an unexpected intersection between short- and long-range mechanisms of intercellular communication and reveal a pathway for GDNF signaling that does not require the RET receptor [13].
  • Here we show oligogenic inheritance of S-HSCR, the 3p21 and 19q12 loci as RET-dependent modifiers, and a parent-of-origin effect at RET [14].
  • Waardenburg syndrome (WS; deafness with pigmentary abnormalities) and Hirschsprung's disease (HSCR; aganglionic megacolon) are congenital disorders caused by defective function of the embryonic neural crest [15].
  • Three mutations in the MET gene are located in codons that are homologous to those in c-kit and RET, proto-oncogenes that are targets of naturally-occurring mutations [16].
  • However, it may be that in rare instances, RET and GDNF mutations act in concert to produce an enteric phenotype [1].

Chemical compound and disease context of RET


Biological context of RET


Anatomical context of RET

  • Although RET's ligand has remained elusive, it is expected to be an extracellular neurotrophic molecule expressed in the developing gut and kidney mesenchyme, based on the phenotypes of intestinal aganglionosis and renal agenesis observed in homozygous RET knockout (Ret -/-) mice [1].
  • In addition, quantitative analysis in PC12 cells reveals that mutation Delta1059 inactivates the ability of RET to transduce a downstream signal whereas mutation L1061P only partially inhibits the signalling of RET [27].
  • We have generated cell lines stably expressing either the RET9 or RET51 protein isoforms and have used these to investigate RET-mediated gene expression patterns by cDNA microarray analyses [24].
  • We also saw increased expression of transcripts normally associated with neural crest or other RET-expressing cell types, suggesting these genes may lie downstream of RET activation in development [24].
  • RET was expressed by B cells, T cells, and monocytes [28].

Associations of RET with chemical compounds

  • Critical and distinct roles for key RET tyrosine docking sites in renal development [29].
  • Molecular modeling studies of the extracellular domain of RET (RETECD) have revealed the existence of four cadherin-like domains (CLD1-4) followed by a cysteine-rich domain [30].
  • This may lead to enhanced MHC class II expression, which may explain why the tissues surrounding RET/PTC-positive cancers are infiltrated with lymphocytes [31].
  • The synthetic glucocorticoid dexamethasone was found to reduce RET expression at both mRNA and protein levels [32].
  • Here, we show that the mouse GFRalpha4 is a functional, N-glycosylated, glycosylphosphatidylinositol (GPI)-anchored protein, which mediates persephin (PSPN)-induced phosphorylation of RET, but has an almost undetectable capacity to recruit RET into the 0.1% Triton X-100 insoluble membrane fraction [33].
  • Using lysosomal and proteasomal inhibitors, we demonstrate that Sorafenib induces RET lysosomal degradation independent of proteasomal targeting [34].
  • Binding of SH2B1beta appears to protect RET from dephosphorylation by protein tyrosine phosphatases, and might represent a likely mechanism contributing to its upregulation [35].

Physical interactions of RET


Enzymatic interactions of RET

  • In this report we demonstrate that the docking protein FRS2 is tyrosine phosphorylated by ligand-stimulated and by constitutively activated oncogenic forms of RET [3].
  • A constitutive complex of Grb2 and Cbl could be recruited to both receptor isoforms via docking of Shc to phosphorylated Tyr-1062 in RET [38].
  • We hypothesized that RET could directly phosphorylate FAK and ERK [39].

Regulatory relationships of RET


Other interactions of RET

  • RETL1 and RETL2 represent new candidate susceptibility genes and/or modifier loci for RET-associated diseases [44].
  • However, loss-of-function HSCR-associated RET mutants exhibit impaired FRS2 binding and reduced MAP kinase activation [3].
  • No (0%) RET and 2 (2.4%) VHL mutations were detected [45].
  • Detection of a novel type of RET rearrangement (PTC5) in thyroid carcinomas after Chernobyl and analysis of the involved RET-fused gene RFG5 [46].
  • We showed that RET expression leads to increased HSF1 activation, which correlates with increased expression of stress response genes [24].

Analytical, diagnostic and therapeutic context of RET


  1. Germline mutations in glial cell line-derived neurotrophic factor (GDNF) and RET in a Hirschsprung disease patient. Angrist, M., Bolk, S., Halushka, M., Lapchak, P.A., Chakravarti, A. Nat. Genet. (1996) [Pubmed]
  2. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Astuti, D., Latif, F., Dallol, A., Dahia, P.L., Douglas, F., George, E., Sköldberg, F., Husebye, E.S., Eng, C., Maher, E.R. Am. J. Hum. Genet. (2001) [Pubmed]
  3. Docking protein FRS2 links the protein tyrosine kinase RET and its oncogenic forms with the mitogen-activated protein kinase signaling cascade. Melillo, R.M., Santoro, M., Ong, S.H., Billaud, M., Fusco, A., Hadari, Y.R., Schlessinger, J., Lax, I. Mol. Cell. Biol. (2001) [Pubmed]
  4. Oncogenic RET receptors display different autophosphorylation sites and substrate binding specificities. Liu, X., Vega, Q.C., Decker, R.A., Pandey, A., Worby, C.A., Dixon, J.E. J. Biol. Chem. (1996) [Pubmed]
  5. RET activation by germline MEN2A and MEN2B mutations. Borrello, M.G., Smith, D.P., Pasini, B., Bongarzone, I., Greco, A., Lorenzo, M.J., Arighi, E., Miranda, C., Eng, C., Alberti, L. Oncogene (1995) [Pubmed]
  6. RET genetic screening in patients with medullary thyroid cancer and their relatives: experience with 807 individuals at one center. Elisei, R., Romei, C., Cosci, B., Agate, L., Bottici, V., Molinaro, E., Sculli, M., Miccoli, P., Basolo, F., Grasso, L., Pacini, F., Pinchera, A. J. Clin. Endocrinol. Metab. (2007) [Pubmed]
  7. Neurotrophic factor receptor RET: structure, cell biology, and inherited diseases. Runeberg-Roos, P., Saarma, M. Ann. Med. (2007) [Pubmed]
  8. Prognostic significance of somatic RET oncogene mutations in sporadic medullary thyroid cancer: a 10-year follow-up study. Elisei, R., Cosci, B., Romei, C., Bottici, V., Renzini, G., Molinaro, E., Agate, L., Vivaldi, A., Faviana, P., Basolo, F., Miccoli, P., Berti, P., Pacini, F., Pinchera, A. J. Clin. Endocrinol. Metab. (2008) [Pubmed]
  9. Germline mutation of the RET proto-oncogene in members of Slovak families with multiple endocrine neoplasia 2. Poturnajova, M., Altanerov, V., Kettmann, R., Feikova, S., Hlubinova, K., Balazovjech, I., Breza, J., Fodo, G., Knotek, J., Matoska, J., Podobov, M., Altaner, C. Neoplasma (2001) [Pubmed]
  10. Reduced endothelin converting enzyme-1 and endothelin-3 mRNA in the developing bowel of male mice may increase expressivity and penetrance of Hirschsprung disease-like distal intestinal aganglionosis. Vohra, B.P., Planer, W., Armon, J., Fu, M., Jain, S., Heuckeroth, R.O. Dev. Dyn. (2007) [Pubmed]
  11. RET in human development and oncogenesis. Edery, P., Eng, C., Munnich, A., Lyonnet, S. Bioessays (1997) [Pubmed]
  12. Mutations of codon 918 in the RET proto-oncogene correlate to poor prognosis in sporadic medullary thyroid carcinomas. Zedenius, J., Larsson, C., Bergholm, U., Bovée, J., Svensson, A., Hallengren, B., Grimelius, L., Bäckdahl, M., Weber, G., Wallin, G. J. Clin. Endocrinol. Metab. (1995) [Pubmed]
  13. The neural cell adhesion molecule NCAM is an alternative signaling receptor for GDNF family ligands. Paratcha, G., Ledda, F., Ibáñez, C.F. Cell (2003) [Pubmed]
  14. Segregation at three loci explains familial and population risk in Hirschsprung disease. Gabriel, S.B., Salomon, R., Pelet, A., Angrist, M., Amiel, J., Fornage, M., Attié-Bitach, T., Olson, J.M., Hofstra, R., Buys, C., Steffann, J., Munnich, A., Lyonnet, S., Chakravarti, A. Nat. Genet. (2002) [Pubmed]
  15. SOX10 mutations in patients with Waardenburg-Hirschsprung disease. Pingault, V., Bondurand, N., Kuhlbrodt, K., Goerich, D.E., Préhu, M.O., Puliti, A., Herbarth, B., Hermans-Borgmeyer, I., Legius, E., Matthijs, G., Amiel, J., Lyonnet, S., Ceccherini, I., Romeo, G., Smith, J.C., Read, A.P., Wegner, M., Goossens, M. Nat. Genet. (1998) [Pubmed]
  16. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Schmidt, L., Duh, F.M., Chen, F., Kishida, T., Glenn, G., Choyke, P., Scherer, S.W., Zhuang, Z., Lubensky, I., Dean, M., Allikmets, R., Chidambaram, A., Bergerheim, U.R., Feltis, J.T., Casadevall, C., Zamarron, A., Bernues, M., Richard, S., Lips, C.J., Walther, M.M., Tsui, L.C., Geil, L., Orcutt, M.L., Stackhouse, T., Lipan, J., Slife, L., Brauch, H., Decker, J., Niehans, G., Hughson, M.D., Moch, H., Storkel, S., Lerman, M.I., Linehan, W.M., Zbar, B. Nat. Genet. (1997) [Pubmed]
  17. The sensitivity of activated Cys Ret mutants to glial cell line-derived neurotrophic factor is mandatory to rescue neuroectodermic cells from apoptosis. Mograbi, B., Bocciardi, R., Bourget, I., Juhel, T., Farahi-Far, D., Romeo, G., Ceccherini, I., Rossi, B. Mol. Cell. Biol. (2001) [Pubmed]
  18. Pheochromocytoma in von Hippel-Lindau disease and neurofibromatosis type 1. Opocher, G., Conton, P., Schiavi, F., Macino, B., Mantero, F. Fam. Cancer (2005) [Pubmed]
  19. ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases. Carlomagno, F., Vitagliano, D., Guida, T., Ciardiello, F., Tortora, G., Vecchio, G., Ryan, A.J., Fontanini, G., Fusco, A., Santoro, M. Cancer Res. (2002) [Pubmed]
  20. High levels of tyrosine phosphorylated proto-ret in sporadic phenochromocytomas. Le Hir, H., Colucci-D'Amato, L.G., Charlet-Berguerand, N., Plouin, P.F., Bertagna, X., de Franciscis, V., Thermes, C. Cancer Res. (2000) [Pubmed]
  21. RET polymorphisms and sporadic medullary thyroid carcinoma in a Portuguese population. Costa, P., Domingues, R., Sobrinho, L.G., Bugalho, M.J. Endocrine (2005) [Pubmed]
  22. De novo mutation of GDNF, ligand for the RET/GDNFR-alpha receptor complex, in Hirschsprung disease. Ivanchuk, S.M., Myers, S.M., Eng, C., Mulligan, L.M. Hum. Mol. Genet. (1996) [Pubmed]
  23. Mutation analysis of glial cell line-derived neurotrophic factor (GDNF), a ligand for the RET/GDNF receptor alpha complex, in sporadic phaeochromocytomas. Dahia, P.L., Toledo, S.P., Mulligan, L.M., Maher, E.R., Grossman, A.B., Eng, C. Cancer Res. (1997) [Pubmed]
  24. The RET receptor is linked to stress response pathways. Myers, S.M., Mulligan, L.M. Cancer Res. (2004) [Pubmed]
  25. 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. Kimura, E.T., Nikiforova, M.N., Zhu, Z., Knauf, J.A., Nikiforov, Y.E., Fagin, J.A. Cancer Res. (2003) [Pubmed]
  26. The oncogenic activity of RET point mutants for follicular thyroid cells may account for the occurrence of papillary thyroid carcinoma in patients affected by familial medullary thyroid carcinoma. Melillo, R.M., Cirafici, A.M., De Falco, V., Bellantoni, M., Chiappetta, G., Fusco, A., Carlomagno, F., Picascia, A., Tramontano, D., Tallini, G., Santoro, M. Am. J. Pathol. (2004) [Pubmed]
  27. Two distinct mutations of the RET receptor causing Hirschsprung's disease impair the binding of signalling effectors to a multifunctional docking site. Geneste, O., Bidaud, C., De Vita, G., Hofstra, R.M., Tartare-Deckert, S., Buys, C.H., Lenoir, G.M., Santoro, M., Billaud, M. Hum. Mol. Genet. (1999) [Pubmed]
  28. Expression and function of glial cell line-derived neurotrophic factor family ligands and their receptors on human immune cells. Vargas-Leal, V., Bruno, R., Derfuss, T., Krumbholz, M., Hohlfeld, R., Meinl, E. J. Immunol. (2005) [Pubmed]
  29. Critical and distinct roles for key RET tyrosine docking sites in renal development. Jain, S., Encinas, M., Johnson, E.M., Milbrandt, J. Genes Dev. (2006) [Pubmed]
  30. Identification of a surface for binding to the GDNF-GFR alpha 1 complex in the first cadherin-like domain of RET. Kjaer, S., Ibáñez, C.F. J. Biol. Chem. (2003) [Pubmed]
  31. Regulation of signal transducer and activator of transcription 1 (STAT1) and STAT1-dependent genes by RET/PTC (rearranged in transformation/papillary thyroid carcinoma) oncogenic tyrosine kinases. Hwang, E.S., Kim, D.W., Hwang, J.H., Jung, H.S., Suh, J.M., Park, Y.J., Chung, H.K., Song, J.H., Park, K.C., Park, S.H., Yun, H.J., Kim, J.M., Shong, M. Mol. Endocrinol. (2004) [Pubmed]
  32. Glucocorticoids differentially inhibit expression of the RET proto-oncogene. Capes-Davis, A., Andrew, S.D., Hyland, V.J., Twigg, S., Learoyd, D.L., Dwight, T., Marsh, D.J., Robinson, B.G. Gene Expr. (1999) [Pubmed]
  33. PSPN/GFRalpha4 has a significantly weaker capacity than GDNF/GFRalpha1 to recruit RET to rafts, but promotes neuronal survival and neurite outgrowth. Yang, J., Lindahl, M., Lindholm, P., Virtanen, H., Coffey, E., Runeberg-Roos, P., Saarma, M. FEBS Lett. (2004) [Pubmed]
  34. Sorafenib functions to potently suppress RET tyrosine kinase activity by direct enzymatic inhibition and promoting RET lysosomal degradation independent of proteasomal targeting. Plaza-Menacho, I., Mologni, L., Sala, E., Gambacorti-Passerini, C., Magee, A.I., Links, T.P., Hofstra, R.M., Barford, D., Isacke, C.M. J. Biol. Chem. (2007) [Pubmed]
  35. SH2B1beta adaptor is a key enhancer of RET tyrosine kinase signaling. Donatello, S., Fiorino, A., Degl'Innocenti, D., Alberti, L., Miranda, C., Gorla, L., Bongarzone, I., Rizzetti, M.G., Pierotti, M.A., Borrello, M.G. Oncogene (2007) [Pubmed]
  36. Identification of SNT/FRS2 docking site on RET receptor tyrosine kinase and its role for signal transduction. Kurokawa, K., Iwashita, T., Murakami, H., Hayashi, H., Kawai, K., Takahashi, M. Oncogene (2001) [Pubmed]
  37. Analysis of SOX10 mutations identified in Waardenburg-Hirschsprung patients: Differential effects on target gene regulation. Chan, K.K., Wong, C.K., Lui, V.C., Tam, P.K., Sham, M.H. J. Cell. Biochem. (2003) [Pubmed]
  38. Distinct turnover of alternatively spliced isoforms of the RET kinase receptor mediated by differential recruitment of the Cbl ubiquitin ligase. Scott, R.P., Eketjäll, S., Aineskog, H., Ibáñez, C.F. J. Biol. Chem. (2005) [Pubmed]
  39. Direct phosphorylation of proliferative and survival pathway proteins by RET. Panta, G.R., Du, L., Nwariaku, F.E., Kim, L.T. Surgery (2005) [Pubmed]
  40. A model for GFR alpha 4 function and a potential modifying role in multiple endocrine neoplasia 2. Vanhorne, J.B., Andrew, S.D., Harrison, K.J., Taylor, S.A., Thomas, B., McDonald, T.J., Ainsworth, P.J., Mulligan, L.M. Oncogene (2005) [Pubmed]
  41. Activation of RET tyrosine kinase regulates interleukin-8 production by multiple signaling pathways. Iwahashi, N., Murakami, H., Nimura, Y., Takahashi, M. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  42. Characterization of intracellular signals via tyrosine 1062 in RET activated by glial cell line-derived neurotrophic factor. Hayashi, H., Ichihara, M., Iwashita, T., Murakami, H., Shimono, Y., Kawai, K., Kurokawa, K., Murakumo, Y., Imai, T., Funahashi, H., Nakao, A., Takahashi, M. Oncogene (2000) [Pubmed]
  43. The RET receptor tyrosine kinase: activation, signalling and significance in neural development and disease. Mason, I. Pharmaceutica acta Helvetiae. (2000) [Pubmed]
  44. Glial cell line-derived neurotrophic factor-dependent RET activation can be mediated by two different cell-surface accessory proteins. Sanicola, M., Hession, C., Worley, D., Carmillo, P., Ehrenfels, C., Walus, L., Robinson, S., Jaworski, G., Wei, H., Tizard, R., Whitty, A., Pepinsky, R.B., Cate, R.L. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  45. Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. Gimenez-Roqueplo, A.P., Favier, J., Rustin, P., Rieubland, C., Crespin, M., Nau, V., Khau Van Kien, P., Corvol, P., Plouin, P.F., Jeunemaitre, X. Cancer Res. (2003) [Pubmed]
  46. Detection of a novel type of RET rearrangement (PTC5) in thyroid carcinomas after Chernobyl and analysis of the involved RET-fused gene RFG5. Klugbauer, S., Demidchik, E.P., Lengfelder, E., Rabes, H.M. Cancer Res. (1998) [Pubmed]
  47. Molecular classification of papillary thyroid carcinoma: distinct BRAF, RAS, and RET/PTC mutation-specific gene expression profiles discovered by DNA microarray analysis. Giordano, T.J., Kuick, R., Thomas, D.G., Misek, D.E., Vinco, M., Sanders, D., Zhu, Z., Ciampi, R., Roh, M., Shedden, K., Gauger, P., Doherty, G., Thompson, N.W., Hanash, S., Koenig, R.J., Nikiforov, Y.E. Oncogene (2005) [Pubmed]
  48. Expression of GDNF receptor (RET and GDNFR-alpha) mRNAs in the spinal cord of patients with amyotrophic lateral sclerosis. Mitsuma, N., Yamamoto, M., Li, M., Ito, Y., Mitsuma, T., Mutoh, T., Takahashi, M., Sobue, G. Brain Res. (1999) [Pubmed]
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