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Gene Review

Ret  -  ret proto-oncogene

Rattus norvegicus

Synonyms: Proto-oncogene tyrosine-protein kinase receptor Ret
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Disease relevance of Ret

  • The results indicate that Shp-2 is a downstream mediator of the mutated receptors RetC634Y and RetM918T, thus suggesting that it may act as a limiting factor in Ret-associated endocrine tumors, in the neoplastic syndromes multiple endocrine neoplasia types 2A and 2B [1].
  • Here we took advantage of two rat pheochromocytoma-derived cell lines (PC12/MEN2A and PC12/MEN2B) to investigate whether Ret-induced nerve growth factor (NGF) unresponsiveness might involve impairment of ERK signaling [2].
  • On the other hand, forced expression of these mutated versions of Ret induces the rat pheochromocytoma cell line, PC12, to differentiate [3].
  • Transient forebrain ischemia induced Ret mRNA expression in the hippocampus, with a peak effect at 12 h [4].
  • The localization of mRNAs corresponding to the two components of the GDNF receptor, GDNF family receptor alpha 1 (GFRalpha1) and Ret, were demonstrated in adult adrenal medullary ganglion cells [5].

High impact information on Ret

  • Therefore, NGF promotes phosphorylation of the heterologous RTK Ret resulting in augmented growth, metabolism, and gene expression [6].
  • A glycosylphosphatidylinositol-linked protein also was important for NTN and GDNF signaling in SCG neurons; phosphatidylinositol-specific phospholipase C treatment of SCG cultures reduced the ability of NTN to phosphorylate Ret and the ability of NTN or GDNF to activate the mitogen-activated protein kinase pathway [7].
  • NTN also caused Ret phosphorylation in fibroblasts that were transfected stably with Ret and GDNFRalpha but not in cells expressing Ret alone [7].
  • In this report, we demonstrate that NTN induces Ret phosphorylation in primary cultures of rat superior cervical ganglion (SCG) neurons [7].
  • Recently, a receptor complex has been identified for GDNF that includes the Ret tyrosine kinase receptor and a glycosylphosphatidylinositol-linked protein termed "GDNFRalpha." However, differences in the phenotype of Ret and GDNF knockout animals suggest that Ret has at least one additional ligand [7].

Chemical compound and disease context of Ret

  • These findings suggest that GDNF modulates the expression of Ret, and that GDNF signaling pathways that involve the Ret receptor tyrosine kinase might play an important role in brain injury induced by ischemia [4].
  • Constitutive activation of the RET proto-oncogene in papillary thyroid carcinomas results from rearrangements linking the promoter(s) and N-terminal domains of unrelated genes to the C-terminus of RET tyrosine kinase (RET/PTC) [8].

Biological context of Ret

  • The Shp-1 and Shp-2, tyrosine phosphatases, are recruited on cell membrane in two distinct molecular complexes including Ret oncogenes [9].
  • Using a multistep RT-PCR approach we have isolated and sequenced the cDNA of the whole rat RET proto-oncogene, reporting the deduced amino acid sequence in comparison with the human and mouse counterparts [10].
  • Postnatal Ret phosphorylation did not require either GFLs or GFR(alpha) coreceptors [6].
  • The neuron-specific Rai (ShcC) adaptor protein inhibits apoptosis by coupling Ret to the phosphatidylinositol 3-kinase/Akt signaling pathway [11].
  • However, even though inhibition of Ras activity was sufficient to revert Ret-induced differentiation, the kinetics of morphological reversion of the Ret-2B- was more rapid than the Ret-2A-transfected cells [3].

Anatomical context of Ret

  • In contrast, artemin, GDNF, GFRalpha1-3 and Ret RNA expression were strongly upregulated in the auditory nerve following deafness, indicating their importance in protecting the auditory nerve against cell damage [12].
  • By using rat pheochromocytoma-derived PC12 cells, here we studied the interactions of Shp-2 and Shp-1 with two activated mutants of Ret receptor, Ret(C634Y) and Ret(M918T) [9].
  • To identify tyrosines in Ret that are autophosphorylation sites in neurons, we generated antibodies specific to phosphorylated Y905Ret, Y1015Ret, Y1062Ret, and Y1096Ret, all of which are autophosphorylated in cell lines [13].
  • Overexpression of Rai in neuronal cell lines promoted survival by reducing apoptosis both under conditions of limited availability of the Ret ligand glial cell line-derived neurotrophic factor (GDNF) and in the absence of Ret activation [11].
  • First, Ret may interact with the alpha-receptors expressed in the same cells (termed interaction "in cis") in many tissues and cell populations that respond to GDNF and/or neurturin, such as the substantia nigra, dorsal root ganglia, spinal cord motoneurons, kidney, and intestine [14].

Associations of Ret with chemical compounds

  • The Shp-2 and Shp-1 non-transmembrane tyrosine phosphatases display different and even opposing effects on downstream signaling events initiated by Ret activation [9].
  • Here we investigated the involvement of the Shp-2 tyrosine phosphatase in determining the downstream signaling pathways initiated by the Ret oncogene, carrying either the cysteine 634 to tyrosine or the methionine 918 to threonine substitutions [1].
  • Treatment with 1 microM 2-(4-morpholinyl)-8-phenylchromone (LY294002) or 100 nM wortmannin, two distinct and potent inhibitors of phosphatidylinositol 3-kinase activity, completely inhibited GDNF-induced phosphatidylinositol 3-kinase activation, but did not affect Ret phosphorylation [15].
  • After addition of retinoic acid, the cells exited the cell cycle, developed thin processes, and became immunoreactive for betaIII-tubulin, while Ret mRNA expression decreased, without changes in the level of GFR-alpha2 mRNA [16].
  • Phosphorylation of extracellular regulated kinase was increased in the presence of heparin, although tyrosine phosphorylation of Ret receptor tyrosine kinase was not affected by heparin [17].

Physical interactions of Ret

  • Both GDNF and neurturin signal via a two-component receptor complex that consists of a ligand-binding GDNF family receptor (GFRalpha-1 or GFRalpha-2) and the receptor protein tyrosine kinase Ret [14].
  • Glial cell line-derived neurotrophic factor (GDNF) has been shown to signal through a multicomponent receptor complex consisting of the Ret receptor tyrosine kinase and a member of the GFRalpha family of glycosylphosphatidylinositol-anchored receptors [18].

Regulatory relationships of Ret

  • We propose that Rai potentiates the MAPK and PI3K signaling pathways and regulates Ret-dependent and -independent survival signals [11].
  • The receptor tyrosine kinase (RTK) Ret is activated by the formation of a complex consisting of ligands such as glial cell line-derived neurotrophic factor (GDNF) and glycerophosphatidylinositol-anchored coreceptors termed GFRalphas [19].

Other interactions of Ret


Analytical, diagnostic and therapeutic context of Ret

  • We show here by in situ hybridization that Ret and the alpha-receptors may be colocalized in the same tissues or expressed separately in projecting and target tissues, respectively, indicating that two distinct modes of interaction between Ret and the alpha-receptors exist in vivo [14].
  • We found that treatment of dopaminergic neuron cultures with 10 ng/ml GDNF induced maximal levels of Ret phosphorylation and produced a profound increase in phosphatidylinositol 3-kinase activity, as measured by western blot analysis and lipid kinase assays [15].
  • Whereas intrahippocampal microinjection of GDNF (1.0 microg) in sham-operated rats induced the expression of Ret mRNA (peak at 6 to 12 h), the expected increase of Ret mRNA induced by ischemia was blunted by local GDNF-pretreatment [4].
  • The proteins binding to the Ret 2 and Ret 3 sites co-eluted in both ion exchange and gel filtration chromatography [23].
  • Immunocytochemistry showed immunostaining in the modiolus for GDNF, GFRalpha-1 and Ret that was confined to spiral ganglion cells [24].


  1. The tyrosine phosphatase Shp-2 mediates intracellular signaling initiated by Ret mutants. D'Alessio, A., Califano, D., Incoronato, M., Santelli, G., Florio, T., Schettini, G., Carlomagno, M.S., Cerchia, L., de Franciscis, V. Endocrinology (2003) [Pubmed]
  2. Abrogation of nerve growth factor-induced terminal differentiation by ret oncogene involves perturbation of nuclear translocation of ERK. Colucci-D'Amato, G.L., D'Alessio, A., Califano, D., Cali, G., Rizzo, C., Nitsch, L., Santelli, G., de Franciscis, V. J. Biol. Chem. (2000) [Pubmed]
  3. Signaling through Ras is essential for ret oncogene-induced cell differentiation in PC12 cells. Califano, D., Rizzo, C., D'Alessio, A., Colucci-D'Amato, G.L., Cali, G., Bartoli, P.C., Santelli, G., Vecchio, G., de Franciscis, V. J. Biol. Chem. (2000) [Pubmed]
  4. Expression of Ret receptor tyrosine kinase after transient forebrain ischemia is modulated by glial cell line-derived neurotrophic factor in rat hippocampus. Miyazaki, H., Nagashima, K., Okuma, Y., Nomura, Y. Neurosci. Lett. (2002) [Pubmed]
  5. Glial-cell-line-derived neurotrophic factor induces nerve fibre formation in primary cultures of adrenal chromaffin cells. Förander, P., Broberger, C., Strömberg, I. Cell Tissue Res. (2001) [Pubmed]
  6. NGF utilizes c-Ret via a novel GFL-independent, inter-RTK signaling mechanism to maintain the trophic status of mature sympathetic neurons. Tsui-Pierchala, B.A., Milbrandt, J., Johnson, E.M. Neuron (2002) [Pubmed]
  7. Neurturin shares receptors and signal transduction pathways with glial cell line-derived neurotrophic factor in sympathetic neurons. Creedon, D.J., Tansey, M.G., Baloh, R.H., Osborne, P.A., Lampe, P.A., Fahrner, T.J., Heuckeroth, R.O., Milbrandt, J., Johnson, E.M. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  8. RET/PTC-induced dedifferentiation of thyroid cells is mediated through Y1062 signaling through SHC-RAS-MAP kinase. Knauf, J.A., Kuroda, H., Basu, S., Fagin, J.A. Oncogene (2003) [Pubmed]
  9. The Shp-1 and Shp-2, tyrosine phosphatases, are recruited on cell membrane in two distinct molecular complexes including Ret oncogenes. Incoronato, M., D'Alessio, A., Paladino, S., Zurzolo, C., Carlomagno, M.S., Cerchia, L., de Franciscis, V. Cell. Signal. (2004) [Pubmed]
  10. cDNA sequence and genomic structure of the rat RET proto-oncogene. Matera, I., De Miguel-Rodríguez, M., Fernández-Santos, J.M., Santamaria, G., Puliti, A., Ravazzolo, R., Romeo, G., Galera-Davidson, H., Ceccherini, I. DNA Seq. (2000) [Pubmed]
  11. The neuron-specific Rai (ShcC) adaptor protein inhibits apoptosis by coupling Ret to the phosphatidylinositol 3-kinase/Akt signaling pathway. Pelicci, G., Troglio, F., Bodini, A., Melillo, R.M., Pettirossi, V., Coda, L., De Giuseppe, A., Santoro, M., Pelicci, P.G. Mol. Cell. Biol. (2002) [Pubmed]
  12. Upregulation of glial cell line-derived neurotrophic factor and artemin mRNA in the auditory nerve of deafened rats. Wissel, K., Wefstaedt, P., Rieger, H., Miller, J.M., Lenarz, T., Stöver, T. Neuroreport (2006) [Pubmed]
  13. The long and short isoforms of Ret function as independent signaling complexes. Tsui-Pierchala, B.A., Ahrens, R.C., Crowder, R.J., Milbrandt, J., Johnson, E.M. J. Biol. Chem. (2002) [Pubmed]
  14. Expression of GDNF family receptor components during development: implications in the mechanisms of interaction. Yu, T., Scully, S., Yu, Y., Fox, G.M., Jing, S., Zhou, R. J. Neurosci. (1998) [Pubmed]
  15. Inhibition of phosphatidylinositol 3-kinase activity blocks cellular differentiation mediated by glial cell line-derived neurotrophic factor in dopaminergic neurons. Pong, K., Xu, R.Y., Baron, W.F., Louis, J.C., Beck, K.D. J. Neurochem. (1998) [Pubmed]
  16. Effect of neurturin on multipotent cells isolated from the adult skeletal muscle. Vourc'h, P., Lacar, B., Mignon, L., Lucas, P.A., Young, H.E., Chesselet, M.F. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  17. Heparin facilitates glial cell line-derived neurotrophic factor signal transduction. Tanaka, M., Xiao, H., Kiuchi, K. Neuroreport (2002) [Pubmed]
  18. Ret-dependent and -independent mechanisms of glial cell line-derived neurotrophic factor signaling in neuronal cells. Trupp, M., Scott, R., Whittemore, S.R., Ibáñez, C.F. J. Biol. Chem. (1999) [Pubmed]
  19. Glial cell line-derived neurotrophic factor-dependent recruitment of Ret into lipid rafts enhances signaling by partitioning Ret from proteasome-dependent degradation. Pierchala, B.A., Milbrandt, J., Johnson, E.M. J. Neurosci. (2006) [Pubmed]
  20. Potential role of glial cell line-derived neurotrophic factor receptors in Müller glial cells during light-induced retinal degeneration. Harada, C., Harada, T., Quah, H.M., Maekawa, F., Yoshida, K., Ohno, S., Wada, K., Parada, L.F., Tanaka, K. Neuroscience (2003) [Pubmed]
  21. Responsiveness to neurturin of subpopulations of embryonic rat spinal motoneuron does not correlate with expression of GFR alpha 1 or GFR alpha 2. Garcès, A., Livet, J., Grillet, N., Henderson, C.E., Delapeyrière, O. Dev. Dyn. (2001) [Pubmed]
  22. Differential regulation of GDNF, neurturin, and their receptors in primary cultures of rat glial cells. Rémy, S., Naveilhan, P., Brachet, P., Neveu, I. J. Neurosci. Res. (2001) [Pubmed]
  23. Shared nuclear protein binding sites in the upstream region of the rat opsin gene. Yu, X., Chung, M., Morabito, M.A., Barnstable, C.J. Biochem. Biophys. Res. Commun. (1993) [Pubmed]
  24. Glial cell line-derived neurotrophic factor (GDNF) and its receptor complex are expressed in the auditory nerve of the mature rat cochlea. Stöver, T., Nam, Y., Gong, T.L., Lomax, M.I., Altschuler, R.A. Hear. Res. (2001) [Pubmed]
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