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Gene Review

Ret  -  ret proto-oncogene

Mus musculus

Synonyms: PTC, Proto-oncogene c-Ret, Proto-oncogene tyrosine-protein kinase receptor Ret, RET51, RET9, ...
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Disease relevance of Ret


Psychiatry related information on Ret

  • We have established two locus noncomplementation assays in mice, using allelic series at Ednrb in the context of Ret kinase-null heterozygotes, to understand the clinical presentation, incomplete penetrance, variation in length of aganglionic segment, and sex bias observed in human HSCR patients [1].

High impact information on Ret

  • Here we show that ureter maturation depends on formation of the 'trigonal wedge', a newly identified epithelial outgrowth from the base of the Wolffian ducts, and that the distal ureter abnormalities seen in Rara(-/-) Rarb2(-/-) and Ret(-/-) mutant mice are probably caused by a failure of this process [5].
  • Distal ureter morphogenesis depends on epithelial cell remodeling mediated by vitamin A and Ret [5].
  • Our studies indicate that formation of the trigonal wedge may be essential for correct insertion of the distal ureters into the bladder, and that these events are mediated by the vitamin A and Ret signaling pathways [5].
  • In the second part of the loop, ureteric bud signals dependent on Ret control stromal cell patterning [6].
  • Our studies indicate the presence of a new reciprocal signaling loop between the ureteric bud epithelium and the stromal mesenchyme, dependent on Ret and vitamin A. In the first part of the loop, vitamin-A-dependent signals secreted by stromal cells control Ret expression in the ureteric bud [6].

Chemical compound and disease context of Ret


Biological context of Ret


Anatomical context of Ret

  • In the anlagen of the enteric nervous system and the sympathetic ganglia, Phox2b is needed for the expression of the GDNF-receptor subunit Ret and for maintaining Mash1 expression [16].
  • Fibroblasts expressing TrnR2 and Ret are approximately 30-fold more sensitive to NTN than to GDNF treatment, whereas those expressing TrnR1 and Ret respond equivalently to both factors, suggesting the TrnR2-Ret complex acts preferentially as a receptor for NTN [17].
  • TrnR2 and Ret are expressed in neurons of the superior cervical and dorsal root ganglia, and in the adult brain [17].
  • The neuronal scaffold protein Shank3 mediates signaling and biological function of the receptor tyrosine kinase Ret in epithelial cells [18].
  • To clarify the role of Ret signaling components in enteric nervous system (ENS) development, we evaluated ENS anatomy and intestinal contractility in mice heterozygous for Ret, GFRalpha1 and Ret ligands [19].

Associations of Ret with chemical compounds


Physical interactions of Ret

  • Recombinant Crx binds in vitro not only to the Ret 4 site but also to the Ret 1 and BAT-1 sites [24].
  • Phosphorylated Y1062 is part of a Ret multiple effector docking site that mediates recruitment of the Shc adapter and of phosphatidylinositol-3 kinase (PI3K) [8].

Enzymatic interactions of Ret

  • Dok-4 could also be phosphorylated by the receptor tyrosine kinase Ret but not by platelet-derived growth factor receptor-beta or IGF-IR [25].

Regulatory relationships of Ret

  • Furthermore, we show that Ret9 but not Ret51 induces epithelial cells to form branched tubular structures in three-dimensional cultures in a Shank3-dependent manner [18].
  • We also measured the levels of Src kinase activity in cell lines expressing isoforms of the Ret receptor activated by different mutations [21].
  • However, few chromaffin cells in Mash1(-/-) mice become PNMT positive and downregulate neurofilament and Ret expression [26].
  • In vitro, GDNF supports the survival of small neurons that express Ret and bind IB4 while failing to support the survival of neurons expressing TrkA and CGRP [27].
  • To study the differential activities of the two RET isoforms further, we generated transgenic mice expressing ligand-dependent and constitutively active forms of RET9 or RET51 under the control of the Hoxb7 regulatory sequences [28].

Other interactions of Ret

  • Gdnf encodes a mesenchymally produced ligand for the Ret tyrosine kinase receptor that is crucial for normal ureteric branching [29].
  • Only mild reductions in neuron size and neuronal fiber counts occur in Ret(+/-) and Gfra1(+/-) mice [19].
  • Ret-mediated mitogenesis requires Src kinase activity [21].
  • Ret and p75 have also been reported to label migratory-stage enteric neuron precursors [30].
  • We conclude that the neural crest cell population that arises from the vagal level of the neural axis and that populates the stomach, midgut, and hindgut expresses Phox2b, Ret, and p75 [30].

Analytical, diagnostic and therapeutic context of Ret

  • Titration of Ednrb in the presence of half the genetic dose of Ret determines the presentation of an enteric phenotype in these strains, revealing or abrogating a sex bias in disease expression depending on the genotype at Ednrb [1].
  • Microinjection of a kinase inactive mutant of c-Src blocked Ret-mediated mitogenic effect [21].
  • The location and sequence of appearance of enteric neuron precursors deduced from the explants grown under the kidney capsule or in organ culture was very similar to that seen with the Phox2b, Ret, and p75 antisera [30].
  • Analysis of the tissue distribution of GFRalpha-1, GFRalpha-2, GFRalpha-3, and Ret by Northern blot reveals overlapping but distinct patterns of expression [31].
  • Western blot analysis showed that proto-Ret proteins are expressed as 140-kDa and 160-kDa glycoproteins in Neuro-2a cells [32].


  1. Phenotype variation in two-locus mouse models of Hirschsprung disease: tissue-specific interaction between Ret and Ednrb. McCallion, A.S., Stames, E., Conlon, R.A., Chakravarti, A. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  2. Distinct roles for GFRalpha1 and GFRalpha2 signalling in different cranial parasympathetic ganglia in vivo. Rossi, J., Tomac, A., Saarma, M., Airaksinen, M.S. Eur. J. Neurosci. (2000) [Pubmed]
  3. Tissue-specific carcinogenesis in transgenic mice expressing the RET proto-oncogene with a multiple endocrine neoplasia type 2A mutation. Kawai, K., Iwashita, T., Murakami, H., Hiraiwa, N., Yoshiki, A., Kusakabe, M., Ono, K., Iida, K., Nakayama, A., Takahashi, M. Cancer Res. (2000) [Pubmed]
  4. Ret oncogene signal transduction via a IRS-2/PI 3-kinase/PKB and a SHC/Grb-2 dependent pathway: possible implication for transforming activity in NIH3T3 cells. Hennige, A.M., Lammers, R., Arlt, D., Höppner, W., Strack, V., Niederfellner, G., Seif, F.J., Häring, H.U., Kellerer, M. Mol. Cell. Endocrinol. (2000) [Pubmed]
  5. Distal ureter morphogenesis depends on epithelial cell remodeling mediated by vitamin A and Ret. Batourina, E., Choi, C., Paragas, N., Bello, N., Hensle, T., Costantini, F.D., Schuchardt, A., Bacallao, R.L., Mendelsohn, C.L. Nat. Genet. (2002) [Pubmed]
  6. Vitamin A controls epithelial/mesenchymal interactions through Ret expression. Batourina, E., Gim, S., Bello, N., Shy, M., Clagett-Dame, M., Srinivas, S., Costantini, F., Mendelsohn, C. Nat. Genet. (2001) [Pubmed]
  7. Glial cell line-derived neurotrophic factor and its receptor ret is a novel ligand-receptor complex critical for survival response during podocyte injury. Tsui, C.C., Shankland, S.J., Pierchala, B.A. J. Am. Soc. Nephrol. (2006) [Pubmed]
  8. Increased in vivo phosphorylation of ret tyrosine 1062 is a potential pathogenetic mechanism of multiple endocrine neoplasia type 2B. Salvatore, D., Melillo, R.M., Monaco, C., Visconti, R., Fenzi, G., Vecchio, G., Fusco, A., Santoro, M. Cancer Res. (2001) [Pubmed]
  9. Animal models of pheochromocytoma. Tischler, A.S., Powers, J.F., Alroy, J. Histol. Histopathol. (2004) [Pubmed]
  10. Targeted expression of the ret/PTC1 oncogene induces papillary thyroid carcinomas. Jhiang, S.M., Sagartz, J.E., Tong, Q., Parker-Thornburg, J., Capen, C.C., Cho, J.Y., Xing, S., Ledent, C. Endocrinology (1996) [Pubmed]
  11. Infrequent detectable somatic mutations of the RET and glial cell line-derived neurotrophic factor (GDNF) genes in human pituitary adenomas. Yoshimoto, K., Tanaka, C., Moritani, M., Shimizu, E., Yamaoka, T., Yamada, S., Sano, T., Itakura, M. Endocr. J. (1999) [Pubmed]
  12. Requirement of signalling by receptor tyrosine kinase RET for the directed migration of enteric nervous system progenitor cells during mammalian embryogenesis. Natarajan, D., Marcos-Gutierrez, C., Pachnis, V., de Graaff, E. Development (2002) [Pubmed]
  13. GDNF family receptors in the embryonic and postnatal rat heart and reduced cholinergic innervation in mice hearts lacking ret or GFRalpha2. Hiltunen, J.O., Laurikainen, A., Airaksinen, M.S., Saarma, M. Dev. Dyn. (2000) [Pubmed]
  14. Glial cell-line derived neurotrophic factor-mediated RET signaling regulates spermatogonial stem cell fate. Naughton, C.K., Jain, S., Strickland, A.M., Gupta, A., Milbrandt, J. Biol. Reprod. (2006) [Pubmed]
  15. The RET receptor tyrosine kinase: activation, signalling and significance in neural development and disease. Mason, I. Pharmaceutica acta Helvetiae. (2000) [Pubmed]
  16. The homeobox gene Phox2b is essential for the development of autonomic neural crest derivatives. Pattyn, A., Morin, X., Cremer, H., Goridis, C., Brunet, J.F. Nature (1999) [Pubmed]
  17. TrnR2, a novel receptor that mediates neurturin and GDNF signaling through Ret. Baloh, R.H., Tansey, M.G., Golden, J.P., Creedon, D.J., Heuckeroth, R.O., Keck, C.L., Zimonjic, D.B., Popescu, N.C., Johnson, E.M., Milbrandt, J. Neuron (1997) [Pubmed]
  18. The neuronal scaffold protein Shank3 mediates signaling and biological function of the receptor tyrosine kinase Ret in epithelial cells. Schuetz, G., Rosário, M., Grimm, J., Boeckers, T.M., Gundelfinger, E.D., Birchmeier, W. J. Cell Biol. (2004) [Pubmed]
  19. GDNF availability determines enteric neuron number by controlling precursor proliferation. Gianino, S., Grider, J.R., Cresswell, J., Enomoto, H., Heuckeroth, R.O. Development (2003) [Pubmed]
  20. Neurturin responsiveness requires a GPI-linked receptor and the Ret receptor tyrosine kinase. Buj-Bello, A., Adu, J., Piñón, L.G., Horton, A., Thompson, J., Rosenthal, A., Chinchetru, M., Buchman, V.L., Davies, A.M. Nature (1997) [Pubmed]
  21. Ret-mediated mitogenesis requires Src kinase activity. Melillo, R.M., Barone, M.V., Lupoli, G., Cirafici, A.M., Carlomagno, F., Visconti, R., Matoskova, B., Di Fiore, P.P., Vecchio, G., Fusco, A., Santoro, M. Cancer Res. (1999) [Pubmed]
  22. Cellular and developmental patterns of expression of Ret and glial cell line-derived neurotrophic factor receptor alpha mRNAs. Nosrat, C.A., Tomac, A., Hoffer, B.J., Olson, L. Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale. (1997) [Pubmed]
  23. Ret deficiency in mice impairs the development of A5 and A6 neurons and the functional maturation of the respiratory rhythm. Viemari, J.C., Maussion, G., Bévengut, M., Burnet, H., Pequignot, J.M., Népote, V., Pachnis, V., Simonneau, M., Hilaire, G. Eur. J. Neurosci. (2005) [Pubmed]
  24. Crx, a novel Otx-like paired-homeodomain protein, binds to and transactivates photoreceptor cell-specific genes. Chen, S., Wang, Q.L., Nie, Z., Sun, H., Lennon, G., Copeland, N.G., Gilbert, D.J., Jenkins, N.A., Zack, D.J. Neuron (1997) [Pubmed]
  25. Pleckstrin homology and phosphotyrosine-binding domain-dependent membrane association and tyrosine phosphorylation of Dok-4, an inhibitory adapter molecule expressed in epithelial cells. Bedirian, A., Baldwin, C., Abe, J., Takano, T., Lemay, S. J. Biol. Chem. (2004) [Pubmed]
  26. Development of chromaffin cells depends on MASH1 function. Huber, K., Brühl, B., Guillemot, F., Olson, E.N., Ernsberger, U., Unsicker, K. Development (2002) [Pubmed]
  27. IB4-binding DRG neurons switch from NGF to GDNF dependence in early postnatal life. Molliver, D.C., Wright, D.E., Leitner, M.L., Parsadanian, A.S., Doster, K., Wen, D., Yan, Q., Snider, W.D. Neuron (1997) [Pubmed]
  28. Differential activities of the RET tyrosine kinase receptor isoforms during mammalian embryogenesis. de Graaff, E., Srinivas, S., Kilkenny, C., D'Agati, V., Mankoo, B.S., Costantini, F., Pachnis, V. Genes Dev. (2001) [Pubmed]
  29. Wnt11 and Ret/Gdnf pathways cooperate in regulating ureteric branching during metanephric kidney development. Majumdar, A., Vainio, S., Kispert, A., McMahon, J., McMahon, A.P. Development (2003) [Pubmed]
  30. A single rostrocaudal colonization of the rodent intestine by enteric neuron precursors is revealed by the expression of Phox2b, Ret, and p75 and by explants grown under the kidney capsule or in organ culture. Young, H.M., Hearn, C.J., Ciampoli, D., Southwell, B.R., Brunet, J.F., Newgreen, D.F. Dev. Biol. (1998) [Pubmed]
  31. GFRalpha-2 and GFRalpha-3 are two new receptors for ligands of the GDNF family. Jing, S., Yu, Y., Fang, M., Hu, Z., Holst, P.L., Boone, T., Delaney, J., Schultz, H., Zhou, R., Fox, G.M. J. Biol. Chem. (1997) [Pubmed]
  32. cDNA cloning of mouse ret proto-oncogene and its sequence similarity to the cadherin superfamily. Iwamoto, T., Taniguchi, M., Asai, N., Ohkusu, K., Nakashima, I., Takahashi, M. Oncogene (1993) [Pubmed]
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