The RET receptor: function in development and dysfunction in congenital malformation.
Germline mutations in the RET proto-oncogene are responsible for two unrelated neural crest disorders: Hirschsprung disease, a congenital absence of the enteric nervous system in the hindgut, and multiple endocrine neoplasia type 2, a dominantly inherited cancer syndrome. Moreover, somatic rearrangements of RET are causally involved in the genesis of papillary thyroid carcinoma. The receptor tyrosine kinase encoded by the RET gene acts as the subunit of a multimolecular complex that binds four distinct ligands and activates a signalling network crucial for neural and kidney development. Over the past few years, a clearer picture of the mode of RET activation and of its multifaceted role during development has started to emerge. These findings, which provide new clues to the molecular mechanisms underlying RET signalling dysfunction in Hirschsprung disease, are summarized in this review.
Manié
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Laboratoire de Génétique, CNRS UMR 5641, Domaine Rockefeller, 8 avenue Rockefeller, 69373 Cedex 08, Lyon, France.
Santoro
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Fusco
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Billaud
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D000818:Animals; D017209:Apoptosis; D029721:Drosophila Proteins; D017615:Enteric Nervous System / Q000002:abnormalities; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D006627:Hirschsprung Disease / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D008024:Ligands; D021962:Membrane Microdomains / Q000502:physiology; D051379:Mice; D009154:Mutation; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000502:physiology; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000502:physiology*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000502:physiology*; D015398:Signal Transduction
D029721:Drosophila Proteins; C495039:GDNF protein, human; C495040:Gdnf protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D008024:Ligands; C000715470:MAS1 protein, human; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; C494999:Ret protein, mouse