RET in human development and oncogenesis.
Hirschsprung disease and the multiple endocrine neoplasia type 2 syndromes are hereditary disorders related to the abnormal migration, proliferation or survival of neural crest cells and their derivatives. Hirschsprung disease is a frequent disorder of the enteric nervous system, resulting in intestinal obstruction. The multiple endocrine neoplasia type 2 syndromes predispose to cancers of neural crest derivatives. Both diseases are associated with heterozygous mutations in the RET proto-oncogene. RET encodes a transmembrane receptor tyrosine kinase expressed in neural crest lineages and whose ligand, glial-cell-line-derived neurotrophic factor, has been very recently identified. In vitro expression studies demonstrate that while Hirschsprung disease mutations result in loss of function of the mutant RET tyrosine kinase, multiple endocrine neoplasia type 2 mutations lead to its constitutive activation. Thus, the two 'faces' of RET, gain of function and loss of function, each lead to a different syndrome, respectively: multiple endocrine neoplasia type 2, a cancer syndrome, or Hirschsprung disease, a developmental defect.
Edery
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Service de Génétique Médicale et Unité de Recherches sur les Handicaps Génétiques de l'Enfant INSERM U-393, Hôpital Necker-Enfants Malades, Paris, France.
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Munnich
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Lyonnet
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D000818:Animals; D029721:Drosophila Proteins; D005314:Embryonic and Fetal Development / Q000235:genetics; D006627:Hirschsprung Disease / Q000201:enzymology / Q000235:genetics; D006801:Humans; D018813:Multiple Endocrine Neoplasia Type 2a / Q000201:enzymology / Q000235:genetics; D009154:Mutation; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret; D011519:Proto-Oncogenes; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism
D029721:Drosophila Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila