title: Biological effects of the dual phenotypic Janus mutation of ret cosegregating with both multiple endocrine neoplasia type 2 and Hirschsprung's disease.
abstract: Gain-of-function mutations of ret receptor tyrosine kinase, the signaling receptor for glial cell line-derived neurotrophic factor, cause sporadic thyroid and adrenal malignancies as well as endocrine cancer syndromes, such as multiple endocrine neoplasia types 2A and 2B (MEN 2A and MEN 2B) and familial medullary thyroid carcinoma. Loss-of-function mutations of ret cause Hirschsprung's disease (HSCR) or colonic aganglionosis. In 20-30% of families with a mutation at residues 609, 611, 618, or 620 of RET, MEN 2A and familial medullary thyroid carcinoma cosegregate with HSCR. These mutations constitutively activate RET due to aberrant disulfide homodimerization and diminish the level of RET at the plasma membrane. It is not known how these mutations simultaneously lead to both gain- and loss-of-function RET-associated diseases. We provide an explanation for the dual phenotypic Janus mutation at Cys620 of RET. In Madin-Darby canine kidney (MDCK) cells, the Janus mutation impairs the glial cell line-derived neurotrophic factor-induced effects of RET on cell migration, differentiation, and survival but simultaneously promotes rapid cell proliferation.
authors.affiliation: Developmental Biology, Institute of Biomedicine, Biomedicum Helsinki, P.O. Box 63, University of Helsinki, Helsinki, Finland FIN-00014.
authors.forename: Elena
authors.initials: E
authors.lastname: Arighi
authors.forename: Anna
authors.initials: A
authors.lastname: Popsueva
authors.forename: Debora
authors.initials: D
authors.lastname: Degl'Innocenti
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Borrello
authors.forename: Cristiana
authors.initials: C
authors.lastname: Carniti
authors.forename: Nina M
authors.initials: NM
authors.lastname: Perälä
authors.forename: Marco A
authors.initials: MA
authors.lastname: Pierotti
authors.forename: Hannu
authors.initials: H
authors.lastname: Sariola
mesh_terms: D000818:Animals; D019281:Dimerization; D004285:Dogs; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006627:Hirschsprung Disease / Q000235:genetics* / Q000378:metabolism; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics* / Q000378:metabolism; D018814:Multiple Endocrine Neoplasia Type 2b / Q000235:genetics* / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D015513:Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D020794:Receptor Protein-Tyrosine Kinases