A novel type of mutation in the cysteine rich domain of the RET receptor causes ligand independent activation.
Multiple endocrine neoplasia type 2A (MEN 2A) is a dominantly inherited cancer syndrome, which involves the triad of MTC, pheochromocytoma, and hyperparathyroidism. Missense mutations in one of six cysteine codons in the extracellular cysteine-rich domain of the RET proto-oncogene predispose to this disease. These mutations cause ligand-independent constitutive activation of the tyrosine kinase receptor by the formation of disulfide-bonded homodimers. We examined a different type of mutation, which results in an additional cysteine in the cysteine rich domain. A duplication of 9 bp in the first case resulted in an insertion of three amino acids between codon 633 and 634. In the second case a 12 bp duplication in exon 11 results in four additional amino acids between codon 634 and 635. Here we demonstrate that an additional cysteine causes a ligand independent dimerization of the RET receptor in transfected NIH3T3 cells, which results in an activation of the intracellular tyrosine kinase.
Institute for Hormone and Fertility Research, University of Hamburg, Germany.
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Arlt
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Baur
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Wagner
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Höppner
D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D003545:Cysteine / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D004220:Disulfides; D029721:Drosophila Proteins; D004789:Enzyme Activation; D051380:GRB2 Adaptor Protein; D006801:Humans; D008024:Ligands; D051379:Mice; D016254:Mutagenesis, Insertional; D011506:Proteins / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D004220:Disulfides; D029721:Drosophila Proteins; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C495949:Grb2 protein, mouse; D008024:Ligands; C000715470:MAS1 protein, human; D011506: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; D003545:Cysteine