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.
Arlt
D H
DH
Institute for Hormone and Fertility Research, University of Hamburg, Germany.
Baur
B
B
Wagner
B
B
Höppner
W
W
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