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A novel type of mutation in the cysteine rich domain of the RET receptor causes ligand independent activation

Abstract

Multiple endocrine neoplasia type 2A (MEN 2A) is a dominantly inherited cancer syndrome, which involves the triad of MTC, pheochromocytoma, and hyperparathyridism. 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.

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Acknowledgements

We are grateful to M Santoro and A Fusco for making the cDNA of the RET short isoform available to us. We thank James Olcese, Ulrike Klein and Natalia Schlabritz for critical reading of the manuscript. The technical assistance of Monika Kistler and the groups of HU Häring (Tübingen) and H Klein (Lübeck) is gratefully acknowledged. This work was supported by Forum Schilddrüse and the Deutsche Forschungsgemeinschaft (Graduiertenkolleg 336).

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Arlt, D., Baur, B., Wagner, B. et al. A novel type of mutation in the cysteine rich domain of the RET receptor causes ligand independent activation. Oncogene 19, 3445–3448 (2000). https://doi.org/10.1038/sj.onc.1203688

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