Iwashita T, Murakami H, Kurokawa K, Kawai K, Miyauchi A, Futami H, Qiao S, Ichihara M, Takahashi M
Department of Pathology, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
Biochem Biophys Res Commun. 2000 Feb 24;268(3):804-8. doi: 10.1006/bbrc.2000.2227.
Multiple endocrine neoplasia (MEN) type 2B mutations have been reported at methionine 918 or alanine 883 in the tyrosine kinase domain of the RET proto-oncogene. Recently, a new combination of two germline missense mutations at valine 804 and tyrosine 806 was identified in a patient with MEN 2B-like clinical phenotypes including medullary thyroid carcinoma, mucosal neuroma, and marfanoid habitus. In this case, valine 804 and tyrosine 806 were replaced with methionine and cysteine, respectively. In the present study, biological activities of RET with these new mutations were compared with those with known MEN 2A or MEN 2B mutations. The transforming activity of RET with the V804M/Y806C mutation was about 8- to 13-fold higher than that of RET with a single V804M or Y806C mutation. Like RET with the M918T or A883F MEN 2B mutation, the transforming activity of RET with the V804M/Y806C mutation was not affected by substitution of phenylalanine for tyrosine 905 that abolished the activity of RET with the MEN 2A mutation. On the other hand, substitution of phenylalanine for tyrosines 864 and 952 drastically diminished the activity of RET with the V804M/Y806C, M918T or A883F mutation, suggesting that these three mutant proteins have similar biological properties.
多发性内分泌腺瘤（MEN）2B型突变已报道于RET原癌基因酪氨酸激酶结构域的甲硫氨酸918或丙氨酸883位点。最近，在一名患有MEN 2B样临床表型（包括甲状腺髓样癌、黏膜神经瘤和类马凡氏体型）的患者中，发现了缬氨酸804和酪氨酸806两个种系错义突变的新组合。在这种情况下，缬氨酸804和酪氨酸806分别被甲硫氨酸和半胱氨酸取代。在本研究中，将具有这些新突变的RET的生物学活性与具有已知MEN 2A或MEN 2B突变的RET的生物学活性进行了比较。具有V804M/Y806C突变的RET的转化活性比具有单一V804M或Y806C突变的RET的转化活性高约8至13倍。与具有M918T或A883F MEN 2B突变的RET一样，具有V804M/Y806C突变的RET的转化活性不受酪氨酸905被苯丙氨酸取代的影响，而这种取代消除了具有MEN 2A突变的RET的活性。另一方面，酪氨酸864和952被苯丙氨酸取代大大降低了具有V804M/Y806C、M918T或A883F突变的RET的活性，这表明这三种突变蛋白具有相似的生物学特性。
