Cirafici A M, Salvatore G, De Vita G, Carlomagno F, Dathan N A, Visconti R, Melillo R M, Fusco A, Santoro M
Dipartimento di Biologia e Patologia Cellulare e Molecolare, Facoltà di Medicina e Chirurgia, Università degli Studi di Napoli Federico II,Italy.
Endocrinology. 1997 Apr;138(4):1450-5. doi: 10.1210/endo.138.4.5073.
Specific point-mutations of the RET receptor tyrosine kinase protooncogene are responsible for the inheritance of multiple endocrine neoplasia type 2A (MEN2A) and 2B (MEN2B), and familial medullary thyroid carcinoma (FMTC). MEN2B is caused by the substitution of methionine 918 by a threonine in the tyrosine kinase (TK) domain of RET. This mutation converts RET into a dominant transforming oncogene. We have substituted Met918 with four different residues and found that RET acquired transforming activity only when Met918 was substituted with a threonine. However, also when serine and valine, but not leucine or phenylalanine, were inserted in position 918, the RET TK function was activated and induced, especially in the case of the RET(918Ser), immmediate-early response genes. We conclude that the preservation of Met918 is critical for the control of RET kinase. However, only when a threonine residue is present in position 918, does RET efficiently couple with a transforming pathway.
RET 受体酪氨酸激酶原癌基因的特定点突变与 2A 型多发性内分泌腺瘤病（MEN2A）、2B 型多发性内分泌腺瘤病（MEN2B）以及家族性甲状腺髓样癌（FMTC）的遗传有关。MEN2B 是由 RET 酪氨酸激酶（TK）结构域中的甲硫氨酸 918 被苏氨酸取代所致。这种突变使 RET 转化为一种显性转化癌基因。我们用四种不同的氨基酸取代了甲硫氨酸 918，发现只有当甲硫氨酸 918 被苏氨酸取代时，RET 才获得转化活性。然而，当丝氨酸和缬氨酸插入 918 位时（亮氨酸或苯丙氨酸插入时则不然），RET 的 TK 功能也会被激活和诱导，尤其是 RET(918Ser)的情况下，会激活早期反应基因。我们得出结论，甲硫氨酸 918 的保留对于 RET 激酶的调控至关重要。然而，只有当 918 位存在苏氨酸残基时，RET 才能有效地与转化途径偶联。
