Gujral Taranjit S, Mulligan Lois M
Division of Cancer Biology and Genetics, Department of Pathology and Molecular Medicine, Cancer Research Institute, Botterell Hall Room 329, Queen's University, Kingston, ON, Canada K7L 3N6.
Ann N Y Acad Sci. 2006 Aug;1073:234-40. doi: 10.1196/annals.1353.025.
Multiple endocrine neoplasia Type 2 (MEN 2) is an inherited cancer syndrome characterized by medullary thyroid carcinoma (MTC). The disease has three subtypes, which are distinguished by the presence of additional phenotypes. In particular, pheochromocytoma occurs in approximately 50% of patients with the MEN 2A or MEN 2B subtypes, but is not found in patients with the milder disease subtype, familial MTC (FMTC). All subtypes of MEN 2 are caused by activating mutations of the RET (REarranged in Transfection) proto-oncogene. RET encodes a transmembrane receptor tyrosine kinase, required for development of neuroendocrine cell types and the kidneys. All MEN 2 subtypes are associated with single amino acid substitution mutations that are found in either the extracellular domain or in the kinase domain of RET. There are strong genotype-phenotype correlations in MEN 2 between patient phenotype and the specific residue that is mutated. MEN 2A is primarily associated with substitutions at five extracellular cysteine residues, while 95% of MEN 2B is associated with a single methionine to threonine mutation in the kinase domain (M918T). In FMTC, RET mutations are more broadly distributed, with both extracellular cysteines and intracellular sites implicated. In all cases, MEN 2-RET mutations result in constitutive activation of the receptor, although the mechanism and relative functional effects of the mutations vary. Recent advances in functional characterization and development of molecular models of RET and of various MEN 2-RET mutants are helping us understand tissue-specific differences in oncogenic potential conferred by the different RET mutations. Here, we discuss and compare several well-characterized mutations of the extracellular and kinase domains, which have quite varied functional implications.
2型多发性内分泌肿瘤（MEN 2）是一种遗传性癌症综合征，其特征为甲状腺髓样癌（MTC）。该疾病有三种亚型，可通过其他表型的存在来区分。特别是，嗜铬细胞瘤发生在约50%的MEN 2A或MEN 2B亚型患者中，但在病情较轻的疾病亚型——家族性MTC（FMTC）患者中未发现。MEN 2的所有亚型均由RET（转染重排）原癌基因的激活突变引起。RET编码一种跨膜受体酪氨酸激酶，是神经内分泌细胞类型和肾脏发育所必需的。MEN 2的所有亚型都与在RET的细胞外结构域或激酶结构域中发现的单氨基酸替代突变相关。在MEN 2中，患者表型与发生突变的特定残基之间存在很强的基因型-表型相关性。MEN 2A主要与五个细胞外半胱氨酸残基的替代相关，而95%的MEN 2B与激酶结构域中的单个甲硫氨酸至苏氨酸突变（M918T）相关。在FMTC中，RET突变分布更广泛，涉及细胞外半胱氨酸和细胞内位点。在所有情况下，MEN 2-RET突变都会导致受体的组成性激活，尽管突变的机制和相对功能效应各不相同。RET以及各种MEN 2-RET突变体的功能表征和分子模型开发方面的最新进展，有助于我们理解不同RET突变赋予的致癌潜力的组织特异性差异。在这里，我们讨论并比较细胞外结构域和激酶结构域的几个特征明确的突变，它们具有相当不同的功能意义。
