多发性内分泌肿瘤中 RET 受体功能障碍的细胞机制 2.

Endocrine-related cancer Pub Date : 2024-12-13 Print Date: 2025-01-01 DOI:10.1530/ERC-24-0187
Timothy J Walker, Lois M Mulligan
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引用次数: 0

摘要

转染过程中的重组受体(RET)是一种对发育非常重要的受体酪氨酸激酶,已被确定为多种癌症的致癌驱动因子。激活的 RET 点突变会导致以甲状腺髓样癌为特征的遗传性癌症综合征多发性内分泌肿瘤 2 型(MEN2)。MEN2 有两种亚型,即 MEN2A 和 MEN2B,它们的肿瘤侵袭性和相关的其他疾病特征各不相同,是由不同的 RET 氨基酸置换突变模式引起的。影响细胞外半胱氨酸残基的 MEN2A-RET 突变可促进配体独立的二聚化和组成型 RET 活性,而 MEN2B 则是由 RET 的酪氨酸激酶结构域中的单个氨基酸变化引起的,这种变化释放了自身抑制作用,产生了活性更强的 MEN2B-RET 激酶,可在没有配体的情况下促进单体或二聚体的信号传导。这些突变会导致 RET 结构和激活发生内在生化变化,但也会引发外在效应,改变 RET 的细胞位置、相互作用和下调机制,从而延长或错位 RET 的活性,改变或增强功能结果。与不同突变相关的 RET 介导效应特定组合的变化共同导致了不同的 MEN2 疾病表型。在此,我们将讨论目前对 RET MEN2A 半胱氨酸突变体和 MEN2B 突变体的内在和外在特征的理解,以及这些特征如何促进细胞过程的转变并导致肿瘤进展和疾病侵袭性的差异。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Cellular mechanisms of RET receptor dysfunction in multiple endocrine neoplasia 2.

Graphical abstract:

Abstract: Rearranged during transfection (RET) is a developmentally important receptor tyrosine kinase that has been identified as an oncogenic driver in a number of cancers. Activating RET point mutations gives rise to the inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN2), characterized by medullary thyroid carcinoma. There are two MEN2 subtypes, MEN2A and MEN2B, that differ in tumour aggressiveness and the associated constellation of other disease features, which are caused by distinct patterns of RET amino acid substitution mutations. MEN2A-RET mutations affecting extracellular cysteine residues promote ligand-independent dimerization and constitutive RET activity, while MEN2B is caused by a single amino acid change in the tyrosine kinase domain of RET, releasing autoinhibition and producing a more active MEN2B-RET kinase that can promote signalling as monomers or dimers in the absence of a ligand. These mutations cause intrinsic biochemical changes in the RET structure and activation but also trigger extrinsic effects that alter RET cellular location, interactions and mechanisms of downregulation that can prolong or mislocate RET activity, changing or enhancing functional outcomes. Furthermore, changes in specific combinations of RET-mediated effects associated with different mutations give rise to the distinct MEN2 disease phenotypes. Here, we discuss the current understanding of the intrinsic and extrinsic characteristics of RET MEN2A cysteine and MEN2B mutants and how these contribute to transforming cellular processes and to the differences in tumour progression and disease aggressiveness.

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