Santoro Massimo, Melillo Rosa Marina, Carlomagno Francesca, Fusco Alfredo, Vecchio Giancarlo
Centro di Endocrinologia ed Oncologia Sperimentale del CNR c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, Facoltá di Medicina e Chirurgia, Universitá di Napoli Federico II, 80131 Naples, Italy.
Ann N Y Acad Sci. 2002 Jun;963:116-21. doi: 10.1111/j.1749-6632.2002.tb04102.x.
Mutations that produce oncogenes with dominant gain of function target receptor protein tyrosine kinases (PTKs) in cancer and confer uncontrolled proliferation, impaired differentiation, or unrestrained survival to the cancer cell. However, insufficient PTK signaling may be responsible for developmental diseases. Gain of function of the RET receptor PTK is associated with human cancer. At the germline level, point mutations of RET are responsible for multiple endocrine neoplasia type 2 (MEN2A, MEN2B, and FMTC). Mutations of extracellular cysteines are found in MEN2A patients, and a Met918Thr mutation is responsible for most MEN2B cases. At the somatic level, gene rearrangements juxtaposing the tyrosine kinase domain of RET to heterologous gene partners are found in papillary carcinomas of the thyroid. These rearrangements generate the chimeric RET/PTC oncogenes. Both MEN2 mutations and PTC gene rearrangements potentiate the intrinsic tyrosine kinase activity of RET and, ultimately, the RET downstream signaling events. A multidocking site of the C-tail of RET is essential for both mitogenic and survival RET signaling. Such a site is involved in the recruitment of several intracellular molecules, such as the Shc, FRS2, IRS1, Gab1/2, and Enigma. The different activating mutations not only potentiate the enzymatic activity of the RET kinase but also may alter qualitatively RET signaling properties by: (1) altering RET autophosphorylation (in the case of the MEN2B mutation), (2) modifying the subcellular distribution of the active kinase, and (3) providing the active kinase with a scaffold for novel protein-protein interactions (as in the case of RET/PTC oncoproteins). This review describes the molecular mechanisms by which the different genetic alterations cause the conversion of RET into a dominant transforming oncogene.
产生具有显性功能获得性的致癌基因的突变，在癌症中靶向受体蛋白酪氨酸激酶（PTK），并赋予癌细胞不受控制的增殖、分化受损或无节制的存活能力。然而，PTK信号不足可能是发育性疾病的原因。RET受体PTK的功能获得与人类癌症相关。在种系水平上，RET的点突变导致2型多发性内分泌肿瘤（MEN2A、MEN2B和FMTC）。在MEN2A患者中发现细胞外半胱氨酸的突变，而Met918Thr突变是大多数MEN2B病例的原因。在体细胞水平上，在甲状腺乳头状癌中发现RET的酪氨酸激酶结构域与异源基因伙伴并列的基因重排。这些重排产生嵌合RET/PTC致癌基因。MEN2突变和PTC基因重排均增强RET的内在酪氨酸激酶活性，并最终增强RET下游信号事件。RET C末端的多对接位点对于有丝分裂和存活RET信号均至关重要。这样一个位点参与募集几种细胞内分子，如Shc、FRS2、IRS1、Gab1/2和Enigma。不同的激活突变不仅增强RET激酶的酶活性，还可能通过以下方式定性改变RET信号特性：（1）改变RET自身磷酸化（如MEN2B突变的情况），（2）改变活性激酶的亚细胞分布，以及（3）为活性激酶提供用于新型蛋白质-蛋白质相互作用的支架（如RET/PTC癌蛋白的情况）。本综述描述了不同基因改变导致RET转化为显性转化致癌基因的分子机制。
