RET Receptor  (RET 受体)

RET 受体蛋白是一种由 RET 原癌基因编码的单次跨膜受体酪氨酸激酶。RET 可以通过胶质细胞系来源的神经营养因子 (GDNF) 家族的配体进行信号转导，目前该家族的神经营养因子包括 GDNF、neuturin (NTN)、artemin (ART) 和persephin (PSP)。GDNF、NRTN、ARTN 和 PSP 分别通过其同源共受体 GFRα1-4 与 RET 结合并特异性激活 RET。RET 的信号转导激活多个第二信使系统，包括 Raf/Mek/ERK1/2、PI3K/Akt、PLCY、Ras、JNK和肌醇磷酸盐通路。RET蛋白由三个结构域组成：胞外配体结合结构域、跨膜结构域和胞质酪氨酸激酶结构域。其胞外区域包含 4 个钙粘蛋白样重复和一个高度保守的富半胱氨酸区域。富含半胱氨酸的区域对于三级结构和通过二硫键形成的二聚作用很重要。 RET 信号对肠神经系统的发育至关重要。RET 还调节交感神经元、副交感神经元、运动神经元和感觉神经元的发育，是后天维持多巴胺能神经元必不可少的。RET 的失活突变导致以巨结肠血管团病为特征的巨结肠巨结肠病。相反，激活突变可导致不同类型的癌症，如多发性内分泌肿瘤 2A 型和 2B 型、家族性甲状腺髓样癌和甲状腺乳头状癌。

The REarranged during Transfection (RET) receptor protein is a single-pass transmembrane receptor tyrosine kinase that is encoded by RET proto-oncogene. RET can transduce signalling by ligands of the glial cell line-derived neurotrophic factor (GDNF) family of neurotrophins which currently comprises GDNF, neuturin (NTN) , artemin (ART) and persephin (PSP). GDNF, NRTN, ARTN and PSP can bind to and specifically activate RET through their cognate co-receptors GFRα1-4, respectively. The signal transduction by RET activates several second messenger systems including the Raf/Mek/ERK1/2, PI3K/Akt, PLCY, Ras, JNK and inositol phosphate pathways. The RET protein is composed of three domains: an extracellular ligand-binding domain, a transmembrane domain, and a cytoplasmic tyrosine kinase domain. The extracellular domain contains four cadherin-like repeats as well as a highly conserved cysteine-rich region. The cysteine-rich region is important for tertiary structure and dimerization through disulfide bond formation. RET signalling is crucial for the development of the enteric nervous system. RET also regulates the development of sympathetic, parasympathetic, motor, and sensory neurons, and is necessary for the postnatal maintenance of dopaminergic neurons. Inactivating mutations in RET cause the Hirschsprung's disease characterized by megacolon aganglionosis. In contrast, activating mutations give rise to different types of cancer, multiple endocrine neoplasia type 2A and type 2B, familial medullary thyroid carcinoma, and papillary thyroid carcinoma.