International Center for Cell and Gene Therapy, Fujita Health University.
Department of Pathology, Nagoya University Graduate School of Medicine.
Proc Jpn Acad Ser B Phys Biol Sci. 2022;98(3):112-125. doi: 10.2183/pjab.98.008.
The RET proto-oncogene encodes a receptor tyrosine kinase whose alterations are responsible for various human cancers and developmental disorders, including thyroid cancer, non-small cell lung cancer, multiple endocrine neoplasia type 2, and Hirschsprung's disease. RET receptors are physiologically activated by glial cell line-derived neurotrophic factor (GDNF) family ligands that bind to the coreceptor GDNF family receptor α (GFRα). Signaling via the GDNF/GFRα1/RET ternary complex plays crucial roles in the development of the enteric nervous system, kidneys, and urinary tract, as well as in the self-renewal of spermatogonial stem cells. In addition, another ligand, growth differentiation factor-15 (GDF15), has been shown to bind to GFRα-like and activate RET, regulating body weight. GDF15 is a stress response cytokine, and its elevated serum levels affect metabolism and anorexia-cachexia syndrome. Moreover, recent development of RET-specific kinase inhibitors contributed significantly to progress in the treatment of patients with RET-altered cancer. This review focuses on the broad roles of RET in development, metabolic diseases, and cancer.
RET 原癌基因编码一种受体酪氨酸激酶，其改变与多种人类癌症和发育障碍有关，包括甲状腺癌、非小细胞肺癌、多发性内分泌肿瘤 2 型和先天性巨结肠。RET 受体通过胶质细胞系衍生的神经营养因子（GDNF）家族配体被生理激活，这些配体与 GDNF 家族受体 α（GFRα）的辅助受体结合。通过 GDNF/GFRα1/RET 三元复合物的信号转导在肠神经系统、肾脏和泌尿道的发育以及精原干细胞的自我更新中发挥着关键作用。此外，另一种配体生长分化因子 15（GDF15）已被证明可以与 GFRα 样结合并激活 RET，从而调节体重。GDF15 是一种应激反应细胞因子，其血清水平升高会影响代谢和恶病质综合征。此外，RET 特异性激酶抑制剂的最新发展为治疗 RET 改变的癌症患者的治疗带来了显著进展。这篇综述重点介绍了 RET 在发育、代谢疾病和癌症中的广泛作用。
