生长分化因子15及其特异性受体GFRAL信号通路  

The Signaling Pathway of Growth Differentiation Factor 15 and Its Receptor GFRAL

作　　者：王刚 林芳 罗茂 WANG Gang;LIN Fang;LUO Mao(Drug Discovery Research Center,Department of Pharmacology,Southwest Medical University,Luzhou 646000,Sichuan,China;Laboratory for Cardiovascular Pharmacology,Department of Pharmacology,Southwest Medical University,Luzhou 646000,Sichuan,China)

机构地区：[1]西南医科大学药物研究中心,四川泸州646000 [2]西南医科大学心血管药理系,四川泸州646000

出　　处：《中国生物化学与分子生物学报》2021年第4期437-448,共12页Chinese Journal of Biochemistry and Molecular Biology

基　　金：国家自然科学基金(No.81800434);四川省科技厅项目(No.2019YJ0487);四川省留学人员科技活动项目择优资助项目(川人社办发(2020)291号);泸州市科技局项目(No.2017LZXNYD-T05)资助。

摘　　要：生长分化因子15(growth differentiation factor 15,GDF15)属于转化生长因子β(transforming growth factorβ,TGF-β)超家族的成员之一,是与转化生长因子β家族成员同源性很低的新一类二聚体多肽。GDF15最初发现于活化的巨噬细胞中,可通过2种不同的细胞途径分泌进入机体循环。GDF15作为一种应激蛋白质,广泛参与到例如磷酸肌醇3激酶/蛋白激酶B、细胞外信号调节激酶、c-Jun氨基末端激酶及核因子-κB等多种信号通路,调节着各种疾病进程。作为一种新型应激分子,GDF15在肥胖、体重减轻、癌症发展、心血管疾病、炎症和自身免疫疾病有着调控及生物标志的作用。胶质细胞源性神经营养因子(glial-derived neurotrophic factor,GDNF)样受体α(GDNF receptor alpha-like,GFRAL)为GDF15的特异性受体。GDF15活性发挥的分子基础是通过GFRAL依赖结合成多聚体来传导信号。GDF15-GFRAL信号通路的干预在减肥药物和癌症愈后恢复的药物开发中有着良好的应用潜力。本文阐述了GDF15-GFRAL信号通路的最新研究动态,概括了GDF15和GFRAL的分子结构,重点介绍GDF15-GFRAL信号通路的作用机制,揭示疾病发生发展中GDF15作为生物标记物的作用和调节能力,展望了调节GDF15-GFRAL信号通路在相关疾病的研究潜力和治疗策略。Growth differentiation factor 15(GDF15),a member of the transforming growth factorβ(TGF-β)superfamily,is a new class of dimeric polypeptides with very low homology with other TGF-βfamily members.GDF15 was originally found in activated macrophages where it was secreted into the body circulation in two different cellular pathways.Moreover,GDF15 as a stress protein is widely involved in many signal pathways such as phosphoinositide 3-kinase/protein kinase B,extracellular signal-regulated kinase,c-Jun N-terminal kinase and nuclear factor-κB,and so on,and thus involved in the regulation of various disease processes.In addition,GDF15 as a new type of stress molecule acts as a biomarker and plays a regulatory role in obesity,weight loss,cancer development,cardiovascular disease,inflammation and autoimmune diseases.Glial-derived neurotrophic factor receptor alpha-like(GFRAL)is the specific receptor of GDF15,and the molecular basis of its activity is to conduct signal transduction through GFRAL-dependent binding into multimers.The intervention of the GDF15-GFRAL signaling pathway has a great application potential in the development of weight-loss drugs and cancer prognosis recovery drugs.This review focuses on the recent progress of GDF15-GFRAL and its related signaling pathways,the molecular structure of GDF15 and GFRAL,and the mechanism of GDF15-GFRAL signaling pathway,which reveals the role and regulatory ability of GDF15 as a biomarker in the development of disease and provides new insights in potential and treatment strategies of regulating the GDF15-GFRAL signaling pathway in related diseases.

关 键 词：生长分化因子15 胶质细胞源性神经营养因子样受体α 代谢紊乱 生物标志物 

分 类 号：R363[医药卫生—病理学] Q51[医药卫生—基础医学]