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胶质细胞系源性神经营养因子(glial cell line derived neurotrophic factor,GDNF)属于神经营养因子超家族,是TGF-β超家族的一个亚家族成员。目前已发现的GDNF家族配体(GDNF family ligand,GFL)有GDNF、neurturin(NRTN)、artemin(ARTN)、persephin(PSPN)4个成员。GDNF家族受体为GFRα1-4,分别对应着GDNF家族配体GDNF、NRTN、ARTN及PSPN。通常GFRα通过糖基磷脂酰肌醇(glycosyl phosphatidyl inositol,GPI)锚着到细胞膜上,经GDNF家族配体刺激后募集受体酪氨酸激酶RET作为共受体并形成GFL/GFRα/RET复合物,使RET酪氨酸激酶磷酸化,进一步活化下游的Ras/MAPK、PI3K、PLCγ信号通路进而调控细胞的功能。最初对GDNF家族成员的功能研究主要集中在神经系统,发现GDNF/GFRα信号对中枢神经系统有特异的营养作用和促轴突生长作用,在参与促进神经元存活及轴突损伤修复等方面有其他生长因子不可比拟的作用。但随着研究的进展,越来越多的资料表明GDNF/GFRα信号在肿瘤的发生发展中也占据一席之地,尤其在促进肿瘤侵袭转移方面具有重要作用。本文聚焦GDNF/GFRα1信号,重点阐述GDNF/GFRα1信号在肿瘤进展和侵袭转移中的作用以及相关分子信号机制,以期为神经-内分泌-肿瘤相关性研究提供参考,为肿瘤的防治提供新的靶点和视角。
Glial cell line derived neurotrophic factor (GDNF) belongs to the neurotrophic factor superfamily and is a subfamily member of the TGF-β superfamily. GDNF family ligands (GDNF family ligands, GFRs) are currently found in GDNF, neurturin (NRTN), artemin (ARTN), persephin (PSPN) 4 members. GDNF family receptor GFRα1-4, corresponding to the GDNF family ligands GDNF, NRTN, ARTN and PSPN. Normally, GFRα is anchored to the cell membrane by glycosyl phosphatidyl inositol (GPI) and recruits receptor tyrosine kinase RET as a coreceptor and stimulates GDNF family ligands to form GFL / GFRα / RET complexes , So that RET tyrosine kinase phosphorylation, further activation of the downstream Ras / MAPK, PI3K, PLCγ signaling pathway and regulation of cell function. The initial study of the function of GDNF family members focused on the nervous system and found that GDNF / GFRα signal specific central nervous system nutrition and axonal growth role in participation in promoting neuronal survival and axonal injury repair and so on Unparalleled role of growth factor. However, as the research progresses, more and more data indicate that GDNF / GFRα signal also occupies a place in the development of tumors, especially in promoting tumor invasion and metastasis. This article focuses on the GDNF / GFRα1 signal, focusing on the role of GDNF / GFRα1 signal in tumor progression and invasion and metastasis, as well as related molecular signaling mechanisms in order to provide a reference for the neuroendocrine-tumor related research, and provide a new target for the prevention and treatment of cancer And perspective.