Treanor J J, Goodman L, de Sauvage F, Stone D M, Poulsen K T, Beck C D, Gray C, Armanini M P, Pollock R A, Hefti F, Phillips H S, Goddard A, Moore M W, Buj-Bello A, Davies A M, Asai N, Takahashi M, Vandlen R, Henderson C E, Rosenthal A
Department of Neuroscience, Genentech, Inc., South San Francisco, California 94080, USA.
Nature. 1996 Jul 4;382(6586):80-3. doi: 10.1038/382080a0.
Glial-cell-line-derived neurotrophic factor (GDNF) is a potent survival factor for central and peripheral neurons, and is essential for the development of kidneys and the enteric nervous system. Despite the potential clinical and physiological importance of GDNF, its mechanism of action is unknown. Here we show that physiological responses to GDNF require the presence of a novel glycosyl-phosphatidylinositol (GPI)-linked protein (designated GDNFR-alpha) that is expressed on GDNF-responsive cells and binds GDNF with a high affinity. We further demonstrate that GDNF promotes the formation of a physical complex between GDNFR-alpha and the orphan tyrosin kinase receptor Ret, thereby inducing its tyrosine phosphorylation. These findings support the hypothesis that GDNF uses a multi-subunit receptor system in which GDNFR-alpha and Ret function as the ligand-binding and signalling components, respectively.
胶质细胞系源性神经营养因子（GDNF）是一种对中枢和外周神经元具有强大作用的存活因子，对肾脏和肠神经系统的发育至关重要。尽管GDNF在临床和生理方面具有潜在重要性，但其作用机制尚不清楚。在此我们表明，对GDNF的生理反应需要一种新型糖基磷脂酰肌醇（GPI）连接蛋白（命名为GDNFR-α）的存在，该蛋白在对GDNF有反应的细胞上表达，并以高亲和力结合GDNF。我们进一步证明，GDNF促进GDNFR-α与孤儿酪氨酸激酶受体Ret之间形成物理复合物，从而诱导其酪氨酸磷酸化。这些发现支持了这样一种假说，即GDNF使用一种多亚基受体系统，其中GDNFR-α和Ret分别作为配体结合和信号传导成分发挥作用。
