Klein R D, Sherman D, Ho W H, Stone D, Bennett G L, Moffat B, Vandlen R, Simmons L, Gu Q, Hongo J A, Devaux B, Poulsen K, Armanini M, Nozaki C, Asai N, Goddard A, Phillips H, Henderson C E, Takahashi M, Rosenthal A
Department of Neuroscience, Genentech, Inc., South San Francisco, California 94080, USA.
Nature. 1997 Jun 12;387(6634):717-21. doi: 10.1038/42722.
Glial-cell-line-derived neurotrophic factor (GDNF) and neurturin (NTN) are two structurally related, potent survival factors for sympathetic, sensory and central nervous system neurons. GDNF mediates its actions through a multicomponent receptor system composed of a ligand-binding glycosyl-phosphatidylinositol (GPI)-linked protein (designated GDNFR-alpha) and the transmembrane protein tyrosine kinase Ret. In contrast, the mechanism by which the NTN signal is transmitted is not well understood. Here we describe the identification and tissue distribution of a GPI-linked protein (designated NTNR-alpha) that is structurally related to GDNFR-alpha. We further demonstrate that NTNR-alpha binds NTN (K[d] approximately 10 pM) but not GDNF with high affinity; that GDNFR-alpha binds to GDNF but not NTN with high affinity; and that cellular responses to NTN require the presence of NTNR-alpha. Finally, we show that NTN, in the presence of NTNR-alpha, induces tyrosine-phosphorylation of Ret, and that NTN, NTNR-alpha and Ret form a physical complex on the cell surface. These findings identify Ret and NTNR-alpha as signalling and ligand-binding components, respectively, of a receptor for NTN and define a novel family of receptors for neurotrophic and differentiation factors composed of a shared transmembrane protein tyrosine kinase and a ligand-specific GPI-linked protein.
胶质细胞源性神经营养因子（GDNF）和神经营养素（NTN）是两种结构相关的强效存活因子，对交感神经、感觉神经和中枢神经系统神经元起作用。GDNF通过一个多组分受体系统介导其作用，该系统由一个配体结合糖基磷脂酰肌醇（GPI）连接蛋白（命名为GDNFR-α）和跨膜蛋白酪氨酸激酶Ret组成。相比之下，NTN信号传导的机制尚不清楚。在这里，我们描述了一种与GDNFR-α结构相关的GPI连接蛋白（命名为NTNR-α）的鉴定和组织分布。我们进一步证明，NTNR-α以高亲和力结合NTN（解离常数K[d]约为10 pM）而不结合GDNF；GDNFR-α以高亲和力结合GDNF而不结合NTN；并且细胞对NTN的反应需要NTNR-α的存在。最后，我们表明，在存在NTNR-α的情况下，NTN诱导Ret的酪氨酸磷酸化，并且NTN、NTNR-α和Ret在细胞表面形成一个物理复合物。这些发现分别确定Ret和NTNR-α为NTN受体的信号传导和配体结合组分，并定义了一个由共享的跨膜蛋白酪氨酸激酶和配体特异性GPI连接蛋白组成的神经营养和分化因子受体新家族。
