Functional receptor for GDNF encoded by the c-ret proto-oncogene
Functional receptor for GDNF encoded by the c-ret proto-oncogene
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DOI：
10.1038/381785a0
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发表时间：
1996-06
期刊：
影响因子：
64.8
通讯作者：
Miles Trupp;E. Arenas;M. Fainzilber;A. Nilsson;B. Sieber;M. Grigoriou;C. Kilkenny;E. Salazar-Grueso;V. Pachnis;U. Arumäe;H. Sariola;M. Saarma;C. Ibáñez
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作者：
Miles Trupp;E. Arenas;M. Fainzilber;A. Nilsson;B. Sieber;M. Grigoriou;C. Kilkenny;E. Salazar-Grueso;V. Pachnis;U. Arumäe;H. Sariola;M. Saarma;C. Ibáñez
胶质细胞源性神经营养因子促进中枢多巴胺1，2，去甲肾上腺素3和运动神经元4-6以及周围感觉和交感神经元7，8各亚群的存活和表型。胶质细胞源性神经营养因子在结构上与转化生长因子-β超家族成员有关，其中几个成员有很好的受体系统10，11；然而，胶质细胞源性神经营养因子受体仍未确定。在这里，我们展示了GDNF结合并诱导GDNF反应性运动神经元细胞系中c-retproto癌基因产物的酪氨酸磷酸化，c-retproto癌基因是一种孤儿受体酪氨酸激酶。RET蛋白还可与GDNF结合，介导对GDNF的存活和生长反应。此外，在成年黑质的多巴胺能神经元中发现高水平的c-retm RNA表达，外源性GDNF可保护Ret阳性神经元免受6-羟基多巴胺诱导的细胞死亡。因此，c-retproto癌基因的产物编码GDNF的功能性受体，可能介导其对运动神经元和多巴胺能神经元的神经营养作用。
GLIAL-CELL-LINE-DERIVED neurotrophic factor (GDNF) promotes the survival and phenotype of central dopaminergic1,2, noradrenergic3and motor neurons4–6, as well as various subpopulations of peripheral sensory and sympathetic neurons7,8. GDNF is structurally related to members of the transforming growth factor (TGF)-β superfamily9, several members of which have well-characterized receptor systems10,11; however, GDNF receptors still remain undefined. Here we show that GDNF binds to, and induces tyrosine phosphorylation of, the product of the c-retproto-oncogene, an orphan receptor tyrosine kinase, in a GDNF responsive motor-neuron cell line. Ret protein could also bind GDNF and mediate survival and growth responses to GDNF upon transfection into naive fibroblasts. Moreover, high levels of c-retmRNA expression were found in dopaminergic neurons of the adult substantia nigra, where exogenous GDNF protected Ret-positive neurons from 6-hydroxydopamine-induced cell death. Thus the product of the c-retproto-oncogene encodes a functional receptor for GDNF that may mediate its neurotrophic effects on motor and dopaminergic neurons.