摘要
胶质细胞源性神经营养因子(GDNF)家族包括GDNF、NRTN(neurturin)、ARTN(artemin)、PSPN(persephin)四个成员。它们不仅可以支持中枢神经系统内中脑多巴胺能神经元与运动神经元等多种神经元的存活和发育,还支持许多外周神经元如交感、副交感、感觉与肠道神经元等的存活并调节其分化。除神经系统外,GDNF还是肾脏发育中的重要的形态形成因子,并在精原细胞分化过程中起关键的调节作用。GDNF家族成员通过其相应受体介导信号转导引起一系列细胞效应,即在GFRα1-4的帮助下与受体Ret结合,促进Ret二聚化和自磷酸化,继而由Ret进一步结合和激活下游信号分子,发生一系列信号级联反应,最终激活Ras/MAPK、PI3-K以及PLCγ等信号转导通路。Ret受体属于受体酪氨酸激酶(RTK, Receptor Tyrosine Kinase)家族成员,是一种跨膜糖蛋白,含胞外域、跨膜段和胞内域三个部分。其中胞内域含酪氨酸激酶活性区和重要的酪氨酸结合位点,如Y1062可以至少和5种入坞蛋白结合:Shc、FRS2、DOK4/5、IRS1/2和enigma,从而激活MAPK或PI-3K等途径,促进神经元存活及轴突生长或分支。
Rap1GAP是1991年发现的第一个对于小G蛋白Rap1具有GTP酶激活活性的蛋白,大小89KDa。小G蛋白Rap1属于Ras亚家族,和Ras有53%的同源性,是和Ras最相近的成员。特异的鸟核苷酸交换因子(GEFs)促进小G蛋白与GDP解离,使其结合GTP而激活小G蛋白;而特异的GTP酶激活蛋白(GAPs)则可加速小G蛋白水解结合在其上的GTP,从而使其活性抑制。Rap1GAP作为GAPs的一种,可水解Rap1结合的GTP使Rap1失活。Rap1GAP蛋白的核心区340个氨基酸(75—415)足以发挥GTPase的水解活性,这个区域和其他小G蛋白的GAP没有任何同源性。以往对Rap1GAP的研究主要和参与肿瘤抑制有关。最近的文献表明,Rap1GAP在神经元的树突生长过程和导致树突棘头部增大的进程中具有重要的调节作用。人们还发现,在PC12细胞中的Gα_Z一旦激活后,内源性Rap1GAP可结合Gα_Z并将其从胞浆募集到膜上,最终抑制NGF引起的PC12细胞分化。
我们在前期研究中,用Ret胞内域为诱饵经酵母双杂交筛选人脑cDNA文库,
Glia cell line-derived neurotrophic factor (GDNF) family contains four members: GDNF, NRTN (neurturin), ARTN (artemin), PSPN (persephin), which could not only support the survival and development of mesencephalic dopaminergic neuron and motoneuron in the central nervous system, but also enhance the survival and differentiation of sympathetic and parasympathetic neuron, sensory neuron and enteric neuron in the peripheral nervous system. GDNF is also an important morphologic factor involved in the development of the kidney and plays a key role in the differentiation of spermatogonial cells. GDNF family ligands mediate signaling pathway through their coreceptors GFRal-4 and Ret, belonging to the receptor kinase family. After binding with their ligands, GFRal-4 would trigger the autophosphorylation of Ret and then activate the downstream signaling pathway such as Ras/MAPK, PI3-K and PLCγ etc. The intracellular domain of Ret, with the tyrosine kinase activity, provides the docking sites for many adaptor proteins. For example, the pY1062 in Ret could at least bind to five docking proteins, such as She, FRS2, DOK4/5, IRS1/2 and enigma, to induce different downstream signaling pathway either leading to neuronal growth or branching.Rap1GAP, a molecular weight-89kDa protein which identified in 1991, was the first protein for which a specific GAP activity towards Rap1. Rap1 belongs to the Ras subfamily of small GTPases and with 53% amino-acid identity to Ras. Like other small GTPases members, rapl is in activated state when bound GTP, and in inactivated state when bound GDP. The nucleotide-loading state is tightly regulated by guanine nucleotide exchange factors (GEFs) that catalyse the dissociation of bound nucleotide, and GTPase activating proteins (GAPs) which accelerate the hydrolysis of bound GTP. A core domain comprising 340 amino acids (75-415) was shown to be necessary and sufficient for this GAP activity. Rap1GAP has been recently reported to be involved in the enlargement of dendrite spine head through inhibiting Rapl
引文
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Yumi Nodaa, b,*, Saburo Horikawac, Tetsushi Furukawad, Keiji Hiraib, Yoshifumi