Structural determinants of heparan sulphate modulation of GDNF signalling
Structural determinants of heparan sulphate modulation of GDNF signalling
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DOI：
10.1080/08977190310001621005
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发表时间：
2003-09-01
期刊：
影响因子：
1.8
通讯作者：
Turnbull, JE
中科院分区：
文献类型：
--
作者：
Davies, JA;Yates, EA;Turnbull, JE
神经胶质细胞系来源的神经营养因子（GDNF）具有多种功能，包括调节肾脏形态发生以及肠、感觉和中枢神经系统中神经元的生长和存活。关于将GDNF用于治疗人类帕金森病患者的报道引发了对GDNF信号传导的强烈临床兴趣。我们最近发现GDNF信号传导需要细胞表面硫酸肝素糖胺聚糖（Barnett et al., 2002， J. cell Sci. 115,4495 -4503）。在这里，我们使用外源性修饰肝素来确定体外实验中抑制GDNF信号传导所需的结构特征。2- O -硫酸盐基团被发现具有高活性，但不是抑制GDNF信号传导的绝对要求。这些发现可能解释了缺乏GDNF的转基因小鼠和缺乏硫酸肝素2-硫转移酶的小鼠表型之间的相似性，硫酸肝素2-硫转移酶是在体内实现2- O -硫酸脲酸的酶。
Glial cell line-derived neurotrophic factor (GDNF) has many functions including regulation of kidney morphogenesis and of neuron growth and survival in the enteric, sensory and central nervous systems. Reports of GDNF being used against Parkinson's disease in human patients have sparked intense clinical interest in GDNF signalling. We recently showed that GDNF signalling requires cell surface heparan sulphate glycosaminoglycans ( Barnett et al., 2002 , J. Cell Sci. 115 , 4495-4503). Here we use exogenous modified heparins to determine those structural features required to inhibit GDNF signalling in ex vivo assays. 2- O -sulphate groups were found to impart high activity but were not absolute requirements for the inhibition of GDNF signalling. These findings may explain the similarities between the phenotypes of transgenic mice lacking GDNF and those lacking heparan sulphate 2-sulphotransferase, the enzyme responsible for achieving 2- O -sulphation of uronic acids in vivo .