Neuregulin-heparan-sulfate proteoglycan interactions produce sustained erbB receptor activation required for the induction of acetylcholine receptors in muscle.
Neuregulin-heparan-sulfate proteoglycan interactions produce sustained erbB receptor activation required for the induction of acetylcholine receptors in muscle.
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DOI：
10.1074/jbc.m104485200
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发表时间：
2001-10
期刊：
影响因子：
--
通讯作者：
Q. Li;J. Loeb
中科院分区：
文献类型：
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作者：
Q. Li;J. Loeb
神经调节蛋白结合并激活酪氨酸激酶的EGF受体家族的成员，其启动诱导神经肌肉突触的突触后膜中乙酰胆碱受体合成的信号级联。除了足以用于受体结合和酪氨酸自磷酸化的EGF样结构域之外，许多剪接形式还具有结合HSPG并在突触处维持高浓度的神经调节蛋白的IG样结构域。在这里，我们表明，IG样结构域的功能，以保持EGF样结构域在足够高的浓度足够长的时间内诱导乙酰胆碱受体基因表达所需的主要鸡肌管。使用重组neuregulins与和没有IG样结构域，我们发现，IG样结构域结合内源性HSPGs产生4倍增加受体磷酸化。这种活性的增强被可溶性肝素或用肝素酶预处理肌细胞所阻断。我们发现，至少12-24小时的神经调节素曝光需要打开大量的乙酰胆碱受体基因的表达，erbB受体需要保持磷酸化在这段时间内。持续的erbB受体激活的需要可能是神经调节蛋白如此高度集中在突触的细胞外基质中的原因。
Neuregulins bind to and activate members of the EGF receptor family of tyrosine kinases that initiate a signaling cascade that induces acetylcholine receptor synthesis in the postsynaptic membrane of neuromuscular synapses. In addition to an EGF-like domain, sufficient for receptor binding and tyrosine auto-phosphorylation, many spliced forms also have an IG-like domain that binds HSPGs and maintains a high concentration of neuregulin at synapses. Here, we show that the IG-like domain functions to keep the EGF-like domain at sufficiently high concentrations for a sufficiently long period of time necessary to induce acetylcholine receptor gene expression in primary chick myotubes. Using recombinant neuregulins with and without the IG-like domain, we found that IG-like domain binding to endogenous HSPGs produces a 4-fold increase in receptor phosphorylation. This enhancement of activity was blocked by soluble heparin or by pretreatment of muscle cells with heparitinase. We show that at least 12-24 h of neuregulin exposure was required to turn on substantial acetylcholine receptor gene expression and that the erbB receptors need to be kept phosphorylated during this time. The need for sustained erbB receptor activation may be the reason why neuregulins are so highly concentrated in the extracellular matrix of synapses.