Direct binding of Reelin to VLDL receptor and ApoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation
Direct binding of Reelin to VLDL receptor and ApoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation
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DOI：
10.1016/s0896-6273(00)80861-2
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发表时间：
1999-10-01
期刊：
影响因子：
16.2
通讯作者：
Herz, J
中科院分区：
文献类型：
--
作者：
Hiesberger, T;Trommsdorff, M;Herz, J
大的细胞外基质蛋白Reelin是由发育中的大脑特定区域的Cajal-Retzius神经元产生的，在那里它控制神经元的迁移和定位。遗传证据表明，迁移神经元对Reelin信号的解释涉及两种神经元细胞表面蛋白，极低密度脂蛋白受体（VLDLR）和apoE受体2 （ApoER2）以及细胞质衔接蛋白残疾-1 （Dab1）。研究表明，在体外实验中，Reelin直接特异性结合VLDLR和ApoER2的外结构域，并且在培养的原代胚胎神经元中，VLDLR和ApoER2的阻断与Reelin诱导的Disabled-1酪氨酸磷酸化的缺失相关。此外，缺乏Reelin或VLDLR和ApoER2的小鼠表现出微管稳定蛋白tau的过度磷酸化。综上所述，这些发现表明Reelin通过VLDLR和ApoER2调节神经元中Disabled-1酪氨酸磷酸化和微管功能。
The large extracellular matrix protein Reelin is produced by Cajal-Retzius neurons in specific regions of the developing brain, where it controls neuronal migration and positioning. Genetic evidence suggests that interpretation of the Reelin signal by migrating neurons involves two neuronal cell surface proteins, the very low density lipoprotein receptor (VLDLR) and the apoE receptor 2 (ApoER2) as well as a cytosolic adaptor protein, Disabled-1 (Dab1). We show that Reelin binds directly and specifically to the ectodomains of VLDLR and ApoER2 in vitro and that blockade of VLDLR and ApoER2 correlates with loss of Reelin-induced tyrosine phosphorylation of Disabled-1 in cultured primary embryonic neurons. Furthermore, mice that lack either Reelin or both VLDLR and ApoER2 exhibit hyperphosphorylation of the microtubule-stabilizing protein tau. Taken together, these findings suggest that Reelin acts via VLDLR and ApoER2 to regulate Disabled-1 tyrosine phosphorylation and microtubule function in neurons.