Myelin suppresses axon regeneration by PIR-B/SHP-mediated inhibition of Trk activity
Myelin suppresses axon regeneration by PIR-B/SHP-mediated inhibition of Trk activity
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DOI：
10.1038/emboj.2011.55
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发表时间：
2011-04-06
期刊：
影响因子：
11.4
通讯作者：
Yamashita, Toshihide
中科院分区：
文献类型：
--
作者：
Fujita, Yuki;Endo, Shota;Yamashita, Toshihide
成对免疫球蛋白样受体B（PIR-B）部分介导髓鞘衍生蛋白Nogo、髓鞘相关糖蛋白（MAG）和少突胶质细胞髓鞘糖蛋白（OMgp）的再生抑制作用。在这项研究中，我们报告说，抑制PIR-B信号级联神经元增强轴突再生的中枢神经系统（CNS）。MAG与PIR-B的结合导致PIR-B与原肌球蛋白受体激酶（Trk）神经营养因子受体的缔合。含Src同源性2的蛋白酪氨酸磷酸酶（SHP）-1和SHP-2在MAG结合后被募集到PIR-B，起到Trk酪氨酸磷酸酶的作用。此外，SHP-1和SHP-2抑制减少MAG诱导的Trk受体的去磷酸化，并消除MAG对神经突生长的抑制作用。因此，PIR-B与Trk相关，通过SHP-1/2下调神经元中基础和神经营养因子调节的Trk活性。此外，体内转染SHP-1或SHP-2的小干扰RNA（siRNA）诱导小鼠视神经损伤后的轴突再生。因此，我们的研究结果确定了一个新的分子靶点，以提高受损的中枢神经系统的再生。The EMBO Journal（2011）30，1389-1401. doi：10.1038/daj.2011.55; 2011年3月1日在线发布
Paired immunoglobulin-like receptor B (PIR-B) partially mediates the regeneration-inhibiting effects of the myelin-derived protein Nogo, myelin-associated glycoprotein (MAG), and oligodendrocyte-myelin glycoprotein (OMgp). In this study, we report that inhibition of the PIR-B signaling cascades in neurons enhances axon regeneration in the central nervous system (CNS). Binding of MAG to PIR-B led to the association of PIR-B with tropomyosin receptor kinase (Trk) neurotrophin receptors. Src homology 2-containing protein tyrosine phosphatase (SHP)-1 and SHP-2, which were recruited to PIR-B upon MAG binding, functioned as Trk tyrosine phosphatases. Further, SHP-1 and SHP-2 inhibition reduced MAG-induced dephosphorylation of Trk receptors and abolished the inhibitory effect of MAG on neurite growth. Thus, PIR-B associated with Trk to downregulate basal and neurotrophin-regulated Trk activity through SHP-1/2 in neurons. Moreover, in vivo transfection of small interfering RNA (siRNA) for SHP-1 or SHP-2 induced axonal regeneration after optic nerve injury in mice. Our results thus identify a new molecular target to enhance regeneration of the injured CNS. The EMBO Journal (2011) 30, 1389-1401. doi:10.1038/emboj.2011.55; Published online 1 March 2011