Intracellular LINGO-1 negatively regulates Trk neurotrophin receptor signaling.
Intracellular LINGO-1 negatively regulates Trk neurotrophin receptor signaling.
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DOI：
10.1016/j.mcn.2015.11.002
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发表时间：
2016-01
期刊：
影响因子：
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通讯作者：
Bothwell M
中科院分区：
文献类型：
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作者：
Meabon JS;de Laat R;Ieguchi K;Serbzhinsky D;Hudson MP;Huber BR;Wiley JC;Bothwell M
神经营养因子是神经元分化和功能的许多方面的重要调节因子，通过四种受体p75、TrkA、TrkB和TrkC进行信号传导。三种Trk旁系同源物是膜蛋白LIG超家族的成员，其共享由富含亮氨酸的重复序列和C2 IG结构域组成的胞外结构域。已报道另一种LIG蛋白LINGO-1结合并影响p75以及TrkA、TrkB和TrkC的信号传导。在这里，我们研究LINGO-1影响TrkA，TrkB和TrkC功能的方式。我们报告说，Trk激活促进Trk协会与LINGO-1，这种协会促进Trk降解的溶酶体机制。这种机制类似于另一种LIG蛋白LRIG1促进受体酪氨酸激酶如EGF受体的溶酶体降解的机制。我们目前的证据表明，Trk/LINGO-1的相互作用发生，部分，内循环内体。我们表明，LINGO-1的突变形式，与大部分的胞外结构域删除，有能力增强在PC12细胞中的TrkA信号，可能通过作为抑制剂的Trk下调全长LINGO-1。我们提出LINGO-1作为信号传导的负反馈调节剂通过同源受体酪氨酸激酶包括TrkA、TrkB和TrkC起作用。
Neurotrophins, essential regulators of many aspects of neuronal differentiation and function, signal via four receptors, p75, TrkA, TrkB and TrkC. The three Trk paralogs are members of the LIG superfamily of membrane proteins, which share extracellular domains consisting of leucine rich repeat and C2 Ig domains. Another LIG protein, LINGO-1 has been reported to bind and influence signaling of p75 as well as TrkA, TrkB and TrkC. Here we examine the manner in which LINGO-1 influences the function of TrkA, TrkB and TrkC. We report that Trk activation promotes Trk association with LINGO-1, and that this association promotes Trk degradation by a lysosomal mechanism. This mechanism resembles the mechanism by which another LIG protein, LRIG1, promotes lysosomal degradation of receptor tyrosine kinases such as the EGF receptor. We present evidence indicating that the Trk/LINGO-1 interaction occurs, in part, within recycling endosomes. We show that a mutant form of LINGO-1, with much of the extracellular domain deleted, has the capacity to enhance TrkA signaling in PC12 cells, possibly by acting as an inhibitor of Trk down-regulation by full length LINGO-1. We propose that LINGO-1 functions as a negative feedback regulator of signaling by cognate receptor tyrosine kinases including TrkA, TrkB and TrkC.