Retrolinkin cooperates with endophilin A1 to mediate BDNF-TrkB early endocytic trafficking and signaling from early endosomes.
Retrolinkin cooperates with endophilin A1 to mediate BDNF-TrkB early endocytic trafficking and signaling from early endosomes.
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DOI：
10.1091/mbc.e11-04-0308
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发表时间：
2011-10
影响因子：
3.3
通讯作者：
Liu JJ
中科院分区：
文献类型：
--
作者：
Fu X;Yang Y;Xu C;Niu Y;Chen T;Zhou Q;Liu JJ
BDNF诱导培养的海马神经元树突状突起生长需要逆转录连接蛋白和其相互作用伙伴内毒素A1。它们依次在BDNF激活的TrkB的早期内吞运输途径中发挥作用，该途径提供了来自内小体的下游ERK信号的时空控制。脑源性神经营养因子(BDNF)与其细胞表面受体TrkB结合，调节神经细胞的分化、发育、突触可塑性和功能维持。BDNF的结合触发TrkB二聚化和自磷酸化，为接头蛋白提供对接位置以招募和激活下游信号分子。BDNF-TrkB胞内转运对于信号通路的时空调控至关重要的分子机制仍有待阐明。在这里，我们证明了逆转录连接蛋白，一种跨膜蛋白，与内嗜素A1相互作用，并介导BDNF激活的TrkB(PTRK)在中枢神经系统神经元中的运输和信号传递。我们发现激活的TrkB与早期的内吞体标记物APPL1共定位并相互作用。BDNF诱导的树突发育和早期内含体的急性细胞外信号调节激酶激活都需要逆转录连接蛋白和亲内蛋白A1。抑制逆转录连接蛋白的表达不仅可以阻止BDNF触发的TrkB内化，还可以阻止亲内毒素A1通过APPL1阳性的内吞体内转运到PTRK囊泡。这些发现揭示了BDNF-TrkB通过特定的膜转运途径在时间和空间上调节信号的新机制。
Both retrolinkin and its interaction partner endophilin A1 are required for BDNF-induced dendrite outgrowth of cultured hippocampal neurons. They function sequentially in an early endocytic trafficking pathway for BDNF-activated TrkB, which provides spatiotemporal control of downstream ERK signaling from endosomes. Brain-derived neurotrophic factor (BDNF) binds to its cell surface receptor TrkB to regulate differentiation, development, synaptic plasticity, and functional maintenance of neuronal cells. Binding of BDNF triggers TrkB dimerization and autophosphorylation, which provides docking sites for adaptor proteins to recruit and activate downstream signaling molecules. The molecular mechanisms underlying BDNF–TrkB endocytic trafficking crucial for spatiotemporal control of signaling pathways remain to be elucidated. Here we show that retrolinkin, a transmembrane protein, interacts with endophilin A1 and mediates BDNF-activated TrkB (pTrk) trafficking and signaling in CNS neurons. We find that activated TrkB colocalizes and interacts with the early endosome marker APPL1. Both retrolinkin and endophilin A1 are required for BDNF-induced dendrite development and acute extracellular signal-regulated kinase activation from early endosomes. Suppression of retrolinkin expression not only blocks BDNF-triggered TrkB internalization, but also prevents recruitment of endophilin A1 to pTrk vesicles trafficking through APPL1-positive endosomes. These findings reveal a novel mechanism for BDNF–TrkB to regulate signaling both in time and space through a specific membrane trafficking pathway.