Essential Role of Hrs in Endocytic Recycling of Full-length TrkB Receptor but Not Its Isoform TrkB.T1
Essential Role of Hrs in Endocytic Recycling of Full-length TrkB Receptor but Not Its Isoform TrkB.T1
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Hrs 在全长 TrkB 受体（而非其亚型 TrkB.T1）内吞再循环中的重要作用
DOI：
10.1074/jbc.m809763200
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发表时间：
2009-05-29
影响因子：
4.8
通讯作者：
Chen, Zhe-Yu
中科院分区：
文献类型：
--
作者：
Huang, Shu-Hong;Zhao, Ling;Chen, Zhe-Yu
脑源性神经营养因子（BDNF）通过其受体TrkB信号传导调节神经元的存活、分化和突触活动。全长TrkB（TrkB-FL）及其亚型T1（TrkB.T1）受体都在神经元中表达;然而，它们在BDNF处理后是否遵循相同的内吞途径尚不清楚。在这项研究中，我们报告TrkB-FL和TrkB.T1受体结合BDNF后穿越不同的内吞途径。我们提供的证据表明，在神经元TrkB.T1受体主要通过“默认”机制回收到细胞表面。然而，内吞的TrkB-FL受体在较小程度上以肝细胞生长因子调节的酪氨酸激酶底物（Hrs）依赖性方式再循环，这依赖于其酪氨酸激酶活性。Hrs在促进内化TrkB-FL受体再循环中的独特作用不依赖于其泛素相互作用基序。此外，Hrs敏感的TrkB-FL再循环在BDNF诱导的延长的丝裂原活化蛋白激酶（MAPK）活化中起作用。这些观察结果为TrkB-FL和TrkB.T1受体的差异胞内后分选提供了证据，以替代细胞内途径。
Brain-derived neurotrophic factor (BDNF) signaling through its receptor, TrkB, modulates survival, differentiation, and synaptic activity of neurons. Both full-length TrkB (TrkB-FL) and its isoform T1 (TrkB.T1) receptors are expressed in neurons; however, whether they follow the same endocytic pathway after BDNF treatment is not known. In this study we report that TrkB-FL and TrkB.T1 receptors traverse divergent endocytic pathways after binding to BDNF. We provide evidence that in neurons TrkB.T1 receptors predominantly recycle back to the cell surface by a "default" mechanism. However, endocytosed TrkB-FL receptors recycle to a lesser extent in a hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs)-dependent manner which relies on its tyrosine kinase activity. The distinct role of Hrs in promoting recycling of internalized TrkB-FL receptors is independent of its ubiquitin-interacting motif. Moreover, Hrs-sensitive TrkB-FL recycling plays a role in BDNF-induced prolonged mitogen-activated protein kinase (MAPK) activation. These observations provide evidence for differential postendocytic sorting of TrkB-FL and TrkB.T1 receptors to alternate intracellular pathways.