Mutual Regulation of Src Family Kinases and the Neurotrophin Receptor TrkB
Mutual Regulation of Src Family Kinases and the Neurotrophin Receptor TrkB
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DOI：
10.1074/jbc.m109.091041
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发表时间：
2010-03-12
影响因子：
4.8
通讯作者：
McNamara, James O.
中科院分区：
文献类型：
--
作者：
Huang, Yang Z.;McNamara, James O.
神经营养因子受体酪氨酸激酶TrkB对多种生物过程至关重要。我们研究了Src家族激酶（SFKs）和TrkB的相互作用，以更好地了解生理和病理条件下TrkB信号传导的机制。我们比较和对比的作用，SFKs在TrkB信号激活后的TrkB的两种机制，其反式激活锌，其激活的原型神经营养因子配体，脑源性神经营养因子（BDNF）。利用培养的啮齿动物神经元的生化、药理学和化学遗传学研究，我们发现锌通过SFK依赖性但不依赖于TrkB激酶的机制促进TrkB的Tyr-705/Tyr-706的优先磷酸化，这是锌对TrkB反式激活的关键信号事件。相比之下，SFK活性对于BDNF介导的TrkB活化不是必需的，然而SFK活性由于BDNF活化TrkB而增加。此外，BDNF诱导的TrkB的Tyr-705/Tyr-706磷酸化被SFK抑制剂抑制，暗示SFK在BDNF激活TrkB中的调节作用。总之，SFK被TrkB激活，并且SFK反过来可以促进TrkB激活。我们提出的模型描绘的相互调节SFKs和TrkB激活TrkB锌和BDNF。
The neurotrophin receptor tyrosine kinase TrkB is critical to diverse biological processes. We investigated the interplay of Src family kinases (SFKs) and TrkB to better understand mechanisms of TrkB signaling in physiological and pathological conditions. We compared and contrasted the role of SFKs in TrkB signaling following activation of TrkB by two mechanisms, its transactivation by zinc, and its activation by its prototypic neurotrophin ligand, brain-derived neurotrophic factor (BDNF). Using biochemical, pharmacological, and chemical genetic studies of cultured rodent neurons, we found that zinc promotes preferential phosphorylation of Tyr-705/Tyr-706 of TrkB by a SFK-dependent but TrkB kinase-independent mechanism, a signaling event critical for transactivation of TrkB by zinc. By contrast, SFK activity is not essential for BDNF-mediated activation of TrkB, yet SFK activity is increased as a consequence of TrkB activation by BDNF. Moreover, BDNF-induced phosphorylation of Tyr-705/Tyr-706 of TrkB was inhibited by SFK inhibitors, implicating a regulatory role of SFKs in TrkB activation by BDNF. In sum, SFKs are activated by TrkB and, in turn, SFKs can promote TrkB activation. We propose models depicting the mutual regulation of SFKs and TrkB following activation of TrkB by zinc and BDNF.