BIT/SHPS-1 enhances brain-derived neurotrophic factor-promoted neuronal survival in cultured cerebral cortical neurons
BIT/SHPS-1 enhances brain-derived neurotrophic factor-promoted neuronal survival in cultured cerebral cortical neurons
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DOI：
10.1046/j.1471-4159.2000.0751502.x
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发表时间：
2000-10-01
影响因子：
4.7
通讯作者：
Hatanaka, H
中科院分区：
文献类型：
--
作者：
Araki, T;Yamada, M;Hatanaka, H
脑源性神经营养因子（BDNF）激活多种信号分子以在神经系统中发挥各种功能，包括神经元分化、存活和突触可塑性的调节。以前，我们已经提出，BIT/SHPS-1（脑免疫球蛋白样分子与酪氨酸为基础的激活基序/SHP底物1）是一个底物的Shp-2，并参与BDNF信号在培养的大脑皮层神经元。为了阐明BIT/SHPS-1在培养的大脑皮层神经元中与其在BDNF信号传导中的作用相关的生物学功能，我们产生了表达野生型大鼠BIT/SHPS-1及其4F突变体的重组腺病毒载体，其中BIT/SHPS-1胞质结构域中的所有酪氨酸残基被苯丙氨酸取代。野生型BIT/SHPS-1的过表达，但4F突变体没有，在培养的大脑皮层神经元中，诱导BIT/SHPS-1本身的酪氨酸磷酸化以及Shp-2与BIT/SHPS-1的缔合，即使没有添加BDNF。我们发现，BDNF促进培养的大脑皮层神经元的生存增强表达的野生型和4F突变体，这表明，这种增强BIT/SHPS-1不依赖于其酪氨酸磷酸化。BDNF诱导的丝裂原活化蛋白激酶的活化并不因这些蛋白的表达而改变。相反，BDNF诱导的Akt激活在表达野生型或4F突变BIT/SHPS-1的神经元中增强。此外，LY294002，一种磷脂酰肌醇3-激酶的特异性抑制剂，阻断了BDNF促进的神经元存活在表达野生型和4F突变BIT/SHPS-1的神经元中的增强。这些结果表明，BIT/SHPS-1有助于BDNF促进培养的大脑皮层神经元的存活，其作用取决于磷脂酰肌醇3-激酶-Akt通路。我们的研究结果表明，一个新的行动BIT/SHPS-1不发生通过酪氨酸磷酸化的BIT/SHPS-1在培养的大脑皮层神经元。
Brain-derived neurotrophic factor (BDNF) activates a variety of signaling molecules to exert various functions in the nervous system, including neuronal differentiation, survival, and regulation of synaptic plasticity. Previously, we have suggested that BIT/SHPS-1 (brain immunoglobulin-like molecule with tyrosine-based activation motifs/SHP substrate 1) is a substrate of Shp-2 and is involved in BDNF signaling in cultured cerebral cortical neurons. To elucidate the biological function of BIT/SHPS-1 in cultured cerebral cortical neurons in connection with its role in BDNF signaling, we generated recombinant adenovirus vectors expressing the wild type of rat BIT/SHPS-1 and its 4F mutant in which all tyrosine residues in the cytoplasmic domain of BIT/SHPS-1 were replaced with phenylalanine, Overexpression of wild-type BIT/SHPS-1, but not the 4F mutant, in cultured cerebral cortical neurons induced tyrosine phosphorylation of BIT/SHPS-1 itself and an association of Shp-2 with BIT/SHPS-1 even without addition of BDNF. We found that BDNF-promoted survival of cultured cerebral cortical neurons was enhanced by expression of the wild type and also 4F mutant, indicating that this enhancement by BIT/SHPS-1 does not depend on its tyrosine phosphorylation. BDNF-induced activation of mitogen-activated protein kinase was not altered by the expression of these proteins. In contrast, BDNF-induced activation of Akt was enhanced in neurons expressing wild-type or 4F mutant BIT/SHPS-1. In addition, LY294002, a specific inhibitor of phosphatidylinositol 3-kinase, blocked the enhancement of BDNF-promoted neuronal survival in both neurons expressing wild-type and 4F mutant BIT/SHPS-1. These results indicate that BIT/SHPS-1 contributes to BDNF-promoted survival of cultured cerebral cortical neurons, and that its effect depends on the phosphatidylinositol 3-kinase-Akt pathway. Our results suggest that a novel action of BIT/SHPS-1 does not occur through tyrosine phosphorylation of BIT/SHPS-1 in cultured cerebral cortical neurons.