SH3-binding Protein 5 Mediates the Neuroprotective Effect of the Secreted Bioactive Peptide Humanin by Inhibiting c-Jun NH2-terminal Kinase*
SH3-binding Protein 5 Mediates the Neuroprotective Effect of the Secreted Bioactive Peptide Humanin by Inhibiting c-Jun NH2-terminal Kinase*
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SH3 结合蛋白 5 通过抑制 c-Jun NH2 末端激酶介导分泌的生物活性肽护脑素的神经保护作用*
DOI：
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发表时间：
2013
影响因子：
4.8
通讯作者：
M. Matsuoka
中科院分区：
文献类型：
--
作者：
Yuji Takeshita;Y. Hashimoto;Mikiro Nawa;H. Uchino;M. Matsuoka
背景：人蛋白是一种分泌的生物活性肽，可抑制多种细胞毒性。结果：发现一种直接抑制JNK活性的细胞内蛋白SH3BP5是Humanin的效应蛋白。结论：SH3BP5是JNK的生理性抑制因子，是首次发现的Humanin效应物。意义：这一发现为JNK和Humanin的作用提供了新的机制见解。人肽是一种分泌性生物活性肽，可抑制多种损伤引起的细胞毒性。Humanin对阿尔茨海默病（AD）相关死亡的神经保护作用是通过与由睫状体神经营养受体α、WSX-1和gp130组成的异三聚体Humanin受体结合，以及激活包括JAK2和STAT3信号轴在内的细胞内信号通路介导的。尽管阐明了Humanin介导其神经保护的信号通路，但作为Humanin效应器的Humanin的转录靶点仍不明确。在本研究中，Humanin增加了神经细胞中SH3结构域结合蛋白5 （SH3BP5）的mRNA和蛋白表达，SH3BP5是已知的JNK相互作用物。与Humanin治疗相似，SH3BP5过表达抑制ad相关神经元死亡，而sirna介导的内源性SH3BP5表达下调则减弱了Humanin的神经保护作用。这些结果表明SH3BP5是Humanin的下游效应因子。此外，生化分析显示SH3BP5与JNK结合，并通过其两个假定的丝裂原活化蛋白激酶相互作用基序（KIMs）直接抑制JNK。
Background: Humanin, a secreted bioactive peptide, suppresses a variety of cell toxicities. Results: An intracellular protein SH3BP5, which directly inhibits JNK activity, is identified as an effector of Humanin. Conclusion: SH3BP5 is a physiological inhibitor of JNK and the firstly identified effector of Humanin. Significance: The discovery provides a novel mechanistic insight into the actions of JNK and Humanin. Humanin is a secreted bioactive peptide that suppresses cell toxicity caused by a variety of insults. The neuroprotective effect of Humanin against Alzheimer disease (AD)-related death is mediated by the binding of Humanin to its heterotrimeric Humanin receptor composed of ciliary neurotrophic receptor α, WSX-1, and gp130, as well as the activation of intracellular signaling pathways including a JAK2 and STAT3 signaling axis. Despite the elucidation of the signaling pathways by which Humanin mediates its neuroprotection, the transcriptional targets of Humanin that behaves as effectors of Humanin remains undefined. In the present study, Humanin increased the mRNA and protein expression of SH3 domain-binding protein 5 (SH3BP5), which has been known to be a JNK interactor, in neuronal cells. Similar to Humanin treatment, overexpression of SH3BP5 inhibited AD-related neuronal death, while siRNA-mediated knockdown of endogenous SH3BP5 expression attenuated the neuroprotective effect of Humanin. These results indicate that SH3BP5 is a downstream effector of Humanin. Furthermore, biochemical analysis has revealed that SH3BP5 binds to JNK and directly inhibits JNK through its two putative mitogen-activated protein kinase interaction motifs (KIMs).
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影响因子：
4
作者：
Chambers, Jeremy W.;Cherry, Lisa;Laughlin, John D.;Figuera-Losada, Mariana;LoGrasso, Philip V.
通讯作者：
LoGrasso, Philip V.
影响因子：
7.4
作者：
Brown, David I.;Griendling, Kathy K.
通讯作者：
Griendling, Kathy K.
影响因子：
56.9
作者：
Dickens, M;Rogers, JS;Davis, RJ
通讯作者：
Davis, RJ
影响因子：
10.8
作者：
Bachar, Adi R.;Scheffer, Lea;Lerman, Amir
通讯作者：
Lerman, Amir
DOI：
10.1016/j.metabol.2009.08.001
发表时间：
2010-03
期刊：
Metabolism: clinical and experimental
影响因子：
--
作者：
Hoang PT;Park P;Cobb LJ;Paharkova-Vatchkova V;Hakimi M;Cohen P;Lee KW
通讯作者：
Lee KW