Khanna Savita, Roy Sashwati, Park Han-A, Sen Chandan K
Laboratory of Molecular Medicine, Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Medical Center, Columbus, Ohio 43210, USA.
J Biol Chem. 2007 Aug 10;282(32):23482-90. doi: 10.1074/jbc.M611269200. Epub 2007 Jun 14.
c-Src is heavily expressed in the brain and in human neural tissues. Our pursuit for characterization of the neuroprotective mechanisms of tocotrienols led to the first evidence demonstrating that rapid c-Src activation plays a central role in executing glutamate-induced neurodegeneration. It is now known that Src deficiency or blockade of Src activity in mice provides cerebral protection following stroke. Here, we sought to examine the mechanisms that regulate inducible c-Src activity in glutamate-challenged HT4 neural cells and primary cortical neurons. Knockdown of c-Src protected cells against glutamate-induced loss of viability. Consistently, microinjection of siRNA against c-Src protected cells against glutamate. Using overexpression and knockdown approaches, we noted that SHP-1 may be implicated in glutamate-induced c-Src activation. Following such activation, Cbp and caveolin-1 were phosphorylated and associated with Csk. Csk was translocated to the membrane where it down-regulated glutamate-induced c-Src activity by catalyzing the inhibitory phosphorylation of a tyrosine residue in c-Src. Findings of this study present a new paradigm that addresses the regulation of c-Src under neurodegenerative conditions.
c-Src在大脑和人类神经组织中大量表达。我们对生育三烯酚神经保护机制特征的探索，首次证明了快速的c-Src激活在谷氨酸诱导的神经退行性变中起核心作用。现在已知，小鼠体内Src缺乏或Src活性被阻断可在中风后提供脑保护。在此，我们试图研究在谷氨酸刺激的HT4神经细胞和原代皮质神经元中调节诱导性c-Src活性的机制。敲低c-Src可保护细胞免受谷氨酸诱导的活力丧失。同样，显微注射针对c-Src的小干扰RNA可保护细胞免受谷氨酸的损伤。通过过表达和敲低方法，我们注意到SHP-1可能与谷氨酸诱导的c-Src激活有关。这种激活后，Cbp和小窝蛋白-1发生磷酸化并与Csk结合。Csk转位至膜上，通过催化c-Src中一个酪氨酸残基的抑制性磷酸化来下调谷氨酸诱导的c-Src活性。本研究结果提出了一种新的模式，用于解决神经退行性疾病条件下c-Src的调节问题。
