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首页> 外文期刊>Molecular and Cellular Biology >Calmodulin Binds to K-Ras, but Not to H- or N-Ras, and Modulates Its Downstream Signaling
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Calmodulin Binds to K-Ras, but Not to H- or N-Ras, and Modulates Its Downstream Signaling

机译：钙调蛋白与K-Ras结合，但不与H-或N-Ras结合，并调节其下游信号传导

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Activation of Ras induces a variety of cellular responses depending on the specific effector activated and the intensity and amplitude of this activation. We have previously shown that calmodulin is an essential molecule in the down-regulation of the Ras/Raf/MEK/extracellularly regulated kinase (ERK) pathway in cultured fibroblasts and that this is due at least in part to an inhibitory effect of calmodulin on Ras activation. Here we show that inhibition of calmodulin synergizes with diverse stimuli (epidermal growth factor, platelet-derived growth factor, bombesin, or fetal bovine serum) to induce ERK activation. Moreover, even in the absence of any added stimuli, activation of Ras by calmodulin inhibition was observed. To identify the calmodulin-binding protein involved in this process, calmodulin affinity chromatography was performed. We show that Ras and Raf from cellular lysates were able to bind to calmodulin. Furthermore, Ras binding to calmodulin was favored in lysates with large amounts of GTP-bound Ras, and it was Raf independent. Interestingly, only one of the Ras isoforms, K-RasB, was able to bind to calmodulin. Furthermore, calmodulin inhibition preferentially activated K-Ras. Interaction between calmodulin and K-RasB is direct and is inhibited by the calmodulin kinase II calmodulin-binding domain. Thus, GTP-bound K-RasB is a calmodulin-binding protein, and we suggest that this binding may be a key element in the modulation of Ras signaling.
机译：Ras的激活可诱导多种细胞反应，具体取决于激活的特定效应子以及此激活的强度和幅度。我们以前已经证明钙调蛋白是培养成纤维细胞中Ras / Raf / MEK /细胞外调节激酶（ERK）通路下调的重要分子，这至少部分是由于钙调蛋白对Ras的抑制作用激活。在这里，我们显示钙调蛋白的抑制与多种刺激（表皮生长因子，血小板衍生的生长因子，蛙皮素或胎牛血清）协同作用以诱导ERK活化。此外，即使在不存在任何附加刺激的情况下，也观察到钙调蛋白抑制作用激活了Ras。为了鉴定参与该过程的钙调蛋白结合蛋白，进行了钙调蛋白亲和层析。我们显示从细胞裂解物中的Ras和Raf能够结合钙调蛋白。此外，在具有大量GTP结合的Ras的裂解物中，Ras与钙调蛋白的结合更为有利，并且与Raf无关。有趣的是，只有一种Ras亚型，即K-RasB，能够与钙调蛋白结合。此外，钙调蛋白抑制优先激活K-Ras。钙调蛋白与K-RasB之间的相互作用是直接的，并且被钙调蛋白激酶II钙调蛋白结合结构域抑制。因此，与GTP结合的K-RasB是一种钙调蛋白结合蛋白，我们建议这种结合可能是Ras信号传导调控中的关键因素。

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