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首页> 外文期刊>Molecular and Cellular Biology >An Activating Mutation in sos-1 Identifies Its Dbl Domain as a Critical Inhibitor of the Epidermal Growth Factor Receptor Pathway during Caenorhabditis elegans Vulval Development
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An Activating Mutation in sos-1 Identifies Its Dbl Domain as a Critical Inhibitor of the Epidermal Growth Factor Receptor Pathway during Caenorhabditis elegans Vulval Development

机译：sos-1中的激活突变将其Dbl结构域鉴定为秀丽隐杆线虫外阴发育过程中表皮生长因子受体途径的关键抑制剂。

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Proper regulation of receptor tyrosine kinase (RTK)-Ras-mitogen-activated protein kinase (MAPK) signaling pathways is critical for normal development and the prevention of cancer. SOS is a dual-function guanine nucleotide exchange factor (GEF) that catalyzes exchange on Ras and Rac. Although the physiologic role of SOS and its CDC25 domain in RTK-mediated Ras activation is well established, the in vivo function of its Dbl Rac GEF domain is less clear. We have identified a novel gain-of-function missense mutation in the Dbl domain of Caenorhabditis elegans SOS-1 that promotes epidermal growth factor receptor (EGFR) signaling in vivo. Our data indicate that a major developmental function of the Dbl domain is to inhibit EGF-dependent MAPK activation. The amount of inhibition conferred by the Dbl domain is equal to that of established trans-acting inhibitors of the EGFR pathway, including c-Cbl and RasGAP, and more than that of MAPK phosphatase. In conjunction with molecular modeling, our data suggest that the C. elegans mutation, as well as an equivalent mutation in human SOS1, activates the MAPK pathway by disrupting an autoinhibitory function of the Dbl domain on Ras activation. Our work suggests that functionally similar point mutations in humans could directly contribute to disease.
机译：适当调节受体酪氨酸激酶（RTK）-拉斯-丝裂原活化蛋白激酶（MAPK）信号通路对于正常发展和预防癌症至关重要。 SOS是一种双功能鸟嘌呤核苷酸交换因子（GEF），可催化Ras和Rac的交换。尽管已经很好地确定了SOS及其CDC25结构域在RTK介导的Ras活化中的生理作用，但是其Dbl Rac GEF结构域的体内功能尚不清楚。我们在秀丽隐杆线虫SOS-1的Dbl结构域中发现了一种新的功能增强错义突变，该突变可促进体内表皮生长因子受体（EGFR）的信号传导。我们的数据表明，Dbl结构域的主要发育功能是抑制EGF依赖性MAPK激活。 Dbl结构域赋予的抑制作用等同于已建立的EGFR途径的反式作用抑制剂，包括c-Cbl和RasGAP，大于MAPK磷酸酶。结合分子建模，我们的数据表明 C。线虫突变以及人类SOS1中的等效突变通过破坏Dbl结构域对Ras激活的自抑制功能来激活MAPK途径。我们的工作表明，人类功能相似的点突变可能直接导致疾病。

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