Ruđer Bošković Institute, Division of Molecular Biology, Bijenička 54, HR-10000, Zagreb, Croatia.
Lab Invest. 2018 May;98(5):589-601. doi: 10.1038/s41374-018-0023-x. Epub 2018 Feb 12.
NME proteins are reported to influence signal transduction activity of small GTPases from the Ras superfamily by diverse mechanisms in addition to their generic NDP kinase activity, which replenishes the cytoplasmic pool of GTP. Comprehensive evidence shows that NME proteins modulate the activity of Ras GTPases, in particular members of the Rho family, via binding to their major activators GEFs. Direct interaction between several NMEs and Ras GTPases were also indicated in vitro and in vivo. These modes of regulation are mainly independent of the NME's kinase activity. NMEs also modulate the Ras-mediated signal transduction by interfering with the formation of a Ras signaling complex at the plasma membrane. In several examples, NMEs were proposed to perform the role of GAP proteins by promoting hydrolysis of the bound GTP, but this activity still requires additional verification. Early suggestions that NMEs can activate small GTPases by direct phosphorylation of the bound GDP, or by high-rate loading of GTP onto a closely apposed GTPase, were largely dismissed. In this review article, we survey and put into perspective published examples of identified and hypothetical mechanisms of Ras signaling modulation by NME proteins. We also point out involvement of NMEs in the transcriptional regulation of components of Ras GTPases-mediated signal transduction pathways, and reciprocal regulation of NME function by small GTPases, particularly related to NME's binding to membranes.
NME 蛋白除了具有通用的 NDP 激酶活性（补充细胞质中 GTP 的储备）外，据报道还通过多种机制影响 Ras 超家族的小 GTP 酶的信号转导活性。综合证据表明，NME 蛋白通过与主要激活因子 GEFs 结合来调节 Ras GTP 酶的活性，特别是 Rho 家族的成员。体外和体内也表明了几种 NME 和 Ras GTP 酶之间的直接相互作用。这些调节模式主要独立于 NME 的激酶活性。NME 还通过干扰质膜上 Ras 信号复合物的形成来调节 Ras 介导的信号转导。在几个例子中，NME 被提议通过促进结合的 GTP 的水解来发挥 GAP 蛋白的作用，但这种活性仍需要进一步验证。早期的观点认为，NME 可以通过直接磷酸化结合的 GDP 或通过紧密相邻的 GTPase 上的高比率加载 GTP 来激活小 GTP 酶，但这些观点在很大程度上被否定了。在这篇综述文章中，我们调查并分析了已确定的和假设的 NME 蛋白调节 Ras 信号转导的机制的发表实例。我们还指出了 NMEs 参与 Ras GTPases 介导的信号转导途径中成分的转录调节，以及小 GTP 酶对 NME 功能的反向调节，特别是与 NME 与膜的结合有关的调节。
