文章：

Ras超家族GEFs和GAPs：癌症治疗的有效靶点？

Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy?

原文发布日期：2010-11-24

DOI: 10.1038/nrc2960

类型: Review Article

开放获取: 否

要点：

1. There is increasing evidence that the aberrant activity of numerous members of the Ras superfamily of small GTPases contributes to cancer growth, invasion and metastasis.
2. Unlike the frequent direct mutational activation of the three Ras proteins (which occurs in ∼33% of human cancers), other Ras superfamily GTPases are deregulated by indirect mechanisms, commonly involving the altered expression or activity of their regulatory proteins.
3. Guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) that control the GDP–GTP cycling of specific members of the Ras superfamily have been shown to contribute to cancer by either promoting or suppressing tumour progression and growth.
4. GEFs and GAPs are deregulated in cancer by somatic mutation, changes in gene expression and through post-translational mechanisms owing to aberrant signalling caused by alterations in upstream oncogene or tumour suppressor function.
5. Although GEFs and GAPs are not considered classically druggable targets, there is growing evidence that supports the feasibility of targeting them. For example, nature has provided examples (such as brefeldin A) that provide proof-of-principle of GEF and GAP druggability.
6. The multi-domain structures of GEFs and GAPs contribute to their regulation by diverse signalling mechanisms and might also identify therapeutic approaches for pharmacological regulation of GEF and GAP activity in cancer.

要点翻译：

1. 越来越多的证据表明，小GTP酶Ras超家族中多个成员的异常活动促进了癌细胞的生长、侵袭和转移。
2. 与三种Ras蛋白频繁发生直接突变激活（约33%的人类癌症中会出现）不同，其他Ras超家族GTP酶通过间接机制失调，通常涉及其调控蛋白的表达或活性改变。
3. 控制Ras超家族特定成员GDP-GTP循环的鸟嘌呤核苷酸交换因子（GEFs）和GTP酶激活蛋白（GAPs）已被证明通过促进或抑制肿瘤进展和生长而在癌症中发挥作用。
4. GEFs和GAPs在癌症中通过体细胞突变、基因表达变化以及由于上游癌基因或肿瘤抑制功能改变引起的异常信号传导导致的翻译后机制而失调。
5. 尽管GEFs和GAPs通常不被认为是经典的可成药靶点，但越来越多的证据支持靶向它们的可行性。例如，自然界已经提供了实例（如布雷菲德菌素A），为GEF和GAP的可成药性提供了原理验证。
6. GEFs和GAPs的多域结构有助于它们通过多种信号机制进行调节，也可能为癌症中GEF和GAP活性的药理学调节提供治疗方法。

英文摘要：

There is now considerable and increasing evidence for a causal role for aberrant activity of the Ras superfamily of small GTPases in human cancers. These GTPases function as GDP–GTP-regulated binary switches that control many fundamental cellular processes. A common mechanism of GTPase deregulation in cancer is the deregulated expression and/or activity of their regulatory proteins, guanine nucleotide exchange factors (GEFs) that promote formation of the active GTP-bound state and GTPase-activating proteins (GAPs) that return the GTPase to its GDP-bound inactive state. In this Review, we assess the association of GEFs and GAPs with cancer and their druggability for cancer therapeutics.

摘要翻译： 

目前已有大量且日益增多的证据表明，Ras超家族小GTP酶异常活性在人类癌症中具有因果作用。这些GTP酶作为GDP–GTP调控的二元开关，控制着许多基本细胞过程。GTP酶在癌症中常见的失调机制是其调控蛋白的表达和/或活性异常：鸟嘌呤核苷酸交换因子（GEFs）促进活性GTP结合态的形成，而GTP酶激活蛋白（GAPs）则使GTP酶回到GDP结合的非活性态。在本综述中，我们评估了GEFs和GAPs与癌症的关联及其作为癌症治疗靶点的可成药性。

原文链接：

Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy?