文章：

PAK信号在癌症发生和发展中的作用

PAK signalling during the development and progression of cancer

原文发布日期：2013-12-23

DOI: 10.1038/nrc3645

类型: Review Article

开放获取: 否

要点：

1. There are two subgroups of p21-activated kinases (PAKs), which comprise three members each: group I (PAK1–3) and group II (PAK 4–6). New genetic models of PAK in mice and fish have shown the unique functions of the six PAK isoforms.
2. PAK expression and activity, in particular those of PAK1 and PAK4, are often upregulated in human tumours. Tumour cells with upregulated PAK tend to become dependent on PAK signalling.
3. In many cell types, PAKs positively regulate at least three key proliferative signalling pathways: ERK, AKT and WNT.
4. In addition to their roles in proliferation, PAKs also have important roles in promoting cell survival, invasion and metastasis, and angiogenesis.
5. Several potent and specific small-molecule inhibitors of all PAKs or of group I or II PAKs are in advanced stages of preclinical development. However, such agents will need to be used with caution, as PAK function may be required for maintaining vascular integrity.
6. Inhibitors that target PAKs may be useful in cancers that have amplified PAK alleles, as well as in cancers that depend on PAK for activation of downstream signalling pathways, such as ERBB2-amplified breast cancer and colon cancers that are driven by mutations in the WNT pathway.

要点翻译：

1. p21激活激酶（PAKs）可分为两个亚群，每个亚群包含三个成员：I组（PAK1–3）和II组（PAK4–6）。小鼠和鱼类的新型PAK遗传模型揭示了六种PAK亚型的独特功能。
2. PAK的表达和活性（尤其是PAK1和PAK4）在人类肿瘤中常出现上调。伴随PAK上调的肿瘤细胞往往会对PAK信号传导产生依赖性。
3. 在多种细胞类型中，PAKs能正向调控至少三条关键增殖信号通路：ERK、AKT与WNT。
4. 除增殖作用外，PAKs在促进细胞存活、侵袭转移以及血管生成中也发挥重要作用。
5. 针对所有PAK或I组/II组PAK的若干高效特异性小分子抑制剂已进入临床前研发后期阶段。但此类药物需谨慎使用，因为PAK可能对维持血管完整性具有重要作用。
6. 靶向PAK的抑制剂或可用于治疗PAK等位基因扩增的癌症，以及依赖PAK激活下游信号通路的癌症，例如ERBB2扩增型乳腺癌和WNT通路突变驱动的结肠癌。

英文摘要：

p21-activated kinases (PAKs) are positioned at the nexus of several oncogenic signalling pathways. Overexpression or mutational activation of PAK isoforms frequently occurs in various human tumours, and recent data suggest that excessive PAK activity drives many of the cellular processes that are the hallmarks of cancer. In this Review, we discuss the mechanisms of PAK activation in cancer, the key substrates that mediate the developmental and oncogenic effects of this family of kinases, and how small-molecule inhibitors of these enzymes might be best developed and deployed for the treatment of cancer.

摘要翻译： 

p21活化激酶（PAKs）处于多条致癌信号通路的交汇点。多种人类肿瘤中常见PAK亚型的过表达或突变激活，最新研究表明，过度活跃的PAK活性驱动了众多符合癌症特征的细胞过程。在本综述中，我们将讨论癌症中PAK激活的机制、介导该激酶家族发育和致癌效应的关键底物，以及如何最好地开发并应用这些小分子抑制剂用于癌症治疗。

原文链接：

PAK signalling during the development and progression of cancer