A transforming mutation in the pleckstrin homology domain of AKT1 in cancer
A transforming mutation in the pleckstrin homology domain of AKT1 in cancer
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DOI：
10.1038/nature05933
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发表时间：
2007-07-26
期刊：
影响因子：
64.8
通讯作者：
Thomas, James E.
中科院分区：
文献类型：
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作者：
Carpten, John D.;Faber, Andrew L.;Thomas, James E.
尽管 AKT1（v-akt 鼠胸腺瘤病毒癌基因同源物 1）激酶可能是癌症中最常激活的增殖和生存途径的核心成员，但 AKT1 的突变尚未得到广泛报道。在此，我们报告了人类乳腺癌、结直肠癌和卵巢癌中体细胞突变的鉴定，该突变导致 AKT1 脂质结合袋中氨基酸 17 (E17K) 处的谷氨酸被赖氨酸取代。 Lys 17 改变口袋的静电相互作用并与磷酸肌醇配体形成新的氢键。这种突变通过病理性定位到质膜来激活 AKT1，刺激下游信号传导，转化细胞并诱发小鼠白血病。这一机制表明 AKT1 在人类癌症中的直接作用，并增加了已知的通过磷脂酰肌醇-3-OH 激酶/AKT 途径促进肿瘤发生的基因改变。此外，E17K 取代降低了对变构激酶抑制剂的敏感性，因此这种突变可能对 AKT 药物开发具有重要的临床用途。
Although AKT1 (v-akt murine thymoma viral oncogene homologue 1) kinase is a central member of possibly the most frequently activated proliferation and survival pathway in cancer, mutation of AKT1 has not been widely reported. Here we report the identification of a somatic mutation in human breast, colorectal and ovarian cancers that results in a glutamic acid to lysine substitution at amino acid 17 (E17K) in the lipid-binding pocket of AKT1. Lys 17 alters the electrostatic interactions of the pocket and forms new hydrogen bonds with a phosphoinositide ligand. This mutation activates AKT1 by means of pathological localization to the plasma membrane, stimulates downstream signalling, transforms cells and induces leukaemia in mice. This mechanism indicates a direct role of AKT1 in human cancer, and adds to the known genetic alterations that promote oncogenesis through the phosphatidylinositol-3-OH kinase/AKT pathway. Furthermore, the E17K substitution decreases the sensitivity to an allosteric kinase inhibitor, so this mutation may have important clinical utility for AKT drug development.