Practicalities of drugging the phosphatidylinositol-3-kinase/Akt cell survival signaling pathway
Practicalities of drugging the phosphatidylinositol-3-kinase/Akt cell survival signaling pathway
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DOI：
10.1158/1078-0432.ccr-06-0617
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发表时间：
2006-05-15
影响因子：
11.5
通讯作者：
Kirkpatrick, D. Lynn
中科院分区：
文献类型：
--
作者：
Powis, Garth;Ihle, Nathan;Kirkpatrick, D. Lynn
背景磷脂酰肌醇-3-激酶/蛋白激酶B（PI 3 K/Akt）信号通路是人类肿瘤中最常见的突变或过度表达的信号异常。PI 3 K通过多种机制激活，包括生长因子受体、整联蛋白和Ras，将磷脂酰肌醇转化为磷脂酰肌醇-3-磷酸（图1）。PI 3 K的这种作用被肿瘤抑制剂磷酸酶和张力蛋白同源物拮抗。Akt（AKR小鼠胸腺瘤）通过其普列克底物蛋白同源结构域与磷脂酰肌醇-3-磷酸结合。Akt被磷酸肌醇依赖性蛋白激酶I和哺乳动物雷帕霉素靶蛋白磷酸化和激活。热休克蛋白90也与Akt结合以调节Akt水平。Akt磷酸化多个下游靶点以调节多种细胞功能。
BackgroundThe phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) signaling pathway is the most frequently mutated or overexpressed signaling abnormality in human cancer. PI3K is activated by a number of mechanisms, including growth factor receptors, integrins, and Ras, converting phosphatidylinositols to phosphatidylinositol-3-phosphates (Fig. 1). This action of PI3K is antagonized by the tumor suppressor phosphatase and tensin homologue. Akt (thymoma in AKR mouse) binds through its pleckstrin homology domain to phosphatidylinositol-3-phosphate. Akt is phosphorylated and activated by phosphoinositide-dependent protein kinase I and mammalian target of rapamycin/rictor. Heat shock protein 90 also binds to Akt to regulate Akt levels. Akt phosphorylates multiple downstream targets to modulate several cell functions.