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首页> 外文期刊>Molecular and Cellular Biology >Role of Phosphatidylinositol 4,5-Bisphosphate in Ras/Rac-Induced Disruption of the Cortactin-Actomyosin II Complex and Malignant Transformation
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Role of Phosphatidylinositol 4,5-Bisphosphate in Ras/Rac-Induced Disruption of the Cortactin-Actomyosin II Complex and Malignant Transformation

机译：磷脂酰肌醇4，5-双磷酸酯在Ras / Rac诱导的Cactactin-Actomyosin II复合物破坏和恶性转化中的作用

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摘要

Oncogenic Ras mutants such as v-Ha-Ras cause a rapid rearrangement of actin cytoskeleton during malignant transformation of fibroblasts or epithelial cells. Both PI-3 kinase and Rac are required for Ras-induced malignant transformation and membrane ruffling. However, the signal transduction pathway(s) downstream of Rac that leads to membrane ruffling and other cytoskeletal change(s) as well as the exact biochemical nature of the cytoskeletal change remain unknown. Cortactin/EMS1 is the first identified molecule that is dissociated in a Rac–phosphatidylinositol 4,5-biphosphate (PIP2)-dependent manner from the actin-myosin II complex during Ras-induced malignant transformation; either the PIP2 binder HS1 or the Rac blocker SCH51344 restores the ability of EMS1 to bind the complex and suppresses the oncogenicity of Ras. Furthermore, while PIP2 inhibits the actin-EMS1 interaction, HS1 reverses the PIP2 effect. Thus, we propose that PIP2, an end-product of the oncogenic Ras/PI-3 kinase/Rac pathway, serves as a second messenger in the Ras/Rac-induced disruption of the actin cytoskeleton and discuss the anticancer drug potential of PIP2-binding molecules.
机译：致癌性Ras突变体（例如v-Ha-Ras）在成纤维细胞或上皮细胞的恶性转化过程中引起肌动蛋白细胞骨架的快速重排。 Ras诱导的恶性转化和膜起皱均需要PI-3激酶和Rac。然而，Rac下游的导致膜起皱和其他细胞骨架变化的信号转导途径以及细胞骨架变化的确切生化性质仍然未知。 Cortactin / EMS1是第一个在Ras诱导的恶性转化过程中以Rac-磷脂酰肌醇4,5-二磷酸（PIP 2 ）依赖性方式从肌动蛋白-肌球蛋白II复合体解离的分子。 PIP 2 粘合剂HS1或Rac阻滞剂SCH51344均可恢复EMS1结合复合物的能力并抑制Ras的致癌性。此外，虽然PIP 2 抑制肌动蛋白-EMS1相互作用，但HS1逆转了PIP 2 的作用。因此，我们建议，致癌性Ras / PI-3激酶/ Rac途径的终产物PIP 2 作为Ras / Rac诱导的肌动蛋白细胞骨架破坏的第二信使。讨论PIP 2 结合分子的抗癌潜力。

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