He H, Watanabe T, Zhan X, Huang C, Schuuring E, Fukami K, Takenawa T, Kumar C C, Simpson R J, Maruta H
Ludwig Institute for Cancer Research, PO Royal Melbourne Hospital, Victoria 3050, Australia.
Mol Cell Biol. 1998 Jul;18(7):3829-37. doi: 10.1128/MCB.18.7.3829.
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.
致癌性Ras突变体，如v-Ha-Ras，在成纤维细胞或上皮细胞发生恶性转化期间会导致肌动蛋白细胞骨架快速重排。PI-3激酶和Rac都是Ras诱导的恶性转化和膜皱褶所必需的。然而，Rac下游导致膜皱褶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。皮层肌动蛋白结合蛋白/EMS1是第一个被鉴定出的分子，在Ras诱导的恶性转化过程中，它以Rac-磷脂酰肌醇4,5-二磷酸（PIP2）依赖的方式从肌动蛋白-肌球蛋白II复合物中解离；PIP2结合剂HS1或Rac阻滞剂SCH51344均可恢复EMS1与该复合物结合的能力，并抑制Ras的致癌性。此外，虽然PIP2抑制肌动蛋白与EMS1的相互作用，但HS1可逆转PIP2的作用。因此，我们提出，致癌性Ras/PI-3激酶/Rac途径的终产物PIP2作为一种第二信使参与Ras/Rac诱导的肌动蛋白细胞骨架破坏，并讨论了PIP2结合分子的抗癌药物潜力。
