Role of phosphatidylinositol 4,5-bisphosphate in Ras/Rac-induced disruption of the cortactin-actomyosin II complex and malignant transformation

被引:70
作者
He, H
Watanabe, T
Zhan, X
Huang, C
Schuuring, E
Fukami, K
Takenawa, T
Kumar, CC
Simpson, RJ
Maruta, H
机构
[1] Ludwig Inst Canc Res, Walter & Eliza Hall Inst, Joint Prot Struct Lab, Melbourne, Vic 3050, Australia
[2] Kyushu Univ, Med Inst Bioregulat, Dept Mol Immunol, Fukuoka 81262, Japan
[3] Univ Tokyo, Inst Med Sci, Dept Biochem, Minato Ku, Tokyo 108, Japan
[4] Amer Red Cross, Jerome H Holland Lab, Dept Expt Pathol, Rockville, MD 20855 USA
[5] Leiden Univ, Dept Pathol, NL-2300 RC Leiden, Netherlands
[6] Schering Plough Corp, Res Inst, Dept Tumor Biol, Kenilworth, NJ 07033 USA
关键词
D O I
10.1128/MCB.18.7.3829
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Oncogenic Pas 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 Pac 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 Pas-induced malignant transformation; either the PIP2 binder HS1 or the Pac blocker SCH51344 restores the ability of EMS1 to bind the complex and suppresses the oncogenicity of Pas. 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.
引用
收藏
页码:3829 / 3837
页数:9
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