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Mol Cell Biol, July 1998, p. 3829-3837, Vol. 18, No. 7
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Role of Phosphatidylinositol 4,5-Bisphosphate in Ras/Rac-Induced Disruption of the Cortactin-Actomyosin II Complex and Malignant Transformation

Hong He,1 Takeshi Watanabe,2 Xi Zhan,3 Cai Huang,3 Ed Schuuring,4 Kiyoko Fukami,5 Tadaomi Takenawa,5 C. Chandra Kumar,6 Richard J. Simpson,7 and Hiroshi Maruta1 *

Ludwig Institute for Cancer Research1 and Joint Protein Structure Laboratory, Ludwig Institute for Cancer Research/Walter & Eliza Hall Institute,7 PO Royal Melbourne Hospital, Victoria 3050, Australia; Department of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-62,2 and Department of Biochemistry, Institute of Medical Sciences, University of Tokyo, Shirokane-dai, Minato-ku, Tokyo 108,5 Japan; Department of Experimental Pathology, Holland Laboratory, American Red Cross, Rockville, Maryland 208553; Department of Pathology, University of Leiden, 2300 RC Leiden, The Netherlands4; and Department of Tumor Biology, Schering-Plough Research Institute, Kenilworth, New Jersey 070336

Received 13 January 1998/Returned for modification 12 March 1998/Accepted 8 April 1998

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.

* Corresponding author. Mailing address: Ludwig Institute for Cancer Resch., P.O. Royal Melbourne Hospital, Melbourne, Victoria 3050, Australia. Phone: 613-9341-3155. Fax: 613-9341-3104. E-mail: hiroshi.maruta{at}ludwig.edu.au.

Mol Cell Biol, July 1998, p. 3829-3837, Vol. 18, No. 7
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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