p120RasGAP Is a Mediator of Rho Pathway Activation and Tumorigenicity in the DLD1 Colorectal Cancer Cell Line |
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| Authors: | Shawna L. Organ Josephine Hai Nikolina Radulovich Christopher B. Marshall Lisa Leung Takehiko Sasazuki Senji Shirasawa Chang-Qi Zhu Roya Navab Mitsuhiko Ikura Ming-Sound Tsao |
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| Affiliation: | 1. Princess Margaret Cancer Centre, Toronto, Ontario, Canada.; 2. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.; 3. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.; 4. Department of Pathology, Research Institute, International Medical Center of Japan, Tokyo, Japan.; 5. Department of Cell Biology, School of Medicine, Fukuoka University, Fukuoka, Japan.; University of San Francisco, United States of America, |
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| Abstract: | KRAS is mutated in ∼40% of colorectal cancer (CRC), and there are limited effective treatments for advanced KRAS mutant CRC. Therefore, it is crucial that downstream mediators of oncogenic KRAS continue to be studied. We identified p190RhoGAP as being phosphorylated in the DLD1 CRC cell line, which expresses a heterozygous KRAS G13D allele, and not in DKO4 in which the mutant allele has been deleted by somatic recombination. We found that a ubiquitous binding partner of p190RhoGAP, p120RasGAP (RasGAP), is expressed in much lower levels in DKO4 cells compared to DLD1, and this expression is regulated by KRAS. Rescue of RasGAP expression in DKO4 rescued Rho pathway activation and partially rescued tumorigenicity in DKO4 cells, indicating that the combination of mutant KRAS and RasGAP expression is crucial to these phenotypes. We conclude that RasGAP is an important effector of mutant KRAS in CRC. |
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