p120RasGAP is a mediator of rho pathway activation and tumorigenicity in the DLD1 colorectal cancer cell line

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Article numbere86103
JournalPloS one
Volume9
Issue number1
DOIs
Publication statusPublished - Jan 21 2014

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p120 GTPase Activating Protein
colorectal neoplasms
Colorectal Neoplasms
Chemical activation
Cells
cell lines
Cell Line
mutants
Alleles
alleles
Genetic Recombination
cells
Phenotype
phenotype
neoplasm cells

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Organ, S. L., Hai, J., Radulovich, N., Marshall, C. B., Leung, L., Sasazuki, T., ... Tsao, M. S. (2014). p120RasGAP is a mediator of rho pathway activation and tumorigenicity in the DLD1 colorectal cancer cell line. PloS one, 9(1), [e86103]. https://doi.org/10.1371/journal.pone.0086103

p120RasGAP is a mediator of rho pathway activation and tumorigenicity in the DLD1 colorectal cancer cell line. / Organ, Shawna L.; Hai, Josephine; Radulovich, Nikolina; Marshall, Christopher B.; Leung, Lisa; Sasazuki, Takehiko; Shirasawa, Senji; Zhu, Chang Qi; Navab, Roya; Ikura, Mitsuhiko; Tsao, Ming Sound.

In: PloS one, Vol. 9, No. 1, e86103, 21.01.2014.

Research output: Contribution to journalArticle

Organ, SL, Hai, J, Radulovich, N, Marshall, CB, Leung, L, Sasazuki, T, Shirasawa, S, Zhu, CQ, Navab, R, Ikura, M & Tsao, MS 2014, 'p120RasGAP is a mediator of rho pathway activation and tumorigenicity in the DLD1 colorectal cancer cell line', PloS one, vol. 9, no. 1, e86103. https://doi.org/10.1371/journal.pone.0086103
Organ, Shawna L. ; Hai, Josephine ; Radulovich, Nikolina ; Marshall, Christopher B. ; Leung, Lisa ; Sasazuki, Takehiko ; Shirasawa, Senji ; Zhu, Chang Qi ; Navab, Roya ; Ikura, Mitsuhiko ; Tsao, Ming Sound. / p120RasGAP is a mediator of rho pathway activation and tumorigenicity in the DLD1 colorectal cancer cell line. In: PloS one. 2014 ; Vol. 9, No. 1.
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AU - Sasazuki, Takehiko

AU - Shirasawa, Senji

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AB - 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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