p120RasGAP is a mediator of rho pathway activation and tumorigenicity in the DLD1 colorectal cancer cell line.
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.
Princess Margaret Cancer Centre, Toronto, Ontario, Canada ; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Shawna L
SL
Organ
Princess Margaret Cancer Centre, Toronto, Ontario, Canada ; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Josephine
J
Hai
Princess Margaret Cancer Centre, Toronto, Ontario, Canada ; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Nikolina
N
Radulovich
Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
Christopher B
CB
Marshall
Princess Margaret Cancer Centre, Toronto, Ontario, Canada ; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Lisa
L
Leung
Department of Pathology, Research Institute, International Medical Center of Japan, Tokyo, Japan.
Takehiko
T
Sasazuki
Department of Cell Biology, School of Medicine, Fukuoka University, Fukuoka, Japan.
Senji
S
Shirasawa
Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
Chang-Qi
CQ
Zhu
Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
Roya
R
Navab
Princess Margaret Cancer Centre, Toronto, Ontario, Canada ; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Mitsuhiko
M
Ikura
Princess Margaret Cancer Centre, Toronto, Ontario, Canada ; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada ; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Ming-Sound
MS
Tsao
D001483:Base Sequence; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D022502:Stress Fibers / Q000378:metabolism; D020729:p120 GTPase Activating Protein / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics
C074560:ARHGAP35 protein, human; D020662:Guanine Nucleotide Exchange Factors; C117307:KRAS protein, human; D050505:Mutant Proteins; D011518:Proto-Oncogene Proteins; C557248:RASA1 protein, human; D012333:RNA, Messenger; D012097:Repressor Proteins; D020729:p120 GTPase Activating Protein; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins