The GTPase and Rho GAP domains of p190, a tumor suppressor protein that binds the M(r) 120,000 Ras GAP, independently function as anti-Ras tumor suppressors.
p190 is a Tyr-phosphorylatable G protein of M(r) 190,000 that binds NH2-terminal SH2 domains of GAP1, a Ras GAP of M(r) 120,000. p190 contains at least two functional domains: a GTPase domain at the NH2 terminus and a GAP domain at the COOH terminus that can attenuate signal-transducing activity of three distinct G proteins (Rac, Rho, and CDC42). Here, we demonstrate that overexpression of either an antisense p190 RNA or a dominant negative mutant (Asn36) of p190 GTPase domain (residues 1-251) but not the wild-type p190 GTPase domain is able to transform normal NIH/3T3 fibroblasts. Furthermore, overexpression of either the wild-type p190 GTPase domain or the COOH-terminal GAP domain can suppress v-Ha-Ras-induced malignant transformation. These results indicate that p190 contains at least two distinct anti-Ras tumor suppressor domains, the GTPase and GAP domains, and suggest that one of the mechanisms underlying the suppression of Ras-transformation by p190 is the attenuation by p190 GAP domain of Rac/Rho/CDC42 signalings, which are essential for Ras-transformation. In fact, the p190 GAP domain alone suppresses the expression of the c-Fos gene, which is mediated by Rac/Rho/CDC42 and is required for oncogenicity of Ras.
Wang
D Z
DZ
Ludwig Institute for Cancer Research, PO Royal Melbourne Hospital, Victoria, Australia.
Nur-E-Kamal
M S
MS
Tikoo
A
A
Montague
W
W
Maruta
H
H
D000818:Animals; D002455:Cell Division / Q000502:physiology; D002461:Cell Line, Transformed; D004268:DNA-Binding Proteins; D005347:Fibroblasts / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D020690:GTPase-Activating Proteins; D016147:Genes, Tumor Suppressor / Q000502:physiology; D011905:Genes, ras / Q000502:physiology; D020662:Guanine Nucleotide Exchange Factors; D051379:Mice; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism / Q000502:physiology*; D011506:Proteins / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016372:RNA, Antisense / Q000378:metabolism; D051381:Rats; D012097:Repressor Proteins; D014410:Tumor Stem Cell Assay; D020703:ras GTPase-Activating Proteins; D020666:ras-GRF1
C513041:Arhgap35 protein, mouse; C513040:Arhgap35 protein, rat; C513042:Arhgap5 protein, mouse; D004268:DNA-Binding Proteins; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011506:Proteins; D016760:Proto-Oncogene Proteins c-fos; D016372:RNA, Antisense; C513037:Rasgrf1 protein, mouse; D012097:Repressor Proteins; D020703:ras GTPase-Activating Proteins; D020666:ras-GRF1; D015240:Phorbol 12,13-Dibutyrate; D020558:GTP Phosphohydrolases