title: The tumor suppressor DiRas3 forms a complex with H-Ras and C-RAF proteins and regulates localization, dimerization, and kinase activity of C-RAF.
abstract: The maternally imprinted Ras-related tumor suppressor gene DiRas3 is lost or down-regulated in more than 60% of ovarian and breast cancers. The anti-tumorigenic effect of DiRas3 is achieved through several mechanisms, including inhibition of cell proliferation, motility, and invasion, as well as induction of apoptosis and autophagy. Re-expression of DiRas3 in cancer cells interferes with the signaling through Ras/MAPK and PI3K. Despite intensive research, the mode of interference of DiRas3 with the Ras/RAF/MEK/ERK signal transduction is still a matter of speculation. In this study, we show that DiRas3 associates with the H-Ras oncogene and that activation of H-Ras enforces this interaction. Furthermore, while associated with DiRas3, H-Ras is able to bind to its effector protein C-RAF. The resulting multimeric complex consisting of DiRas3, C-RAF, and active H-Ras is more stable than the two protein complexes H-Ras·C-RAF or H-Ras·DiRas3, respectively. The consequence of this complex formation is a DiRas3-mediated recruitment and anchorage of C-RAF to components of the membrane skeleton, suppression of C-RAF/B-RAF heterodimerization, and inhibition of C-RAF kinase activity.
authors.affiliation: Theodor Boveri Institute of Bioscience, Department of Microbiology, University of Wuerzburg, 97074 Wuerzburg, Germany. angela_baljuls@gmx.de
authors.forename: Angela
authors.initials: A
authors.lastname: Baljuls
authors.forename: Matthias
authors.initials: M
authors.lastname: Beck
authors.forename: Ayla
authors.initials: A
authors.lastname: Oenel
authors.forename: Armin
authors.initials: A
authors.lastname: Robubi
authors.forename: Ruth
authors.initials: R
authors.lastname: Kroschewski
authors.forename: Mirko
authors.initials: M
authors.lastname: Hekman
authors.forename: Thomas
authors.initials: T
authors.lastname: Rudel
authors.forename: Ulf R
authors.initials: UR
authors.lastname: Rapp
mesh_terms: D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000378:metabolism; D002522:Chlorocebus aethiops; D003599:Cytoskeleton / Q000378:metabolism; D019281:Dimerization; D016147:Genes, Tumor Suppressor / Q000502:physiology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D046912:Multiprotein Complexes / Q000378:metabolism; D054876:Prenylation / Q000502:physiology; D019908:Proto-Oncogene Proteins c-raf / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C117386:DIRAS3 protein, human; D046912:Multiprotein Complexes; D019908:Proto-Oncogene Proteins c-raf; D016283:Proto-Oncogene Proteins p21(ras); D020741:rho GTP-Binding Proteins