title: The Ras-related protein Rheb is farnesylated and antagonizes Ras signaling and transformation.
abstract: Presently, nothing is known about the function of the Ras-related protein Rheb. Since Rheb shares significant sequence identity with the core effector domains of Ras and KRev-1/Rap1A, it may share functional similarities with these two structurally related, yet functionally distinct, small GTPases. Furthermore, since like Ras, Rheb terminates with a COOH terminus that is likely to signal for farnesylation, it may be a target for the farnesyltransferase inhibitors that block Ras processing and function. To compare Rheb function with those of Ras and KRev-1, we introduced mutations into Rheb that generate constitutively active or dominant negative forms of Ras and Ras-related proteins and were designated Rheb(64L) and Rheb(20N), respectively. Expression of wild type or mutant Rheb did not alter the morphology or growth properties of NIH 3T3 cells. Thus, aberrant Rheb function is distinct from that of Ras and fails to cause cellular transformation. Instead, similar to KRev-1, co-expression of Rheb antagonized oncogenic Ras transformation and signaling. In vitro and in vivo analyses showed that like Ras, Rheb proteins are farnesylated and are sensitive to farnesyltransferase inhibition. Thus, it is possible that Rheb function may be inhibited by farnesyltransferase inhibitors treatment and, consequently, may contribute to the ability of these inhibitors to impair Ras transformation.
authors.affiliation: Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: G J
authors.initials: GJ
authors.lastname: Clark
authors.forename: M S
authors.initials: MS
authors.lastname: Kinch
authors.forename: K
authors.initials: K
authors.lastname: Rogers-Graham
authors.forename: S M
authors.initials: SM
authors.lastname: Sebti
authors.forename: A D
authors.initials: AD
authors.lastname: Hamilton
authors.forename: C J
authors.initials: CJ
authors.lastname: Der
mesh_terms: D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D018076:DNA, Complementary; D005333:Fetus; D019204:GTP-Binding Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D015723:Gene Library; D011905:Genes, ras; D006133:Growth Substances / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D020559:Monomeric GTP-Binding Proteins; D009479:Neuropeptides / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D009865:Oocytes / Q000502:physiology; D017368:Protein Prenylation; D000076205:Ras Homolog Enriched in Brain Protein; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D015533:Transcriptional Activation; D014162:Transfection; D014982:Xenopus laevis; D018631:ras Proteins / Q000737:chemistry
chemical_list: D018076:DNA, Complementary; D006133:Growth Substances; D009479:Neuropeptides; D000076205:Ras Homolog Enriched in Brain Protein; D011993:Recombinant Fusion Proteins; C490213:Rheb protein, mouse; C087693:Rheb protein, rat; D019204:GTP-Binding Proteins; D020559:Monomeric GTP-Binding Proteins; D018631:ras Proteins