Rig is a novel Ras-related protein and potential neural tumor suppressor

Abstract

The Ras superfamily consists of a large group of monomeric GTPases demonstrating homology to Ras oncoproteins. Although structurally similar, Ras-superfamily proteins are functionally diverse. Whereas some members exhibit oncogenic properties, others may serve as tumor suppressors. We have identified a novel Ras-related protein that suppresses cell growth and have designated it Rig (Ras-related inhibitor of cell growth). Overexpression of Rig inhibited Ras-mediated cellular transformation and activation of downstream signaling in NIH 3T3 cells. rig mRNA is expressed at high levels in normal cardiac and neural tissue. However, Rig protein expression is frequently lost or down-regulated in neural tumor-derived cell lines and primary human neural tumors. Moreover, expression of exogenous Rig in human astrocytoma cells suppressed growth. Rig has a C-terminal CAAX motif that codes for posttranslational modification by both farnesyl and geranylgeranyl isoprenoid lipids. Consequently, Rig may play a role in the cellular response to farnesyl transferase inhibitors. Rig bears 63% overall sequence homology to a recently described Ras-family member Noey2, a tumor suppressor in breast and ovarian tissue. Therefore, Rig and Noey2 may represent a new subfamily of Ras-like tumor suppressors. S mall, Ras-related GTPases form a large superfamily of structurally related proteins in mammalian cells (1). These proteins are typically regulated by guanine nucleotide binding and undergo C-terminal isoprenylation. Ras-superfamily proteins mediate pleiotropic cellular effects ranging from growth control to cytoskeletal rearrangements, various aspects of intracellular transport, cell survival, and apoptosis (2, 3). Although the Ras-, Ral-, Rit-, and Rho-subfamily proteins function as oncoproteins (4, 5), Noey2͞Ahri1 and Rap1A have been described as tumor suppressors (6, 7). Thus, even closely related Ras-superfamily members can exert quite different biological effects.The relationship between structure and function of Rasrelated proteins is now sufficiently well understood that certain biological and biochemical characteristics may be inferred simply from an examination of their primary amino acid sequence. For example, the region of these proteins essential for effector interaction (the effector domain) has been identified and the residues important for particular effector interactions characterized (8). Furthermore, many Ras-related proteins contain a C-terminal CAAX motif (cysteine-aliphatic-aliphatic-X) that serves as a target for posttranslational isoprenoid lipid modification (9). It is now known that the X amino acid residue is critical for determining the type of covalent isoprenylation, farnesyl (F) (15-carbon) or geranylgeranyl (GG) (20-carbon). Typically, serine, phenylalanine, methionine, and cysteine residues are substrates for F transferases whereas GG transferases recognize leucine and phenylalanine residues (9, 10).The vast majority of Ras-related proteins undergo GG isoprenoid lipid modification whereas the relatively ra...

The Ras-related protein AGS1/RASD1 suppresses cell growth

“…AGS1/RASD1 falls into a functional grouping with three other Ras-like proteins (RIG, RERG, ARH1/ NOEY2), which were recently shown to suppress cell growth and/or exhibit altered expression in various tumors (Finlin et al, 2001;Ellis et al, 2002;Luo et al, 2003). The AGS1/RASD1 gene maps to human chromosome 17p11.2, a region associated with a high incidence of loss of heterozygosity and deletions in cancers (Soenen et al, 1998;Stacey et al, 1999;Koga et al, 2002).…”

Salvador Protein Is a Tumor Suppressor Effector of RASSF1A with Hippo Pathway-independent Functions

“…Luciferase Assays-Dual luciferase assays using a Renilla luciferase internal control were performed using the pG13-Luciferase reporter in MCF-7 cells with a Promega dual luciferase kit, essentially as described previously (32).…”

RASSF6 is a novel member of the RASSF family of tumor suppressors

“…Cells were plated in soft agar after 24 h as described previously (Vos et al, 2003b). Dual luciferase assays were performed as described in Ellis et al (2002).…”