Disease relevance of RRAS2

• TC21 is a Ras-like GTPase with high oncogenic potential that is found mutated in some human tumors and overexpressed in breast cancer cell lines [1].
• Thus, we conclude that mutations in TC21 are uncommon in breast carcinomas [2].
• TC21 is a ras family member that shares close homology to H-, K- and N-ras, and activating mutations have been found in ovarian carcinoma and leiomyosarcoma cell lines [2].
• We recently identified TC21/R-Ras2, a small GTP-binding protein (SMG) in esophageal squamous cell carcinomas (ESCCs) by differential display [3].

High impact information on RRAS2

• Here we show that stable expression of activated R-Ras or the closely related TC21 (R-Ras 2) induced integrin-mediated migration and invasion of breast epithelial cells through collagen and disrupted differentiation into tubule structures, whereas dominant negative R-Ras had opposite effects [4].
• These results imply novel roles for R-Ras and TC21 in promoting a transformed phenotype and in the basal migration and polarization of these cells [4].
• A potent transforming gene was detected by transfection analysis and identified as TC21, a recently cloned member of the RAS gene superfamily [5].
• TC21-induced alterations in cellular morphology in NIH 3T3 and PC12 cells are also PI-3K dependent [6].
• In both cases, the effector domain region of TC21 is required since point mutations in this region can interfere with activation of downstream signaling [6].

Biological context of RRAS2

• R-Ras has a high degree of sequence homology with Ras and other members of the Ras subfamily, including Rap, TC21, and M-Ras [7].
• Signal transduction elements of TC21, an oncogenic member of the R-Ras subfamily of GTP-binding proteins [1].
• The signaling pathways of TC21-mediated transformation and cell survival are not well-established [8].
• Therefore, like Ras, TC21 may activate signaling pathways that control normal cell growth and differentiation [9].
• We have identified an additional member of the Ras gene family which shows significant sequence similarity to the human TC21 gene [10].

Anatomical context of RRAS2

• Many members of the Ras superfamily (Ha-Ras, N-Ras, TC21, and RhoA) are prenylated in the cytoplasm and then transit through the endomembrane system on their way to the plasma membrane [11].
• We show that inhibition of Ral signaling blocks DNA synthesis in human tumor cell lines containing activating mutations in TC21, demonstrating for the first time that this pathway is required for the proliferation of human tumor cells [6].
• Consistent with this observation, we found that Ras- but not TC21-transformed NIH 3T3 cells possessed constitutively elevated Raf-1 and B-Raf kinase activity [9].
• We have used the yeast two hybrid system to identify proteins that interact with an oncogenic form of the TC21 protein. cDNA clones encoding the carboxy-terminal region of the RalGDS protein were isolated from human B-cell and HeLa cDNA libraries [12].
• TC21-transformed MCF-10A cells exhibited altered cellular morphology associated with a disruption of cell-cell adherens junctions, formed colonies in soft agar, and showed enhanced motility in vitro [13].

Associations of RRAS2 with chemical compounds

• Thus, the exchange of guanosine nucleotides in wild type TC21 is catalyzed by Ras exchange factors [1].
• Loose control was associated with increased rates of whole-body leucine oxidation (LC 25 +/- 7 vs TC 21 +/- 8 mumol.kg-1.h-1) and protein degradation (LC 127 +/- 12 vs TC 118 +/- 18 mumol.kg-1.h-1) (both p < 0.05) [14].
• There is now evidence that the actions of chemotherapy may involve Ras, tyrosine kinases (epidermal growth factor receptor, HER2), TC21, or similar molecules [15].

Physical interactions of RRAS2

• Moreover, RalGDS only binds to TC21 in its active, GTP-loaded configuration [12].

Regulatory relationships of RRAS2

• From these results, we conclude that TC21 promotes Ras-like responses in diverse cell types due to the use of overlapping, if not identical, signaling elements of the Ras oncogenic pathway [1].

Other interactions of RRAS2

• Regulatory proteins of R-Ras, TC21/R-Ras2, and M-Ras/R-Ras3 [16].
• GTPase-activating proteins (GAPs) for Ras, Gap1(m), p120 GAP, and NF-1 stimulated all of the R-Ras, TC21, and M-Ras proteins, whereas R-Ras GAP stimulated R-Ras and TC21 but not M-Ras [16].
• However, we observed that both SOS1 and CDC25 were activators of normal TC21, but not R-Ras, transforming activities [17].

Analytical, diagnostic and therapeutic context of RRAS2

• The cellular localization of TC21 was determined by confocal microscopy [3].
• Immunoblotting and semi-quantitative RT-PCR confirmed TC21 expression in dysplastias and ESCCs [3].

References