The Ras superfamily of
GTPases is involved in the modification of many cellular processes including cellular motility, proliferation and differentiation. Our laboratory has previously identified the
RalGDS-related (Rgr) oncogene in a DMBA (7,12-dimethylbenz[α]
anthracene)-induced rabbit
squamous cell carcinoma and its human orthologue, hRgr. In this study, we analyzed the expression levels of the human hRgr transcript in a panel of human
hematopoietic malignancies and found that a truncated form (diseased-truncated (Dtr-hrgr)) was significantly overexpressed in many T-cell-derived
neoplasms. Although the Rgr proto-oncogene belongs to the
RalGDS family of
guanine nucleotide exchange factors (GEFs), we show that upon the introduction of hRgr into fibroblast cell lines, it is able to elicit the activation of both Ral and
Ras GTPases. Moreover, in vitro
guanine nucleotide exchange assays confirm that hRgr promotes Ral and Ras activation through
GDP dissociation, which is a critical characteristic of GEF
proteins. hRgr has
guanine nucleotide exchange activity for both
small GTPases and this activity was reduced when a point mutation within the catalytic domain (CDC25) of the
protein, (cd) Dtr-hRgr, was utilized. These observations prompted the analysis of the
biological effects of hRgr and (cd) hRgr expression in cultured cells. Here, we show that hRgr increases proliferation in low serum, increases invasion, reduces anchorage dependence and promotes the progression into the S phase of the cell cycle; properties that are abolished or severely reduced in the presence of the catalytic dead mutant. We conclude that the ability of hRgr to activate both Ral and Ras is responsible for its transformation-inducing phenotype and it could be an important contributor in the development of some T-cell
malignancies.