Stimulation of gene induction and cell growth by the Ras effector Rlf

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Abstract
Rlf is a ubiquitously expressed distinct relative of RalGDS that interacts with active Ras in vitro . We now demonstrate that Rlf, when co‐expressed with Ras mutants, associates in vivo with RasV12 and the effector‐domain mutant RasV12G37, but not with RasV12E38 or RasV12C40. Rlf exhibits guanine nucleotide exchange activity towards the small GTPase Ral and, importantly, Rlf‐induced Ral activation is stimulated by active Ras. In addition, RasV12 and RasV12G37 synergize with Rlf in the transcriptional activation of the c‐ fos promoter. Rlf, when targeted to the plasma membrane using the Ras farnesyl attachment site (Rlf–CAAX), is constitutively active, inducing both Ral activation and c‐ fos promoter activity. Rlf–CAAX‐induced gene expression is insensitive to dominant negative Ras and the MEK inhibitor PD98059, and involves activation of the serum response element. Furthermore, expression of Rlf–CAAX is sufficient to induce proliferation of NIH 3T3 cells under low‐serum conditions. These data demonstrate that Rlf is an effector of Ras which functions as an exchange factor for Ral. Rlf mediates a distinct Ras‐induced signalling pathway to gene induction. Finally, a constitutively active form of Rlf can stimulate transcriptional activation and cell growth.