RAS-DEPENDENT ACTIVATION OF THE SMALL GTPASE RAL

The small GTPase Rat is a Ras-like GTPase [1] that has been implicated in growth-factor-induced and Ras-induced DNA synthesis [2-4], and Ras -induced oncogenic transformation [3,5]. Recently, we and others found that three different Ral guanine nucleotide exchange factors (Ral GEF s) -Ral GDS, Rgl and Rlf bind specifically to the GTP-bound form of se veral Raslike GTPases [6-9]. Although oncogenic Ras is able to activat e these Ral GEFs [2,5,10], it is unknown whether growth factors can in duce the activation of Ral and, if so, which small GTPase is involved in this process. Here, we show that stimulation of various growth fact or receptors, including receptor tyrosine kinases and serpentine recep tors, results in rapid activation of Ral. This activation correlates w ith the activation of Ras, and dominant-negative Ras completely inhibi ts Ral activation induced by insulin and epidermal growth factor (EGF) . From these results, we conclude that Ral activation is a direct down stream effect of growth-factor-induced Ras activation. (C) Current Bio logy Ltd ISSN 0960-9822.