MicroinJection of either Ki-ms,.Vl.2 p21 or the GDP-bound form of Ki-ras p21 plus smg GDP dissociation stimulator (GDS), a stimulatory GDP/GTP exchange protein for Ki-ras p21, smg/rapllKrev-l p21, and rho p21, into quiescent Swiss 3T3 cells induced DNA synthesis irrespective of the presence or absence of insulin. The guanosine 5'-(3-0-thio)triphosphate (GTPyS)-bound form of smg p21B or the GDP-bound form of smg p21B plus smg GDS also induced DNA The smg p21 family, consisting of two members, A and B, belongs to the ras p21-related small GTP-binding protein (G protein) superfamily (for reviews, see references 3 and 41). smg p21A is identical to raplA p21 and Krev-1 p21, and smg p21B is identical to raplB p21 (22,24,28,35,36). Among many small G proteins, smg p21 has the same amino acid sequence as does the effector region of ras p21 (3,22,24,28,35,36,41). This structural property suggests that smg p21 can share the effector(s) with ras p21 and exert actions similar or antagonistic to those of ras p21. Consistently, Krev-1 p21 has been shown to suppress the transforming activity of v-Ki-ras p21 in NIH 3T3 cells (24). smg p21B and raplA p21 inhibit the ras p21 GTPase-activating protein (GAP) activity in a manner competitive with ras p21 in a cell-free system (10, 13). ras p21 GAP has been shown to interact with the effector domain of ras p21 and to stimulate its GTPase activity (for a review, see reference 29). Moreover, our recent studies have revealed that overexpression of smg p21 in NIH 3T3 cells inhibits the ras p21-, plateletderived growth factor (PDGF)-, and 12-O-tetradecanoylphorbol-13-acetate-induced activation of the c-fos promoter/ enhancer element but does not inhibit the c-raf-l-induced activation of this element (39). There are several lines of evidence that ras p21 is a downstream molecule of the PDGF receptor and protein kinase C and that the c-raf-1 protein kinase mediates at least a part of the actions of ras p21 (6,7,16,18,25,32,40). These results indicate that smg p21 may antagonize ras p21 actions presumably by competing for the proteins interacting with the effector domain of ras p21. Although ras p21 GAP interacts with the effector domain of ras p21, there is increasing evidence that this protein is a negative regulatory protein which converts ras p21 from the GTP-bound active form to the GDP-bound inactive form (29, * Corresponding author. 33,43,45). At present, the effector protein of ras p21 in mammalian cells is unknown.The conversion of smg p21 from the GDP-bound inactive form to the GTP-bound active form is stimulated by a GDP/GTP exchange protein, named smg GDP dissociation stimulator (GDS) (17,44). This smg GDS is active not only on smg p21 but also on Ki-ras p21 and rho p21 (31). On the other hand, smg p21 is directly phosphorylated by cyclic AMP-dependent protein kinase (protein kinase A) and cyclic GMP-dependent protein kinase (protein kinase G) at the same serine residue (Ser-179), which is located between the polybasic region and the geranylgeranylated cysteine residue in the C...