In T cells, signals initiated at the TCR, and in particular activation of protein kinase C (PKC), can activate the p21ras proteins. Triggering of the TCR and PKC is required for the efficient production of the T cell growth factor, IL-2. IL-2 gene transcription is controlled by a 275-bp enhancer that is known to contain binding sites for many transcription factors including the octamer family of proteins, NF kappa B, AP-1, and a T cell-specific factor, NFAT (nuclear factor of activated T cells). NFAT binds to a region of the IL-2 enhancer that has been defined as a TCR response element (ARRE-2), and is induced in response to increases in intracellular calcium, stimulation of PKC, or triggering of the TCR. To determine whether p21ras is involved in the signals that regulate NFAT, we examined the effect of expression of a constitutively active p21ras mutant, v-Ha-ras, and a dominant inhibitory mutant of p21ras, c-Ha-ras(asn)17, on the induction of a NFAT-driven reporter gene (NFAT CAT) during T cell activation. The constitutively active Ras mutant could synergize with the calcium ionophore ionomycin to induce NFAT. In addition, expression of p21v-Ha-ras could enhance NFAT CAT induction in response to TCR and PKC agonists. The dominant inhibitory mutant of p21ras could prevent NFAT CAT expression in response to PKC or TCR triggering. These data show that Ras regulates NFAT, and that p21ras function is important for the TCR- and PKC-regulated pathways that regulate NFAT.