Cyclooxygenase-2 (COX-2) is rapidly induced by angiotensin (Ang)-II in the non-tumorigenic, rat intestinal epithelial cell line, IEC-18, through its G-protein coupled receptor, AT₁R. Here, we investigate the ability of Ang II to regulate transcription of the COX-2 promoter and a Gal4-CREB heterologous promoter in IEC-18 cells. Ang II and EGF induced similar levels of transcription from the COX-2 and Gal4-CREB promoters. Over-expression of constitutively active Gα proteins q, 11, 12 and 13, showed induction by Gαq^Q209L and by Gα11^Q209L for both the COX-2 and Gal4-CREB promoters. Co-expression of RGS 2, 3 or 4 but not the RGS domain of p115^RhoGEF inhibited Ang II-dependent induction of the COX-2 and Gal4-CREB promoters. Expression of constitutively active MKK6 EE but not MKK3 EE induced the COX-2 and Gal4-CREB promoters via p38^MAPK. SB202190 but not PD98059 inhibited induction of the COX-2 promoter by over-expression of the constitutively active PAK1^T423E. Expression of the kinase-inactive PAK1^K299R inhibited both Ang II-dependent induction of the COX-2 promoter and induction of the COX-2 and Gal4-CREB promoters by Gαq^Q209L. These data demonstrate that in IEC-18 cells, Ang II-dependent activation of the COX-2 promoter is mediated primarily through Gq/11 signaling via a PAK/MKK6/p38β/CREB signaling cascade.