CREB is a regulatory target for the protein kinase Akt/PKB. CREB, when phosphorylated at Ser-133 by protein kinase A, activates target gene expression by recruiting the co-activator CBP. Recent studies show that CREB and its paralog CREM are essential for cell survival. This study demonstrates that Akt/PKB promotes CREB phosphorylation at Ser-133 and recruits CBP, thereby activating cellular gene expression via a CRE-dependent mechanism. Akt/PKB-induced CREB activity is dependent on serum stimulation and is suppressed by the PI3-K inhibitor LY 294002. These results suggest that Akt/PKB promotes cell survival, at least in part, by stimulating the expression of cellular genes via the CREB/CBP pathway. Akt/PKB, originally characterized by its sequence homology with the v-Akt oncogene and protein kinase A, has been shown to block apoptosis and promote cell survival in response to growth factors. Akt/PKB-mediated phosphorylation of BAD blocks apoptosis by promoting BAD binding to 14-3-3 protein and sequestering BAD from Bcl-XL. Following activation by PI3-K, Akt/PKB translocates to the nucleus where it regulates specific genetic programs by phosphorylating nuclear factors. Growth factors and hormones stimulate gene expression by inducing CREB phosphorylation at Ser-133. CREB is also phosphorylated by other kinases, including protein kinase C, pp90 RSK, calmodulin kinases II and IV, and microtubule-activated protein kinase-activated protein 2. Recent studies with transgenic and knockout mice indicate that CREB and CREM are important for cell survival. CREM-deficient mice exhibit spermatogenesis defects due to enhanced germ cell apoptosis. Overexpression of a dominant negative CREB transgene induces T cell apoptosis following growth factor stimulation. The involvement of CREB family members in cell survival and the similarity of Akt/PKB to protein kinase A prompted the investigation of whether CREB is a regulatory target for Akt/PKB. The results show that Akt/PKB promotes CREB phosphorylation, stimulates CBP recruitment, and activates cellular gene expression via a CRE-dependent mechanism. These findings suggest that CREB may contribute significantly to cell survival in response to growth factor stimulation.CREB is a regulatory target for the protein kinase Akt/PKB. CREB, when phosphorylated at Ser-133 by protein kinase A, activates target gene expression by recruiting the co-activator CBP. Recent studies show that CREB and its paralog CREM are essential for cell survival. This study demonstrates that Akt/PKB promotes CREB phosphorylation at Ser-133 and recruits CBP, thereby activating cellular gene expression via a CRE-dependent mechanism. Akt/PKB-induced CREB activity is dependent on serum stimulation and is suppressed by the PI3-K inhibitor LY 294002. These results suggest that Akt/PKB promotes cell survival, at least in part, by stimulating the expression of cellular genes via the CREB/CBP pathway. Akt/PKB, originally characterized by its sequence homology with the v-Akt oncogene and protein kinase A, has been shown to block apoptosis and promote cell survival in response to growth factors. Akt/PKB-mediated phosphorylation of BAD blocks apoptosis by promoting BAD binding to 14-3-3 protein and sequestering BAD from Bcl-XL. Following activation by PI3-K, Akt/PKB translocates to the nucleus where it regulates specific genetic programs by phosphorylating nuclear factors. Growth factors and hormones stimulate gene expression by inducing CREB phosphorylation at Ser-133. CREB is also phosphorylated by other kinases, including protein kinase C, pp90 RSK, calmodulin kinases II and IV, and microtubule-activated protein kinase-activated protein 2. Recent studies with transgenic and knockout mice indicate that CREB and CREM are important for cell survival. CREM-deficient mice exhibit spermatogenesis defects due to enhanced germ cell apoptosis. Overexpression of a dominant negative CREB transgene induces T cell apoptosis following growth factor stimulation. The involvement of CREB family members in cell survival and the similarity of Akt/PKB to protein kinase A prompted the investigation of whether CREB is a regulatory target for Akt/PKB. The results show that Akt/PKB promotes CREB phosphorylation, stimulates CBP recruitment, and activates cellular gene expression via a CRE-dependent mechanism. These findings suggest that CREB may contribute significantly to cell survival in response to growth factor stimulation.