GGAP2/PIKE-A is a GTP-binding protein that can enhance Akt activity. Increased activation of the AKT and nuclear factor-kappaB (NF-kappaB) pathways have been identified as critical steps in cancer initiation and progression in a variety of human cancers. We have found significantly increased expression GGAP2 in the majority of human prostate cancers and GGAP2 expression increases Akt activation in prostate cancer cells. Thus, increased GGAP2 expression is a common mechanism for enhancing the activity of the Akt pathway in prostate cancers. In addition, we have found that activated Akt can bind and phosphorylate GGAP2 at serine 629, which enhances GTP binding by GGAP2. Phosphorylated GGAP2 can bind the p50 subunit of NF-kappaB and enhances NF-kappaB transcriptional activity. When expressed in prostate cancer cells, GGAP2 enhances proliferation, foci formation, and tumor progression in vivo. Thus, increased GGAP2 expression, which is present in three quarters of human prostate cancers, can activate two critical pathways that have been linked to prostate cancer initiation and progression.