Constitutive activity of NF-kappa B is associated with various human cancers including adult T-cell leukemia (ATL). In this study, we have found Tgat that activates NF-kappa B by screening a cDNA expression library derived from ATL cells. We previously identified Tgat as the oncogene, which consists of the Rho-guanine nucleotide exchange factor (Rho-GEF) domain and the unique C-terminal region, as a consequence of alternative splicing of the Trio transcript. Tgat activated the IKK activity by binding with the I kappa B kinase (IKK) complex. The Tgat mutants lacking the C-terminal region failed to associate with the IKK complex suggesting an essential role of the unique sequence. The mutation causing the loss of GEF activity also abolished the NF-kappa B activation. Moreover, co-expressed p100 was efficiently processed into p52 in the Tgat-expressing cells, suggesting the co-involvement of non-canonical pathway. (c) 2007 Elsevier Inc. All rights reserved.