Tgat, a Rho-specific guanine nucleotide exchange factor, activates NF-kappaB via physical association with IkappaB kinase complexes.
Constitutive activity of NF-kappaB is associated with various human cancers including adult T-cell leukemia (ATL). In this study, we have found Tgat that activates NF-kappaB 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 IkappaB 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-kappaB activation. Moreover, co-expressed p100 was efficiently processed into p52 in the Tgat-expressing cells, suggesting the co-involvement of non-canonical pathway.
Yamada
Kenji
K
Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
Moriuchi
Ryozo
R
Mori
Tsuyoshi
T
Okazaki
Eiko
E
Kohno
Tomoko
T
Nagayasu
Takeshi
T
Matsuyama
Toshifumi
T
Katamine
Shigeru
S
D002460:Cell Line; D018076:DNA, Complementary / Q000235:genetics; D017930:Genes, Reporter; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D007668:Kidney; D007700:Kinetics; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection
D018076:DNA, Complementary; D020662:Guanine Nucleotide Exchange Factors; D016328:NF-kappa B; D010750:Phosphoproteins; D011994:Recombinant Proteins; D017346:Protein Serine-Threonine Kinases; C099628:TRIO protein, human; D051550:I-kappa B Kinase