TAK1 MAPK kinase kinase mediates transforming growth factor-beta signaling by targeting SnoN oncoprotein for degradation.
Transforming growth factor-beta (TGF-beta) regulates a variety of physiologic processes through essential intracellular mediators Smads. The SnoN oncoprotein is an inhibitor of TGF-beta signaling. SnoN recruits transcriptional repressor complex to block Smad-dependent transcriptional activation of TGF-beta-responsive genes. Following TGF-beta stimulation, SnoN is rapidly degraded, thereby allowing the activation of TGF-beta target genes. Here, we report the role of TAK1 as a SnoN protein kinase. TAK1 interacted with and phosphorylated SnoN, and this phosphorylation regulated the stability of SnoN. Inactivation of TAK1 prevented TGF-beta-induced SnoN degradation and impaired induction of the TGF-beta-responsive genes. These data suggest that TAK1 modulates TGF-beta-dependent cellular responses by targeting SnoN for degradation.
Kajino
Taisuke
T
Department of Molecular Biology, Graduate School of Science, Nagoya University, Nagoya 464-8602, Japan.
Omori
Emily
E
Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina 27695-7633.
Ishii
Shunsuke
S
Laboratory of Molecular Genetics, RIKEN Tsukuba Institute, Ibaraki 305-0074, Japan.
Matsumoto
Kunihiro
K
Department of Molecular Biology, Graduate School of Science, Nagoya University, Nagoya 464-8602, Japan; Solution Oriented Research for Science and Technology, Japan Science and Technology Agency, Japan.
Ninomiya-Tsuji
Jun
J
Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina 27695-7633; Solution Oriented Research for Science and Technology, Japan Science and Technology Agency, Japan. Electronic address: Jun_Tsuji@ncsu.edu.
D002461:Cell Line, Transformed; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000502:physiology*; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*; D000099151:MAP Kinase Kinase Kinase 7
D047908:Intracellular Signaling Peptides and Proteins; D020930:MAP Kinase Kinase Kinases; D011518:Proto-Oncogene Proteins; D016212:Transforming Growth Factor beta; D000099151:MAP Kinase Kinase Kinase 7; C060615:SKIL protein, human