Smad7 binds to the adaptors TAB2 and TAB3 to block recruitment of the kinase TAK1 to the adaptor TRAF2.
Transforming growth factor-beta1 (TGF-beta1) regulates inflammation and can inhibit activation of the transcription factor NF-kappaB in certain cell types. Here we show that the TGF-beta-induced signaling protein Smad7 bound to TAB2 and TAB3, which are adaptors that link the kinase TAK1 to 'upstream' regulators in the proinflammatory tumor necrosis factor (TNF) signaling pathway. Smad7 thereby promoted TGF-beta-mediated anti-inflammatory effects. The formation of Smad7-TAB2 and Smad7-TAB3 complexes resulted in the suppression of TNF signaling through the adaptors TRAF2, TAB2 and/or TAB3, and TAK1. Furthermore, expression of a transgene encoding Smad7 in mouse skin suppressed inflammation and NF-kappaB nuclear translocation substantially and disrupted the formation of endogenous TRAF2-TAK1-TAB2 and TRAF2-TAK1-TAB3 complexes. Thus, Smad7 is a critical mediator of TGF-beta signals that block proinflammatory TNF signals.
Hong
Suntaek
S
Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, Maryland 20892-50551, USA.
Lim
Seunghwan
S
Li
Allen G
AG
Lee
Chan
C
Lee
Youn Sook
YS
Lee
Eun-Kyung
EK
Park
Seok Hee
SH
Wang
Xiao-Jing
XJ
Kim
Seong-Jin
SJ
D048868:Adaptor Proteins, Signal Transducing; D002478:Cells, Cultured; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051906:Smad7 Protein / Q000378:metabolism*; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D000099151:MAP Kinase Kinase Kinase 7
D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D020930:MAP Kinase Kinase Kinases; D051906:Smad7 Protein; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; D000099151:MAP Kinase Kinase Kinase 7; C497806:SMAD7 protein, human; C481053:TAB3 protein, human