Jab1/CSN5, a component of the COP9 signalosome, regulates transforming growth factor beta signaling by binding to Smad7 and promoting its degradation.
Smad7 inhibits responses mediated by transforming growth factor beta (TGF-beta) and acts in a negative-feedback loop to regulate the intensity or duration of the TGF-beta signal. However, the aberrant expression and continued presence of Smad7 may cause TGF-beta resistance. Here we report that Jab1/CSN5, which is a component of the COP9 signalosome complex, associates constitutively with Smad7 and that overexpression of Jab1/CSN5 causes the translocation of Smad7 from the nucleus to the cytoplasm, promoting its degradation. Overexpression of Jab1/CSN5 increases Smad2 phosphorylation and enhances TGF-beta-induced transcriptional activity. The inhibition of endogenous Jab1/CSN5 expression by small interfering RNA (siRNA) induces Smad7 expression. This study thus defines Jab1/CSN5 as an adapter that targets Smad7 for degradation, thus releasing Smad7-mediated suppression of TGF-beta signaling.
Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-5055, USA.
Byung-Chul
BC
Kim
Ho-Jae
HJ
Lee
Seok Hee
SH
Park
Sae Ra
SR
Lee
Tatiana S
TS
Karpova
James G
JG
McNally
Angelina
A
Felici
Dug Keun
DK
Lee
Seong-Jin
SJ
Kim
D000818:Animals; D000075686:COP9 Signalosome Complex; D019556:COS Cells; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D006801:Humans; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D008954:Models, Biological; D046912:Multiprotein Complexes; D010447:Peptide Hydrolases; D011485:Protein Binding; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction; D051899:Smad2 Protein; D051906:Smad7 Protein; D013347:Subcellular Fractions / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D020798:Two-Hybrid System Techniques
D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D011506:Proteins; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; C497782:SMAD2 protein, human; C497806:SMAD7 protein, human; D051899:Smad2 Protein; D051906:Smad7 Protein; C508960:TGFB1 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D010447:Peptide Hydrolases; C501488:COPS5 protein, human; D000075686:COP9 Signalosome Complex