title: Sumoylation of Smad3 stimulates its nuclear export during PIASy-mediated suppression of TGF-beta signaling.
abstract: Sma- and MAD-related protein 3 (Smad3) plays crucial roles in the transforming growth factor-beta (TGF-beta)-mediated signaling pathway, which produce a variety of cellular responses, including cell proliferation and differentiation. In our previous study, we demonstrated that protein inhibitor of activated STATy (PIASy) suppresses TGF-beta signaling by interacting with and sumoylating Smad3. In the present study, we examined the molecular mechanisms of Smad3 sumoylation during PIASy-mediated suppression of TGF-beta signaling. We found that small-interfering RNA-mediated reduction of endogenous PIASy expression enhanced TGF-beta-induced gene expression. Importantly, coexpression of Smad3 with PIASy and SUMO1 affected the DNA-binding activity of Smad3. Furthermore, coexpression of Smad3 with PIASy and SUMO1 stimulated the nuclear export of Smad3. Finally, fluorescence resonance energy transfer analyses revealed that Smad3 interacted with SUMO1 in the cytoplasm. These results suggest that PIASy regulates TGF-beta/Smad3-mediated signaling by stimulating sumoylation and nuclear export of Smad3.
authors.affiliation: Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-Ku Kita 12 Nishi 6, Sapporo 060-0812, Japan.
authors.forename: Seiyu
authors.initials: S
authors.lastname: Imoto
authors.forename: Norihiko
authors.initials: N
authors.lastname: Ohbayashi
authors.forename: Osamu
authors.initials: O
authors.lastname: Ikeda
authors.forename: Shinya
authors.initials: S
authors.lastname: Kamitani
authors.forename: Ryuta
authors.initials: R
authors.lastname: Muromoto
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sekine
authors.forename: Tadashi
authors.initials: T
authors.lastname: Matsuda
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D031541:Fluorescence Resonance Energy Transfer; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D000075223:Poly-ADP-Ribose Binding Proteins; D050828:Protein Inhibitors of Activated STAT / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D025842:SUMO-1 Protein / Q000378:metabolism*; D015398:Signal Transduction; D051900:Smad3 Protein / Q000032:analysis / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C485891:PIAS4 protein, human; D000075223:Poly-ADP-Ribose Binding Proteins; D050828:Protein Inhibitors of Activated STAT; D034741:RNA, Small Interfering; C497790:SMAD3 protein, human; D025842:SUMO-1 Protein; C495501:SUMO1 protein, human; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta