Nuclear export of Smad2 and Smad3 by RanBP3 facilitates termination of TGF-beta signaling.
Smad2 and Smad3 (Smad2/3) are key intracellular signal transducers for TGF-beta signaling, and their transcriptional activities are controlled through reversible phosphorylation and nucleocytoplasmic shuttling. However, the precise mechanism underlying nuclear export of Smad2/3 remains elusive. Here we report the essential function of RanBP3 in selective nuclear export of Smad2/3 in the TGF-beta pathway. RanBP3 directly recognizes dephosphorylated Smad2/3, which results from the activity of nuclear Smad phosphatases, and mediates nuclear export of Smad2/3 in a Ran-dependent manner. As a result, increased expression of RanBP3 inhibits TGF-beta signaling in mammalian cells and Xenopus embryos. Conversely, depletion of RanBP3 expression or dominant-negative inhibition of RanBP3 enhances TGFbeta-induced antiproliferative and transcriptional responses. In conclusion, our study supports a definitive role for RanBP3 in mediating Smad2/3 nuclear export and terminating TGF-beta signaling.
Dai
Fangyan
F
Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Lin
Xia
X
Chang
Chenbei
C
Feng
Xin-Hua
XH
D021581:Active Transport, Cell Nucleus; D028341:Activins / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D066298:In Vitro Techniques; D008954:Models, Biological; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D029543:Nucleocytoplasmic Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014981:Xenopus
D019485:Bone Morphogenetic Proteins; D009687:Nuclear Proteins; D029543:Nucleocytoplasmic Transport Proteins; C112820:RANBP3 protein, human; D034741:RNA, Small Interfering; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D028341:Activins