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.