Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Active Transport, Cell Nucleus
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Activins / metabolism
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Animals
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Base Sequence
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Bone Morphogenetic Proteins / metabolism
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Cell Line
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Humans
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In Vitro Techniques
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Models, Biological
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Nuclear Proteins / antagonists & inhibitors
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Nucleocytoplasmic Transport Proteins / antagonists & inhibitors
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Nucleocytoplasmic Transport Proteins / genetics
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Nucleocytoplasmic Transport Proteins / metabolism*
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Phosphorylation
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Protein Binding
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RNA Interference
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RNA, Small Interfering / genetics
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Signal Transduction
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Smad2 Protein / metabolism*
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Smad3 Protein / metabolism*
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Transcriptional Activation
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Transfection
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Transforming Growth Factor beta / metabolism*
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Xenopus
Substances
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Bone Morphogenetic Proteins
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Nuclear Proteins
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Nucleocytoplasmic Transport Proteins
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RANBP3 protein, human
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RNA, Small Interfering
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SMAD2 protein, human
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SMAD3 protein, human
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Smad2 Protein
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Smad3 Protein
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Transforming Growth Factor beta
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Activins