Abstract
The transcription factor Smad2 is released from cytoplasmic retention by TGFbeta receptor-mediated phosphorylation, accumulating in the nucleus where it associates with cofactors to regulate transcription. We uncovered direct interactions of Smad2 with the nucleoporins CAN/Nup214 and Nup153. These interactions mediate constitutive nucleocytoplasmic shuttling of Smad2. CAN/Nup214 and Nup153 compete with the cytoplasmic retention factor SARA and the nuclear Smad2 partner FAST-1 for binding to a hydrophobic corridor on the MH2 surface of Smad2. TGFbeta receptor-mediated phosphorylation stimulates nuclear accumulation of Smad2 by modifying its affinity for SARA and Smad4 but not for CAN/Nup214 or Nup153. Thus, by directly contacting the nuclear pore complex, Smad2 undergoes constant shuttling, providing a dynamic pool that is competitively drawn by cytoplasmic and nuclear signal transduction partners.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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3T3 Cells
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Active Transport, Cell Nucleus
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Animals
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COS Cells
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Cell Nucleus / metabolism*
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Cytoplasm / metabolism*
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DNA-Binding Proteins / chemistry
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DNA-Binding Proteins / metabolism*
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Exportin 1 Protein
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HeLa Cells
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Humans
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Karyopherins / metabolism
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Mice
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Nuclear Pore / metabolism
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Nuclear Pore Complex Proteins / metabolism*
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Peptide Fragments / metabolism
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Protein Binding
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Protein Transport
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Receptors, Cytoplasmic and Nuclear*
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Signal Transduction*
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Smad2 Protein
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Trans-Activators / chemistry
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Trans-Activators / metabolism*
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Transforming Growth Factor beta / metabolism*
Substances
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DNA-Binding Proteins
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Karyopherins
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NUP153 protein, human
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NUP214 protein, human
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Nuclear Pore Complex Proteins
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Nup153 protein, mouse
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Nup214 protein, mouse
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Peptide Fragments
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Receptors, Cytoplasmic and Nuclear
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SMAD2 protein, human
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Smad2 Protein
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Smad2 protein, mouse
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Trans-Activators
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Transforming Growth Factor beta