Smad2 nucleocytoplasmic shuttling by nucleoporins CAN/Nup214 and Nup153 feeds TGFbeta signaling complexes in the cytoplasm and nucleus.
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.
Cell Biology Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Lan
L
Xu
Yibin
Y
Kang
Seda
S
Cöl
Joan
J
Massagué
D016475:3T3 Cells; D021581:Active Transport, Cell Nucleus; D000818:Animals; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D028884:Karyopherins / Q000378:metabolism; D051379:Mice; D022022:Nuclear Pore / Q000378:metabolism; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D018160:Receptors, Cytoplasmic and Nuclear; D015398:Signal Transduction; D051899:Smad2 Protein; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D000097606:Exportin 1 Protein
D004268:DNA-Binding Proteins; D028884:Karyopherins; D028861:Nuclear Pore Complex Proteins; D010446:Peptide Fragments; D018160:Receptors, Cytoplasmic and Nuclear; D051899:Smad2 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D000097606:Exportin 1 Protein; C079377:NUP153 protein, human; C085914:NUP214 protein, human; C513084:Nup153 protein, mouse; C490093:Nup214 protein, mouse; C497782:SMAD2 protein, human; C497783:Smad2 protein, mouse