Sorting nexin 9 differentiates ligand-activated Smad3 from Smad2 for nuclear import and transforming growth factor β signaling.
Transforming growth factor β (TGFβ) is a pleiotropic protein secreted from essentially all cell types and primary tissues. While TGFβ's actions reflect the activity of a number of signaling networks, the primary mediator of TGFβ responses are the Smad proteins. Following receptor activation, these cytoplasmic proteins form hetero-oligomeric complexes that translocate to the nucleus and affect gene transcription. Here, through biological, biochemical, and immunofluorescence approaches, sorting nexin 9 (SNX9) is identified as being required for Smad3-dependent responses. SNX9 interacts with phosphorylated (p) Smad3 independent of Smad2 or Smad4 and promotes more rapid nuclear delivery than that observed independent of ligand. Although SNX9 does not bind nucleoporins Nup153 or Nup214 or some β importins (Imp7 or Impβ), it mediates the association of pSmad3 with Imp8 and the nuclear membrane. This facilitates nuclear translocation of pSmad3 but not SNX9.
Thoracic Diseases Research Unit, Department of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905.
Mark C
MC
Wilkes
Thoracic Diseases Research Unit, Department of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905.
Claire E
CE
Repellin
Thoracic Diseases Research Unit, Department of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905.
Jeong-Han
JH
Kang
Thoracic Diseases Research Unit, Department of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905.
Mahefatiana
M
Andrianifahanana
Thoracic Diseases Research Unit, Department of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905.
Xueqian
X
Yin
Thoracic Diseases Research Unit, Department of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905 leof.edward@mayo.edu.
Edward B
EB
Leof
D021581:Active Transport, Cell Nucleus; D000818:Animals; D018929:Cell Culture Techniques; D002467:Cell Nucleus / Q000378:metabolism; D006801:Humans; D028884:Karyopherins / Q000378:metabolism; D008024:Ligands; D051379:Mice; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D021381:Protein Transport; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D051899:Smad2 Protein / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism*; D051901:Smad4 Protein / Q000378:metabolism; D058305:Sorting Nexins / Q000235:genetics* / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
D028884:Karyopherins; D008024:Ligands; D028861:Nuclear Pore Complex Proteins; C497782:SMAD2 protein, human; C400533:SNX9 protein, human; D051785:Smad Proteins; D051899:Smad2 Protein; D051900:Smad3 Protein; D051901:Smad4 Protein; D058305:Sorting Nexins; D015534:Trans-Activators; D016212:Transforming Growth Factor beta