Transforming growth factor beta1 induces nuclear export of inhibitory Smad7.
Transforming growth factor beta (TGF-beta) signals from membrane to nucleus through serine/threonine kinase receptors and their downstream effector molecules, termed Smad proteins. Recently, Smad6 and Smad7 were identified, which antagonize TGF-beta family signaling by preventing the activation of signal-transducing Smad complexes. Here we report that Smad7, but not Smad6, inhibits TGF-beta1-induced growth inhibition and the expression of immediate early response genes, including Smad7. Interestingly, in the absence of ligand, Smad7 was found to be predominantly localized in the nucleus, whereas Smad7 accumulated in the cytoplasm upon TGF-beta receptor activation. The latter is in accordance with the physical association of Smad7 with the ligand-activated TGF-beta receptor complex in the cell membrane. Whereas the ectopically expressed C-terminal domain of Smad7 was also exported from the nucleus to the cytoplasm upon TGF-beta challenge, a Smad7 mutant with a small deletion at the C terminus or only the N-terminal domain of Smad7 was localized mainly in the cytoplasm in the absence or presence of ligand. This suggests that an intact Mad homology 2 domain is important for nuclear localization of Smad7. The nuclear localization of Smad7 suggests a functional role distinct from its antagonistic effect in receptor-mediated Smad activation.
Itóh
S
S
Ludwig Institute for Cancer Research, Biomedical Center Box 595, S-751 24 Uppsala, Sweden.
Landström
M
M
Hermansson
A
A
Itoh
F
F
Heldin
C H
CH
Heldin
N E
NE
ten Dijke
P
P
D000818:Animals; D001692:Biological Transport; D019556:COS Cells; D002455:Cell Division / Q000502:physiology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D008907:Mink; D017384:Sequence Deletion; D015398:Signal Transduction / Q000502:physiology; D051906:Smad7 Protein; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000502:physiology*
D004268:DNA-Binding Proteins; D051906:Smad7 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta