Nucleocytoplasmic shuttling of Smads 2, 3, and 4 permits sensing of TGF-beta receptor activity.
Transforming growth factor (TGF)-beta stimulation leads to phosphorylation and activation of Smad2 and Smad3, which form complexes with Smad4 that accumulate in the nucleus and regulate transcription of target genes. Here we demonstrate that, following TGF-beta stimulation of epithelial cells, receptors remain active for at least 3-4 hr, and continuous receptor activity is required to maintain active Smads in the nucleus and for TGF-beta-induced transcription. We show that continuous nucleocytoplasmic shuttling of the Smads during active TGF-beta signaling provides the mechanism whereby the intracellular transducers of the signal continuously monitor receptor activity. Our data therefore explain how, at all times, the concentration of active Smads in the nucleus is directly dictated by the levels of activated receptors in the cytoplasm.
Laboratory of Developmental Signalling, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, United Kingdom.
Gareth J
GJ
Inman
Francisco J
FJ
Nicolás
Caroline S
CS
Hill
D016475:3T3 Cells; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008954:Models, Biological; D010766:Phosphorylation; D011485:Protein Binding; D021381:Protein Transport; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein; D051900:Smad3 Protein; D051901:Smad4 Protein; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D004268:DNA-Binding Proteins; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; C497796:SMAD4 protein, human; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta