Regulation of intracellular dynamics of Smad4 by its leucine-rich nuclear export signal.
Smad family proteins play a pivotal role in transmitting the transforming growth factor-beta (TGF-beta) superfamily signals from the cell surface to the nucleus. In response to ligand stimulation, Smad4 forms a complex with respective receptor-specific Smads, and the complex translocates into the nucleus and regulates gene expression. Thus, the nuclear entry of the Smad complex is one of the key steps in signal transduction. However, little is known about regulatory mechanisms for nucleocytoplasmic transport of Smads. Here we report identification of a functional, leucine-rich nuclear export signal (NES) in Smad4, which regulates subcellular distribution of Smad4. We then show evidence suggesting that the NES-dependent cytoplasmic localization of Smad4 is important for ensuring optimal TGF-beta responsivenesses in transcriptional activation. Moreover, we show that the NES of Smad4 is specifically inactivated by the stimulus-dependent hetero-oligomerization with receptor-specific Smads during the TGF-beta-induced nuclear translocation of Smad4. Taken together, these results suggest an important regulatory role of the NES of Smad4 in TGF-beta signaling.
Department of Biophysics, Graduate School of Science, Kyoto University, Japan.
M
M
Watanabe
N
N
Masuyama
M
M
Fukuda
E
E
Nishida
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D020816:Amino Acid Motifs; D002467:Cell Nucleus / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D008856:Microscopy, Fluorescence; D021382:Protein Sorting Signals; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051901:Smad4 Protein; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism
D004268:DNA-Binding Proteins; D021382:Protein Sorting Signals; D011993:Recombinant Fusion Proteins; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta