A novel ability of Smad3 to regulate proteasomal degradation of a Cas family member HEF1.

Smad3 is a key signal transducer of transforming growth factor-ss (TGF-ss) and activin, and is known to be a DNA-binding transcriptional regulator. Here we report a novel property of Smad3 in regulating the proteasomal degradation of the human enhancer of filamentation 1 (HEF1), which is a member of the Cas ...
family of cytoplasmic docking proteins. Our studies revealed that Smad3 interacts with HEF1 and triggers the proteasomal degradation of HEF1 in overexpression systems. In addition, TGF-ss stimulation induces rapid proteasomal degradation of endogenous HEF1 in different TGF-ss-responsive cell lines. Interestingly, the degradation of HEF1 protein in epithelial cells is followed closely by an increase in HEF1 mRNA, resulting in a time-dependent increase in HEF1 protein level in TGF-ss-treated cells. Furthermore, we observed that an elevated HEF1 protein level inhibits TGF-ss-induced Smad3-mediated gene responses. These data provide the first evidence for a novel cytoplasmic activity of Smad3 in regulating proteasomal degradation of HEF1 and also suggest a role for HEF1 in a negative feedback mechanism of the TGF-ss signaling pathway.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Cell Line, Cysteine Endopeptidases, DNA-Binding Proteins, Epithelial Cells, Gene Expression Regulation, Genes, Reporter, Humans, Luciferases, Multienzyme Complexes, Phosphoproteins, Proteasome Endopeptidase Complex, Recombinant Proteins, Saccharomyces cerevisiae, Signal Transduction, Smad3 Protein, Trans-Activators, Transcription, Genetic, Transforming Growth Factor beta
EMBO J.
Date: Dec. 15, 2000
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