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.
Liu
X
X
Department of Surgery, Massachusetts General Hospital and Department of Genetics, Harvard Medical School, Boston, MA 02114, USA.
Elia
A E
AE
Law
S F
SF
Golemis
E A
EA
Farley
J
J
Wang
T
T
D048868:Adaptor Proteins, Signal Transducing; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000235:genetics; D009097:Multienzyme Complexes / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012441:Saccharomyces cerevisiae; D015398:Signal Transduction / Q000502:physiology*; D051900:Smad3 Protein; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000494:pharmacology / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D009097:Multienzyme Complexes; C099942:NEDD9 protein, human; D010750:Phosphoproteins; D011994:Recombinant Proteins; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D008156:Luciferases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex