A novel link between the proteasome pathway and the signal transduction pathway of the bone morphogenetic proteins (BMPs).
BACKGROUND
The intracellular signaling events of the bone morphogenetic proteins (BMPs) involve the R-Smad family members Smad1, Smad5, Smad8 and the Co-Smad, Smad4. Smads are currently considered to be DNA-binding transcriptional modulators and shown to recruit the master transcriptional co-activator CBP/p300 for transcriptional activation. SNIP1 is a recently discovered novel repressor of CBP/p300. Currently, the detailed molecular mechanisms that allow R-Smads and Co-Smad to co-operatively modulate transcription events are not fully understood.


RESULTS
Here we report a novel physical and functional link between Smad1 and the 26S proteasome that contributes to Smad1- and Smad4-mediated transcriptional regulation. Smad1 forms a complex with a proteasome beta subunit HsN3 and the ornithine decarboxylase antizyme (Az). The interaction is enhanced upon BMP type I receptor activation and occur prior to the incorporation of HsN3 into the mature 20S proteasome. Furthermore, BMPs trigger the translocation of Smad1, HsN3 and Az into the nucleus, where the novel CBP/p300 repressor protein SNIP1 is further recruited to Smad1/HsN3/Az complex and degraded in a Smad1-, Smad4- and Az-dependent fashion. The degradation of the CBP/p300 repressor SNIP1 is likely an essential step for Smad1-, Smad4-mediated transcriptional activation, since increased SNIP1 expression inhibits BMP-induced gene responses.


CONCLUSIONS
Our studies thus add two additional important functional partners of Smad1 into the signaling web of BMPs and also suggest a novel mechanism for Smad1 and Smad4 to co-modulate transcription via regulating proteasomal degradation of CBP/p300 repressor SNIP1.
Lin
Yin
Y
Virginia Mason Research Center, 1201 Ninth Ave, Seattle WA 98101, USA. yinlinn@yahoo.com
Martin
Jennifer
J
Gruendler
Cornelia
C
Farley
Jennifer
J
Meng
Xianwang
X
Li
Bi-Yu
BY
Lechleider
Robert
R
Huff
Carla
C
Kim
Richard H
RH
Grasser
William A
WA
Paralkar
Vishwas
V
Wang
Tongwen
T
D000818:Animals; D015153:Blotting, Western; D055396:Bone Morphogenetic Protein 2; D052005:Bone Morphogenetic Protein Receptors, Type I; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D009097:Multienzyme Complexes / Q000378:metabolism*; D009154:Mutation; D011233:Precipitin Tests; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding / Q000187:drug effects; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins; D017978:Receptors, Growth Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins; D051898:Smad1 Protein; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta; D014407:Tumor Cells, Cultured; D020798:Two-Hybrid System Techniques
C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009097:Multienzyme Complexes; D011498:Protein Precursors; D016601:RNA-Binding Proteins; D017978:Receptors, Growth Factor; C497399:SMAD1 protein, human; C411545:SNIP1 protein, human; D051785:Smad Proteins; D051898:Smad1 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D052005:Bone Morphogenetic Protein Receptors, Type I; D003546:Cysteine Endopeptidases; C108898:PSMB4 protein, human; D046988:Proteasome Endopeptidase Complex