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A novel link between the proteasome pathway and the signal transduction pathway of the Bone Morphogenetic Proteins (BMPs)

Yin Lin4, Jennifer Martin1, Cornelia Gruendler1, Jennifer Farley1, Xianwang Meng1, Bi-Yu Li1, Robert Lechleider3, Carla Huff3, Richard H Kim3, William Grasser2, Vishwas Paralkar2 and Tongwen Wang1*

Author affiliations

1 From Virginia Mason Research Center, 1201 Ninth Ave., Seattle WA 98101; Department of Immunology, University of Washington, Seattle, WA 98195; Department of Surgery/Genetics, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA

2 Dept. of Cardiovascular/Metabolic Diseases, Pfizer Inc., Eastern Point Rd., Groton, CT 06340, USA

3 Laboratory of Chemoprevention, National Cancer Institute, 9000 Rockville Pike, 41/C629, Bethesda, Maryland 20892, USA

4 Department of Molecular Genetics and Biochemistry, University of Pittsburgh, Medical school, PA15213, USA

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Citation and License

BMC Cell Biology 2002, 3:15  doi:10.1186/1471-2121-3-15

Published: 21 June 2002



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.


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 β 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.


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.