Figure 10

Mechanisms and functions of proteasomal targeting of Smad1 in signaling pathways of BMPs. A. A cartoon to illustrate a novel mechanism for BMP-induced proteasomal targeting of Smad1 induced by BMPs. The activation of BMP type I receptor enhances the interaction between Smad1 and two other proteins Az and HsN3. The newly synthesized HsN3 is in its prosequence-containing form, which forms a ternary complex with Smad1 and Az. The assembly of HsN3 brings Smad1 and Az to assembly intermediates (see step 3). The final maturation of the 20S proteasome may lead to the unfolding and trapping of Smad1 inside the degradation chamber and the ultimate proteasomal degradation of Smad1. Alternatively, Smad1/Az complex may be docked to a receptor of Az on 19S complex for the final delivery of Smad1 to proteasome for degradation. Two other proteins, UMP1 and Hsp73, which are known to be associated with proteasome assembly intermediates, are also shown. Upon the assembly of 20S proteasome, UMP1 is trapped inside of the 20S proteasome for degradation [46]. Hsp73 may play a role in unfolding proteins [35]. B. A cartoon to illustrate proteasomal targeting of Smad1 as an integral event along the signaling pathways of BMPs. The activation of the BMP type I receptor is proceeded by type II receptor-mediated phosphorylation of the type I receptor and by the dissociation of the cytoplasmic inhibitor FKBP12 from the type I receptor. The activated type I receptor induces Smad1 phosphorylation and the subsequent formation of a complex of Smad1, Smad4, Az and HsN3, which is in its pre-assembled form containing the prosequence. The complex is then translocated into the nucleus, where Smad1 and Smad4 are recruited to specific DNA-binding sites near those of other DNA-binding transcription factors (DBs). In cells where most of the CBP/p300 is bound to SNIP1, the removal of SNIP1 from CBP/p300 may be a critical step for the successful recruitment of CBP/p300 to DBs. One way to remove SNIP1 could be via the recruitment of SNIP1 to Az and HsN3 in the complex containing Smad1 and Smad4. The targeting of Smad1 to proteasome, as illustrated in panel A, could then mediate the co-targeting of SNIP1 to proteasome for degradation. The removal of SNIP1 then allows the subsequent recruitment of CBP/p300 to DBs for transcription. Possible cytoplasmic targeting of Smad1-containing complex via HsN3 assembly pathway is also suggested. See text for details.