| Structural highlights
Function
SMUF1_HUMAN E3 ubiquitin-protein ligase that acts as a negative regulator of BMP signaling pathway. Mediates ubiquitination and degradation of SMAD1 and SMAD5, 2 receptor-regulated SMADs specific for the BMP pathway. Promotes ubiquitination and subsequent proteasomal degradation of TRAF family members and RHOA.[1] [2] [3]
Publication Abstract from PubMed
When directed to the nucleus by TGF-beta or BMP signals, Smad proteins undergo cyclin-dependent kinase 8/9 (CDK8/9) and glycogen synthase kinase-3 (GSK3) phosphorylations that mediate the binding of YAP and Pin1 for transcriptional action, and of ubiquitin ligases Smurf1 and Nedd4L for Smad destruction. Here we demonstrate that there is an order of events-Smad activation first and destruction later-and that it is controlled by a switch in the recognition of Smad phosphoserines by WW domains in their binding partners. In the BMP pathway, Smad1 phosphorylation by CDK8/9 creates binding sites for the WW domains of YAP, and subsequent phosphorylation by GSK3 switches off YAP binding and adds binding sites for Smurf1 WW domains. Similarly, in the TGF-beta pathway, Smad3 phosphorylation by CDK8/9 creates binding sites for Pin1 and GSK3, then adds sites to enhance Nedd4L binding. Thus, a Smad phosphoserine code and a set of WW domain code readers provide an efficient solution to the problem of coupling TGF-beta signal delivery to turnover of the Smad signal transducers.
A Smad action turnover switch operated by WW domain readers of a phosphoserine code.,Aragon E, Goerner N, Zaromytidou AI, Xi Q, Escobedo A, Massague J, Macias MJ Genes Dev. 2011 Jun 15;25(12):1275-88. PMID:21685363[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Zhu H, Kavsak P, Abdollah S, Wrana JL, Thomsen GH. A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation. Nature. 1999 Aug 12;400(6745):687-93. PMID:10458166 doi:10.1038/23293
- ↑ Li S, Lu K, Wang J, An L, Yang G, Chen H, Cui Y, Yin X, Xie P, Xing G, He F, Zhang L. Ubiquitin ligase Smurf1 targets TRAF family proteins for ubiquitination and degradation. Mol Cell Biochem. 2010 May;338(1-2):11-7. doi: 10.1007/s11010-009-0315-y. Epub, 2009 Nov 24. PMID:19937093 doi:10.1007/s11010-009-0315-y
- ↑ Lu K, Li P, Zhang M, Xing G, Li X, Zhou W, Bartlam M, Zhang L, Rao Z, He F. Pivotal role of the C2 domain of the Smurf1 ubiquitin ligase in substrate selection. J Biol Chem. 2011 May 13;286(19):16861-70. Epub 2011 Mar 14. PMID:21402695 doi:10.1074/jbc.M110.211979
- ↑ Aragon E, Goerner N, Zaromytidou AI, Xi Q, Escobedo A, Massague J, Macias MJ. A Smad action turnover switch operated by WW domain readers of a phosphoserine code. Genes Dev. 2011 Jun 15;25(12):1275-88. PMID:21685363 doi:10.1101/gad.2060811
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