Reversible ubiquitination regulates the Smad/TGF-beta signalling pathway.
Reversible ubiquitination regulates the Smad/TGF-beta signalling pathway.
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发表时间：
2006
影响因子：
3.9
通讯作者：
Stephen J. Wicks;T. Grocott;Katherine Haros;M. Maillard;P. Dijke;Andrew Chantry
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文献类型：
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作者：
Stephen J. Wicks;T. Grocott;Katherine Haros;M. Maillard;P. Dijke;Andrew Chantry
tgf - β（转化生长因子- β）信号通过丝氨酸/苏氨酸激酶受体和细胞内Smad转录因子。一个重要的调控步骤涉及Smurfs （smad -泛素调节因子）的特异性泛素化，Smurfs是HECT （e6相关蛋白c端同源）泛素连接酶家族的成员，它介导smad和/或受体的蛋白酶体降解。最近，我们定义了Smads和UCH37（泛素c端水解酶37）之间的一种新的相互作用，UCH37是一种去泛素化酶，可以潜在地抵消smurf介导的泛素化。我们已经证明了UCH37与抑制性Smad7之间的特定相互作用，以及与Smad2和Smad3的较弱关联。重要的是，Smad7可以作为一个适配器，能够招募UCH37到I型tgf - β受体。因此，UCH37通过去泛素化和稳定I型tgf - β受体，显著上调tgf - β依赖基因的表达。我们的研究结果表明，泛素连接酶和dub与Smad7复合物的竞争作用可以在各种生理和病理条件下微调对tgf - β的反应。目前研究正在使用基于活性的HA（血凝素）标记的泛素探针来识别影响Smad/ tgf - β信号活性的全谱dub。
TGF-beta (transforming growth factor-beta) signals through serine/threonine kinase receptors and intracellular Smad transcription factors. An important regulatory step involves specific ubiquitination by Smurfs (Smad-ubiquitin regulatory factors), members of the HECT (homologous to E6-associated protein C-terminus) ubiquitin ligase family, which mediate the proteasomal degradation of Smads and/or receptors. Recently, we have defined a novel interaction between Smads and UCH37 (ubiquitin C-terminal hydrolase 37), a DUB (de-ubiquitinating enzyme) that could potentially counteract Smurf-mediated ubiquitination. We have demonstrated specific interactions between UCH37 and inhibitory Smad7, as well as weaker associations with Smad2 and Smad3. Importantly, Smad7 can act as an adaptor able to recruit UCH37 to the type I TGF-beta receptor. Consequently, UCH37 dramatically up-regulates TGF-beta-dependent gene expression by de-ubiquitinating and stabilizing the type I TGF-beta receptor. Our findings suggest that competing effects of ubiquitin ligases and DUBs in complex with Smad7 can serve to fine-tune responses to TGF-betas under various physiological and pathological conditions. Studies are currently under way using activity-based HA (haemagglutinin)-tagged ubiquitin probes to identify the full spectrum of DUBs that impact on Smad/TGF-beta signalling activity.