Wicks S J, Grocott T, Haros K, Maillard M, ten Dijke P, Chantry A
School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, UK.
Biochem Soc Trans. 2006 Nov;34(Pt 5):761-3. doi: 10.1042/BST0340761.
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.
转化生长因子-β（TGF-β）通过丝氨酸/苏氨酸激酶受体和细胞内Smad转录因子发出信号。一个重要的调控步骤涉及Smurf（Smad泛素调节因子）的特异性泛素化，Smurf是HECT（与E6相关蛋白C末端同源）泛素连接酶家族的成员，介导Smad和/或受体的蛋白酶体降解。最近，我们确定了Smad与UCH37（泛素C末端水解酶37）之间的一种新型相互作用，UCH37是一种去泛素化酶（DUB），可能会抵消Smurf介导的泛素化作用。我们已经证明UCH37与抑制性Smad7之间存在特异性相互作用，与Smad2和Smad3的结合较弱。重要的是，Smad7可以作为一种衔接蛋白，能够将UCH37招募到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依赖性基因表达。我们的研究结果表明，与Smad7结合的泛素连接酶和去泛素化酶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。目前正在进行研究，使用基于活性的带有血凝素（HA）标签的泛素探针来鉴定影响Smad/TGF-β信号活性的去泛素化酶的完整谱系。
