Early phase TGFβ receptor signalling dynamics stabilised by the deubiquitinase UCH37 promotes cell migratory responses
Early phase TGFβ receptor signalling dynamics stabilised by the deubiquitinase UCH37 promotes cell migratory responses
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DOI：
10.1016/j.biocel.2010.12.018
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发表时间：
2011-04-01
影响因子：
4
通讯作者：
Chantry, Andrew
中科院分区：
文献类型：
--
作者：
Cutts, Anthony J.;Soond, Surinder M.;Chantry, Andrew
TGF β通过丝/苏激酶受体和细胞内Smad转录因子发出信号。一个重要的调节步骤涉及通过特异性泛素连接酶对Smads和/或TGF β受体的泛素化，该过程可以被去泛素化酶UCH 37逆转。这里，为了探索UCH 37在TGF β信号传导中的生理作用，我们产生了稳定的和可诱导的HaCAT角质形成细胞和错误表达UCH 37的科洛-357胰腺癌细胞系。我们发现，UCH 37敲低显著抑制TGF β依赖性基因报告基因的活性，并选择性降低一些TGF β依赖性靶基因的水平，特别是p21和派-1，但仅在TGF β受体活化的早期阶段。有趣的是，在科洛-357细胞中敲低UCH 37对TGF β依赖的细胞增殖和上皮-间质转化没有影响，但显著损害了细胞迁移。总的来说，我们的数据表明，UCH 37维持早期TGF β途径活化动力学，决定阈值特异性基因表达模式，并且泛素连接酶和去泛素化酶的相反作用影响不同的生物学TGF β依赖性生物反应。此外，我们认为UCH 37可能是新型和选择性癌症治疗的可行靶点。(C)2010爱思唯尔有限公司版权所有。
TGF beta signals through serine/threonine kinase receptors and intracellular Smad transcription factors. An important regulatory step involves ubiquitination of Smads and/or TGF beta receptors by specific ubiquitin ligases, in a process that can be reversed by the deubiquitinating enzyme UCH37. Here, to explore the physiological role of UCH37 in TGF beta signalling we have generated stable and inducible HaCAT keratinocyte and Colo-357 pancreatic carcinoma cell lines mis-expressing UCH37. We show that UCH37 knockdown significantly inhibits the activity of a TGF beta-dependent gene reporter and selectively decreases levels of some TGF beta-dependent target genes, notably p21 and PAI-1, but only during the early phase of TGF beta receptor activation. Interestingly, UCH37 knockdown in Colo-357 cells had no effect on TGF beta-dependent cell proliferation and epithelial-mesenchymal transition, yet significantly impaired cell migration. Collectively, our data indicate that UCH37 sustains early TGF beta pathway activation kinetics that determines threshold-specific gene expression patterns, and that opposing actions of ubiquitin ligases and deubiquitinases influences distinct biological TGF beta-dependent biological responses. Moreover, we suggest that UCH37 could represent a viable target for novel and selective cancer therapeutics. (C) 2010 Elsevier Ltd. All rights reserved.