PDLIM5 inhibits STUB1-mediated degradation of SMAD3 and promotes the migration and invasion of lung cancer cells
PDLIM5 inhibits STUB1-mediated degradation of SMAD3 and promotes the migration and invasion of lung cancer cells
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PDLIM5抑制STUB1介导的SMAD3降解并促进肺癌细胞的迁移和侵袭
DOI：
10.1074/jbc.ra120.014976
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发表时间：
2020-10-02
影响因子：
4.8
通讯作者：
Cheng, Hongqiang
中科院分区：
文献类型：
--
作者：
Shi, Yueli;Wang, Xinyu;Cheng, Hongqiang
转化生长因子β（TGF β）信号传导在调节肿瘤恶性程度中起重要作用，包括在非小细胞肺癌（NSCLC）中。TGF β信号传导的主要生物学应答由效应蛋白SMAD 2和SMAD 3决定。然而，TGF β-SMAD信号转导的调节因子尚未完全揭示。在这里，我们发现支架蛋白PDLIM 5（PDZ和LIM结构域蛋白5，ENH）通过维持SMAD 3在NSCLC中的稳定性来促进TGF β信号传导。首先，PDLIM 5在NSCLC中的表达高于癌旁正常组织，PDLIM 5高表达与预后不良相关。在NSCLC细胞中PDLIM 5的敲低降低了体外的迁移和侵袭以及体内的肺转移。此外，TGF β信号传导和TGF β诱导的上皮-间充质转化被PDLIM 5敲低所抑制。从机制上讲，PDLIM 5敲低导致SMAD 3蛋白水平降低。SMAD 3的过表达逆转了PDLIM 5敲低诱导的TGF β信号转导抑制和抗迁移作用。值得注意的是，PDLIM 5与SMAD 3相互作用，但不与SMAD 2相互作用，并竞争性抑制SMAD 3与其E3泛素连接酶STUB 1之间的相互作用。因此，PDLIM 5保护SMAD 3免受STUB 1介导的蛋白酶体降解。STUB 1敲除恢复了PDLIM 5敲除细胞中SMAD 3蛋白水平、细胞迁移和侵袭。总的来说，我们的研究结果表明PDLIM 5是基础SMAD 3稳定性的一种新型调节剂，对控制TGF β信号传导和NSCLC进展具有意义。
Transforming growth factor beta (TGF beta) signaling plays an important role in regulating tumor malignancy, including in non-small cell lung cancer (NSCLC). The major biological responses of TGF beta signaling are determined by the effector proteins SMAD2 and SMAD3. However, the regulators of TGF beta-SMAD signaling are not completely revealed yet. Here, we showed that the scaffolding protein PDLIM5 (PDZ and LIM domain protein 5, ENH) critically promotes TGF beta signaling by maintaining SMAD3 stability in NSCLC. First, PDLIM5 was highly expressed in NSCLC compared with that in adjacent normal tissues, and high PDLIM5 expression was associated with poor outcome. Knockdown of PDLIM5 in NSCLC cells decreased migration and invasionin vitroand lung metastasisin vivo. In addition, TGF beta signaling and TGF beta-induced epithelial-mesenchymal transition was repressed by PDLIM5 knockdown. Mechanistically, PDLIM5 knockdown resulted in a reduction of SMAD3 protein levels. Overexpression of SMAD3 reversed the TGF beta-signaling-repressing and anti-migration effects induced by PDLIM5 knockdown. Notably, PDLIM5 interacted with SMAD3 but not SMAD2 and competitively suppressed the interaction between SMAD3 and its E3 ubiquitin ligase STUB1. Therefore, PDLIM5 protected SMAD3 from STUB1-mediated proteasome degradation. STUB1 knockdown restored SMAD3 protein levels, cell migration, and invasion in PDLIM5-knockdown cells. Collectively, our findings indicate that PDLIM5 is a novel regulator of basal SMAD3 stability, with implications for controlling TGF beta signaling and NSCLC progression.