PPM1A 去磷酸化 RanBP3 以促进 Smad2 和 Smad3 的有效核输出。
PPM1A dephosphorylates RanBP3 to enable efficient nuclear export of Smad2 and Smad3.
机构信息
Department of Molecular & Cellular Biology, Texas A&M Health Sciences Center, Houston, Texas 77030, USA.
出版信息
EMBO Rep. 2011 Oct 28;12(11):1175-81. doi: 10.1038/embor.2011.174.
Abstract
Smad2 and Smad3 (Smad2/3) are essential signal transducers and transcription factors in the canonical transforming growth factor-β (TGF-β) signalling pathway. Active Smad2/3 signalling in the nucleus is terminated by dephosphorylation and subsequent nuclear export of Smad2/3. Here we report that protein phosphatase PPM1A regulates the nuclear export of Smad2/3 through targeting nuclear exporter RanBP3. PPM1A directly interacted with and dephosphorylated RanBP3 at Ser 58 in vitro and in vivo. Consistently, RanBP3 phosphorylation was elevated in PPM1A-null mouse embryonic fibroblasts. Dephosphorylation of RanBP3 at Ser 58 promoted its ability to export Smad2/3 and terminate TGF-β responses. Our findings indicate the critical role of PPM1A in maximizing exporter activity of RanBP3 for efficient termination of canonical TGF-β signalling.
摘要
Smad2 和 Smad3（Smad2/3）是经典转化生长因子-β（TGF-β）信号通路中的必需信号转导蛋白和转录因子。Smad2/3 的活性信号在细胞核中通过磷酸化和随后的 Smad2/3 核输出而终止。在这里，我们报告蛋白磷酸酶 PPM1A 通过靶向核输出 RanBP3 来调节 Smad2/3 的核输出。PPM1A 在体外和体内均直接与核输出 RanBP3 相互作用，并使其第 58 位丝氨酸磷酸化。一致地，PPM1A 缺失的小鼠胚胎成纤维细胞中的 RanBP3 磷酸化水平升高。RanBP3 第 58 位丝氨酸的去磷酸化促进了其将 Smad2/3 输出并终止 TGF-β 反应的能力。我们的研究结果表明 PPM1A 在最大限度地提高 RanBP3 的输出活性以有效终止经典 TGF-β 信号转导方面起着关键作用。
相似文献
1
PPM1A dephosphorylates RanBP3 to enable efficient nuclear export of Smad2 and Smad3.PPM1A 去磷酸化 RanBP3 以促进 Smad2 和 Smad3 的有效核输出。
EMBO Rep. 2011 Oct 28;12(11):1175-81. doi: 10.1038/embor.2011.174.
2
Nuclear export of Smad2 and Smad3 by RanBP3 facilitates termination of TGF-beta signaling.RanBP3介导的Smad2和Smad3的核输出促进TGF-β信号传导的终止。
Dev Cell. 2009 Mar;16(3):345-57. doi: 10.1016/j.devcel.2009.01.022.
3
Inhibition of TGF-β signaling at the nuclear envelope: characterization of interactions between MAN1, Smad2 and Smad3, and PPM1A.核膜上 TGF-β 信号的抑制：MAN1、Smad2 和 Smad3 与 PPM1A 之间相互作用的特征。
Sci Signal. 2013 Jun 18;6(280):ra49. doi: 10.1126/scisignal.2003411.
4
Opposite effects of dihydrosphingosine 1-phosphate and sphingosine 1-phosphate on transforming growth factor-beta/Smad signaling are mediated through the PTEN/PPM1A-dependent pathway.二氢神经鞘氨醇1-磷酸酯和神经鞘氨醇1-磷酸酯对转化生长因子-β/Smad信号传导的相反作用是通过PTEN/PPM1A依赖性途径介导的。
J Biol Chem. 2008 Jul 11;283(28):19593-602. doi: 10.1074/jbc.M802417200. Epub 2008 May 15.
5
PPM1A functions as a Smad phosphatase to terminate TGFbeta signaling.PPM1A作为一种Smad磷酸酶发挥作用，以终止转化生长因子β信号传导。
Cell. 2006 Jun 2;125(5):915-28. doi: 10.1016/j.cell.2006.03.044.
6
Protein phosphatase 5 modulates SMAD3 function in the transforming growth factor-β pathway.蛋白磷酸酶 5 调节转化生长因子-β 通路中 SMAD3 的功能。
Cell Signal. 2012 Nov;24(11):1999-2006. doi: 10.1016/j.cellsig.2012.07.003. Epub 2012 Jul 7.
7
Redox-induced Src kinase and caveolin-1 signaling in TGF-β1-initiated SMAD2/3 activation and PAI-1 expression.氧化还原诱导的 Src 激酶和小窝蛋白-1 信号转导在 TGF-β1 引发的 SMAD2/3 激活和 PAI-1 表达中的作用。
PLoS One. 2011;6(7):e22896. doi: 10.1371/journal.pone.0022896. Epub 2011 Jul 28.
8
Coupling of dephosphorylation and nuclear export of Smads in TGF-beta signaling.TGF-β信号通路中Smads的去磷酸化与核输出偶联
Methods Mol Biol. 2010;647:125-37. doi: 10.1007/978-1-60761-738-9_7.
9
Loss of PPM1A expression enhances invasion and the epithelial-to-mesenchymal transition in bladder cancer by activating the TGF-β/Smad signaling pathway.PPM1A表达缺失通过激活TGF-β/Smad信号通路增强膀胱癌的侵袭及上皮-间质转化。
Oncotarget. 2014 Jul 30;5(14):5700-11. doi: 10.18632/oncotarget.2144.
10
PPM1A suppresses the proliferation and invasiveness of RCC cells via Smad2/3 signaling inhibition.PPM1A通过抑制Smad2/3信号传导来抑制肾癌细胞的增殖和侵袭能力。
J Recept Signal Transduct Res. 2021 Jun;41(3):245-254. doi: 10.1080/10799893.2020.1806316. Epub 2020 Sep 2.
引用本文的文献
1
Suppression of TGF-β/SMAD signaling by an inner nuclear membrane phosphatase complex.内核膜磷酸酶复合物对TGF-β/SMAD信号通路的抑制作用。
Nat Commun. 2025 Apr 11;16(1):3474. doi: 10.1038/s41467-025-58681-x.
2
Cytoplasmic Aggregates of Splicing Factor Proline-Glutamine Rich Disrupt Nucleocytoplasmic Transport and Induce Persistent Stress Granules.富含脯氨酸-谷氨酰胺的剪接因子的细胞质聚集体破坏核质运输并诱导持续性应激颗粒形成。
J Cell Mol Med. 2024 Dec;28(23):e70261. doi: 10.1111/jcmm.70261.
3
CGMega: explainable graph neural network framework with attention mechanisms for cancer gene module dissection.CGMega：具有注意力机制的可解释图神经网络框架，用于癌症基因模块剖析。
Nat Commun. 2024 Jul 17;15(1):5997. doi: 10.1038/s41467-024-50426-6.
4
Targeting SMAD-Dependent Signaling: Considerations in Epithelial and Mesenchymal Solid Tumors.靶向SMAD依赖信号传导：上皮性和间叶性实体瘤的相关考量
Pharmaceuticals (Basel). 2024 Mar 1;17(3):326. doi: 10.3390/ph17030326.
5
The protein phosphatase PPM1A dephosphorylates and activates YAP to govern mammalian intestinal and liver regeneration.蛋白磷酸酶 PPM1A 去磷酸化并激活 YAP 以调控哺乳动物的肠道和肝脏再生。
PLoS Biol. 2021 Feb 25;19(2):e3001122. doi: 10.1371/journal.pbio.3001122. eCollection 2021 Feb.
6
Leveraging New Definitions of the LxVP SLiM To Discover Novel Calcineurin Regulators and Substrates.利用 LxVP SLiM 的新定义发现新型钙调神经磷酸酶调节剂和底物。
ACS Chem Biol. 2019 Dec 20;14(12):2672-2682. doi: 10.1021/acschembio.9b00606. Epub 2019 Nov 1.
7
Rotavirus Induces Formation of Remodeled Stress Granules and P Bodies and Their Sequestration in Viroplasms To Promote Progeny Virus Production.轮状病毒诱导形成重塑的应激颗粒和 P 体，并将其隔离在类病毒体中，以促进子代病毒的产生。
J Virol. 2018 Nov 27;92(24). doi: 10.1128/JVI.01363-18. Print 2018 Dec 15.
8
FHL3 links cell growth and self-renewal by modulating SOX4 in glioma.FHL3 通过调节 SOX4 在神经胶质瘤中连接细胞生长和自我更新。
Cell Death Differ. 2019 May;26(5):796-811. doi: 10.1038/s41418-018-0152-1. Epub 2018 Jun 28.
9
Posttranslational Regulation of Smads.Smads的翻译后调控
Cold Spring Harb Perspect Biol. 2016 Dec 1;8(12):a022087. doi: 10.1101/cshperspect.a022087.
10
PPM1A silences cytosolic RNA sensing and antiviral defense through direct dephosphorylation of MAVS and TBK1.PPM1A 通过直接去磷酸化 MAVS 和 TBK1 来沉默细胞质 RNA 感应和抗病毒防御。
Sci Adv. 2016 Jul 1;2(7):e1501889. doi: 10.1126/sciadv.1501889. eCollection 2016 Jul.
本文引用的文献
1
Nuclear export of Smad2 and Smad3 by RanBP3 facilitates termination of TGF-beta signaling.RanBP3介导的Smad2和Smad3的核输出促进TGF-β信号传导的终止。
Dev Cell. 2009 Mar;16(3):345-57. doi: 10.1016/j.devcel.2009.01.022.
2
Tgf-beta superfamily signaling in embryonic development and homeostasis.胚胎发育与内环境稳定中的转化生长因子-β超家族信号传导
Dev Cell. 2009 Mar;16(3):329-43. doi: 10.1016/j.devcel.2009.02.012.
3
Mechanism of TGF-beta signaling to growth arrest, apoptosis, and epithelial-mesenchymal transition.转化生长因子-β信号传导至生长停滞、细胞凋亡及上皮-间质转化的机制。
Curr Opin Cell Biol. 2009 Apr;21(2):166-76. doi: 10.1016/j.ceb.2009.01.021. Epub 2009 Feb 23.
4
Nucleocytoplasmic shuttling of Smad proteins.Smad蛋白的核质穿梭
Cell Res. 2009 Jan;19(1):36-46. doi: 10.1038/cr.2008.325.
5
TGFbeta in Cancer.癌症中的转化生长因子β
Cell. 2008 Jul 25;134(2):215-30. doi: 10.1016/j.cell.2008.07.001.
6
Ran-binding protein 3 phosphorylation links the Ras and PI3-kinase pathways to nucleocytoplasmic transport.Ran结合蛋白3磷酸化将Ras和PI3激酶途径与核质运输联系起来。
Mol Cell. 2008 Feb 15;29(3):362-75. doi: 10.1016/j.molcel.2007.12.024.
7
PPM1A functions as a Smad phosphatase to terminate TGFbeta signaling.PPM1A作为一种Smad磷酸酶发挥作用，以终止转化生长因子β信号传导。
Cell. 2006 Jun 2;125(5):915-28. doi: 10.1016/j.cell.2006.03.044.
8
The mechanism of nuclear export of Smad3 involves exportin 4 and Ran.Smad3的核输出机制涉及输出蛋白4和Ran。
Mol Cell Biol. 2006 Feb;26(4):1318-32. doi: 10.1128/MCB.26.4.1318-1332.2006.
9
Smad transcription factors.Smad转录因子。
Genes Dev. 2005 Dec 1;19(23):2783-810. doi: 10.1101/gad.1350705.
10
RanBP3 enhances nuclear export of active (beta)-catenin independently of CRM1.RanBP3 可独立于 CRM1 增强活性 β-连环蛋白的核输出。
J Cell Biol. 2005 Dec 5;171(5):785-97. doi: 10.1083/jcb.200502141. Epub 2005 Nov 28.
Zotero 插件