更新于：2024-09-19

SMURF1

更新于：2024-09-19

基本信息

别名

E3 ubiquitin-protein ligase SMURF1、HECT-type E3 ubiquitin transferase SMURF1、hSMURF1

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简介

E3 ubiquitin-protein ligase that acts as a negative regulator of BMP signaling pathway. Mediates ubiquitination and degradation of SMAD1 and SMAD5, 2 receptor-regulated SMADs specific for the BMP pathway. Promotes ubiquitination and subsequent proteasomal degradation of TRAF family members and RHOA. Promotes ubiquitination and subsequent proteasomal degradation of MAVS (PubMed:23087404). Acts as an antagonist of TGF-beta signaling by ubiquitinating TGFBR1 and targeting it for degradation (PubMed:21791611). Plays a role in dendrite formation by melanocytes (PubMed:23999003).

关联

项与 SMURF1 相关的药物

LTP-001

靶点

SMURF1

作用机制

SMURF1拮抗剂

在研机构

Novartis Pharmaceuticals Corp.

原研机构

Novartis AG

在研适应症

特发性肺纤维化

非在研适应症

肺动脉高压

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

项与 SMURF1 相关的临床试验

NCT05764265 / Terminated临床2期

An Open-label Extension Study to Investigate Efficacy, Safety and Tolerability of LTP001 in Participants With Pulmonary Arterial Hypertension

The purpose of this study is to measure the long-term safety and efficacy profile of LTP001 in participants with pulmonary arterial hypertension (PAH). The study offers participants who had completed the CLTP001A12201 double-blind parent study in PAH an opportunity to receive LTP001 (whether they were on LTP001 or not). Unblinding of the treatment received in CLTP001A12201 is generally not needed, but can occur on request by the investigator.

开始日期2023-03-27

申办/合作机构

Novartis Pharmaceuticals Corp.

NCT05497284 / Active, not recruiting临床2期

A Participant- and Investigator-blinded, Randomized, Placebo-controlled, Multicenter, Platform Study to Investigate Efficacy, Safety, and Tolerability of Various Single Treatments in Participants With Idiopathic Pulmonary Fibrosis

A participant- and investigator-blinded, randomized, placebo-controlled, multicenter, platform study to investigate efficacy, safety, and tolerability of various single treatments in participants with idiopathic pulmonary fibrosis

开始日期2022-11-10

申办/合作机构

Novartis Pharmaceuticals Corp.

NCT05135000 / Terminated临床2期

A Randomized, Participant- and Investigator-blinded, Placebo-controlled Study to Investigate Efficacy, Safety, and Tolerability of LTP001 in Participants With Pulmonary Arterial Hypertension

The purpose of this study is to explore the efficacy and safety of LTP001 in participants with pulmonary arterial hypertension (PAH) to determine if LTP001 has an adequate clinical profile to warrant further clinical development in this indication.

开始日期2022-06-30

申办/合作机构

Novartis Pharmaceuticals Corp.

100 项与 SMURF1 相关的临床结果

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100 项与 SMURF1 相关的转化医学

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0 项与 SMURF1 相关的专利（医药）

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456

项与 SMURF1 相关的文献（医药）

2024-10-01·Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

E3 ubiquitin ligases SMURF1 and HECW1 regulate hepcidin-induced degradation of ferroportin in HeLa cells

Article

作者: Lemberg, Marius K ; Marques, Oriana ; Knopf, Julia D ; Link, Camille J ; Muckenthaler, Martina U

2024-10-01·Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

AMPK induces PIAS3 mediated SUMOylation of E3 ubiquitin ligase Smurf1 impairing osteogenic differentiation and traumatic heterotopic ossification

Article

作者: Dang, Yan-Miao ; Xiong, Lixia ; Gao, Linqing ; Liu, Meng-Chao ; Lin, Hui ; Guan, Tianshu ; Hu, Anxin ; Chen, Jie

AMP-activated protein kinase (AMPK) is a typical sensor of intracellular energy metabolism. Our previous study revealed the role of activated AMPK in the suppression of osteogenic differentiation and traumatic heterotopic ossification, but the underlying mechanism remains poorly understood. The E3 ubiquitin ligase Smurf1 is a crucial regulator of osteogenic differentiation and bone formation. We report here that Smurf1 is primarily SUMOylated at a C-terminal lysine residue (K324), which enhances its activity, facilitating ALK2 proteolysis and subsequent bone morphogenetic protein (BMP) signaling pathway inhibition. Furthermore, SUMOylation of the SUMO E3 ligase PIAS3 and Smurf1 SUMOylation was suppressed during the osteogenic differentiation and traumatic heterotopic ossification. More importantly, we found that AMPK activation enhances the SUMOylation of Smurf1, which is mediated by PIAS3 and increases the association between PIAS3 and AMPK. Overall, our study revealed that Smurf1 can be SUMOylated by PIAS3, Furthermore, Smurf1 SUMOylation mediates osteogenic differentiation and traumatic heterotopic ossification through suppression of the BMP signaling pathway. This study revealed that promotion of Smurf1 SUMOylation by AMPK activation may be implicated in traumatic heterotopic ossification treatment.

2024-08-01·Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

Exosomes secreted by adipose mesenchymal stem cells overexpressing circPIP5K1C exert

Article

作者: Xu, Bin ; Li, Wengfeng ; Mao, Yuanshen ; Wang, Jiangyi ; Lu, Chao ; Gu, Xin ; Hua, Bao ; Liang, Li ; Yang, Qing

BACKGROUNDErectile dysfunction (ED) seriously affects men's normal life, and obstructive sleep apnoea (OSA) has been diagnosed as a causative factor. Currently, exosomes secreted by adipose mesenchymal stem cells (ADSC) have been used in the non-clinical experimental treatment of ED disease with prominent efficacy due to the advantages of high stability and no immune exclusion.METHODSIn this study, chronic intermittent hypoxia (CIH) exposure was used to induce ED-corresponding phenotypes in Sprague Dawley (SD) rats as well as in cavernous smooth muscle cells (CCSMCs). ED symptoms were treated using exosomes secreted by ADSCs overexpressing circPIP5K1C (EXO-circ) injected into the rat corpus cavernosum.RESULTSEXO-circ has the effect of ameliorating ED induced by CIH exposure in rats, the mechanism of which is to promote the expression of the downstream target gene SMURF1 after adsorption of miR-153-3p through the sponge so that SMURF1 and PFKFB3 occur protein-protein binding and ubiquitination degradation of PFKFB3 appears to inhibit the occurrence of spongiotic smooth muscle cells glycolysis, and to restore the function of the smooth muscle.CONCLUSIONSThese findings show that EXO-circ have a promising therapeutic potential in OSA-induced ED.

项与 SMURF1 相关的新闻（医药）

2024-04-07

·生物探索

Circulation | 扬州大学龚开政等团队合作发现维持肺血管稳态的调控新机制

引言BRCC3 (BRCA1/BRCA2-containing complex亚基3)在特发性肺动脉高压患者和实验性肺动脉高压动物的肺组织中表达降低。激活素受体样激酶2 (ALK2)的BRCC3去泛素化激活了肺血管平滑肌细胞中TGF-β(转化生长因子-β)信号的BMP(骨形态发生蛋白)臂。BRCC3功能获得可能降低人类肺动脉高压易感性。2024年4月2日，扬州大学龚开政、加州大学圣地亚哥分校John Y.-J. Shyy及 Jason X.-J. Yuan共同通讯在Circulation（IF 38）在线发表题为“BRCC3 Regulation of ALK2 in Vascular Smooth Muscle Cells: Implication in Pulmonary Hypertension”的研究论文，该研究发现BRCC3通过维持BMP信号(即ALK2-Smad1/5-PPARγ轴)的完整性，同时抑制PASMCs中TGF-β信号，在维持肺血管稳态中起关键作用。在PAH患者和实验性肺动脉高压动物的pasmc中，BRCC3显著下调。BRCC3通过在Lys-472和Lys-475位点去泛素化ALK2，激活受体调控的Smad1/5/9 (Smad1/5/9)，从而导致BMP调控的PPARγ、p53和Id1的转录激活。BRCC3过表达也通过下调TGF-β表达和抑制Smad3磷酸化来减弱TGF-β信号传导。体外实验表明，BRCC3或去泛素样ALK2-K472/475R的过表达可减弱PASMC的增殖和迁移，增强PASMC的凋亡。在SM22α-BRCC3-Tg小鼠中，由于PASMCs中ALK2-Smad1/5-PPARγ轴的激活，肺动脉高压得到改善。相比之下，Brcc3-/-小鼠由于抑制ALK2-Smad1/5信号通路，对实验性肺动脉高压的易感性增加。总之，这些结果表明，BRCC3通过维持BMP信号(即ALK2-Smad1/5-PPARγ轴)的完整性，同时抑制PASMCs中TGF-β信号，在维持肺血管稳态中起关键作用。这种BMP/TGF-β通路的再平衡对于PAH的缓解具有重要的临床转化意义。BMPR2(骨形态发生蛋白2型受体)的突变和功能障碍与特发性和遗传性肺动脉高压(PAH)的发展有关。BMPR2在缺乏遗传原因的PAH患者中趋于下调，可能是由于炎症或环境影响。在BMP(骨形态发生蛋白)结合后，BMPR2结合并磷酸化其同源I型受体ALK2 (激活素受体样激酶-2；也被称为激活素A受体，I型)来激活BMP-BMPR2-Smad1/5/9信号级联。磷酸化的(p) Smad1/5/9易位进入细胞核，导致典型转录因子如Id1和非典型转录因子包括PPARγ和p53的激活，这些转录因子对肺动脉平滑肌细胞(PASMCs)发挥抗增殖和促凋亡作用。TGF-β(转化生长因子-β)或激活素-A结合后，TGF-β受体通过磷酸化Smad2/3发出信号，对肺血管细胞产生促增殖作用。然而，BMP和TGF-β臂对血管细胞的增殖、肥大、分化和存活有不同的影响，这取决于谱系和生物学背景。TGF-β家族受体(包括BMPR2/ALK2和TGF-β r2 /R1)和受体调节(R) Smads (Smad1/5/9或Smad2/3)的翻译后修饰(如磷酸化和泛素化)显著影响其活性，从而调节靶细胞命运。与K48相关的蛋白质泛素化通常与其蛋白酶体降解有关，而与K63相关的泛素化则参与多种细胞事件，包括DNA修复、细胞内蛋白质运输和激酶信号传导。SMURF1 (Smad泛素化调节因子1)作为HECT (E6AP C端同源)型E3泛素连接酶的成员，泛素化R-Smads (Smad1/5)进行蛋白酶体降解，从而阻断BMP信号传导。此外，SMURF1通过I-Smads对BMPRI和Smad1/5的降解，下调BMP信号。在实验性肺动脉高压(PH)啮齿动物中，SMURF1显著升高。然而，SMURF1是否介导多环芳烃肺血管中BMP成分蛋白的泛素化以及任何再平衡机制目前尚不清楚。BRCC3在PAH减轻中的保护作用示意图（Credit: Circulation）PASMCs向高增殖状态的表型变化与肺血管重构和小动脉肌肉化的发展有关。在PAH患者和实验性PH动物的PASMCs中，抗增殖BMP信号下调，而TGF-β、激活素和GDFs(生长分化因子)诱导的促增殖信号增强。事实上，ActRIIA(一种激活素受体IIA的融合蛋白配体陷阱)能够抑制促增殖TGF-β信号，降低肺血管阻力，提高PAH患者的生存率(PulSAR和STELLAR试验)。该研究表明，BRCC3水平在人类多环芳烃疾病和啮齿动物PH模型中较低。BRCC3通过在PASMCs中去泛素化ALK2激活ALK2-Smad1/5/9-PPAR γ轴。因此，BRCC3似乎在疾病发病机制中拮抗SMURF1，上调和激活BRCC3可能是PAH/PH的一种新的治疗策略。原文链接https://doi-org.libproxy1.nus.edu.sg/10.1161/CIRCULATIONAHA.123.066430责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Nature | 破除传统：为何我们需要重新思考肿瘤的命名方式热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文CRISPR技术进化史 | 24年Cell综述

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