更新于：2024-05-01

RHOA

ras homolog family member A

更新于：2024-05-01

基本信息

别名

ARH12、ARHA、h12

+ [6]

简介

Small GTPase which cycles between an active GTP-bound and an inactive GDP-bound state. Mainly associated with cytoskeleton organization, in active state binds to a variety of effector proteins to regulate cellular responses such as cytoskeletal dynamics, cell migration and cell cycle (PubMed:23871831). Regulates a signal transduction pathway linking plasma membrane receptors to the assembly of focal adhesions and actin stress fibers (PubMed:8910519, PubMed:9121475, PubMed:31570889). Involved in a microtubule-dependent signal that is required for the myosin contractile ring formation during cell cycle cytokinesis (PubMed:16236794, PubMed:12900402). Plays an essential role in cleavage furrow formation. Required for the apical junction formation of keratinocyte cell-cell adhesion (PubMed:20974804, PubMed:23940119). Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly (PubMed:19934221). The MEMO1-RHOA-DIAPH1 signaling pathway plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex. It controls the localization of APC and CLASP2 to the cell membrane, via the regulation of GSK3B activity. In turn, membrane-bound APC allows the localization of the MACF1 to the cell membrane, which is required for microtubule capture and stabilization (PubMed:20937854). Regulates KCNA2 potassium channel activity by reducing its location at the cell surface in response to CHRM1 activation; promotes KCNA2 endocytosis (PubMed:9635436, PubMed:19403695). Acts as an allosteric activator of guanine nucleotide exchange factor ECT2 by binding in its activated GTP-bound form to the PH domain of ECT2 which stimulates the release of PH inhibition and promotes the binding of substrate RHOA to the ECT2 catalytic center (PubMed:31888991). May be an activator of PLCE1 (PubMed:16103226). In neurons, involved in the inhibition of the initial spine growth. Upon activation by CaMKII, modulates dendritic spine structural plasticity by relaying CaMKII transient activation to synapse-specific, long-term signaling (By similarity). Acts as a regulator of platelet alpha-granule release during activation and aggregation of platelets (By similarity). (Microbial infection) Serves as a target for the yopT cysteine peptidase from Yersinia pestis, vector of the plague.

关联

项与 RHOA 相关的药物

SAMMA

靶点

HIV envelope protein gp120 x RHOA

作用机制

HIV包膜蛋白gp120抑制剂 [+1]

在研机构

Yaso Therapeutics, Inc.

原研机构

University of Illinois

在研适应症

避孕 [+2]

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

DC-Rhoin04

靶点-

作用机制

RHOA抑制剂

在研机构

中国科学院上海药物研究所

原研机构

中国科学院上海药物研究所

在研适应症

肿瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

BGS-1933

靶点

RhoA Y42C

作用机制

RhoA Y42C抑制剂

在研机构

Bridgene Biosciences, Inc.

原研机构

Bridgene Biosciences, Inc.

在研适应症

肿瘤

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 RHOA 相关的临床结果

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100 项与 RHOA 相关的转化医学

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0 项与 RHOA 相关的专利（医药）

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11,624

项与 RHOA 相关的文献（医药）

2024-04-01·Neural regeneration research

Blockade of Rho-associated kinase prevents inhibition of axon regeneration of peripheral nerves induced by anti-ganglioside antibodies.

Article

作者: Andrés Berardo ; Cristian R Bacaglio ; Bárbara B Báez ; Rubén Sambuelli ; Kazim A Sheikh ; Pablo H H Lopez

Anti-ganglioside antibodies are associated with delayed/poor clinical recovery in Guillain-Barrè syndrome, mostly related to halted axon regeneration. Cross-linking of cell surface gangliosides by anti-ganglioside antibodies triggers inhibition of nerve repair in in vitro and in vivo paradigms of axon regeneration. These effects involve the activation of the small GTPase RhoA/ROCK signaling pathways, which negatively modulate growth cone cytoskeleton, similarly to well stablished inhibitors of axon regeneration described so far. The aim of this work was to perform a proof of concept study to demonstrate the effectiveness of Y-27632, a selective pharmacological inhibitor of ROCK, in a mouse model of axon regeneration of peripheral nerves, where the passive immunization with a monoclonal antibody targeting gangliosides GD1a and GT1b was previously reported to exert a potent inhibitory effect on regeneration of both myelinated and unmyelinated fibers. Our results demonstrate a differential sensitivity of myelinated and unmyelinated axons to the pro-regenerative effect of Y-27632. Treatment with a total dosage of 9 mg/kg of Y-27632 resulted in a complete prevention of anti-GD1a/GT1b monoclonal antibody-mediated inhibition of axon regeneration of unmyelinated fibers to skin and the functional recovery of mechanical cutaneous sensitivity. In contrast, the same dose showed toxic effects on the regeneration of myelinated fibers. Interestingly, scale down of the dosage of Y-27632 to 5 mg/kg resulted in a significant although not complete recovery of regenerated myelinated axons exposed to anti-GD1a/GT1b monoclonal antibody in the absence of toxicity in animals exposed to only Y-27632. Overall, these findings confirm the in vivo participation of RhoA/ROCK signaling pathways in the molecular mechanisms associated with the inhibition of axon regeneration induced by anti-GD1a/GT1b monoclonal antibody. Our findings open the possibility of therapeutic pharmacological intervention targeting RhoA/Rock pathway in immune neuropathies associated with the presence of anti-ganglioside antibodies and delayed or incomplete clinical recovery after injury in the peripheral nervous system.

2024-03-01·Journal of cell science

PALS1 is a key regulator of the lateral distribution of tight junction proteins in renal epithelial cells.

Article

作者: Ann-Christin Groh ; Annika Möller-Kerutt ; Kevin Gilhaus ; Verena Höffken ; Pavel Nedvetsky ; Simon Kleimann ; Malina Behrens ; Sujasha Ghosh ; Uwe Hansen ; Michael P Krahn ; Klaus Ebnet ; Hermann Pavenstädt ; Alexander Ludwig ; Thomas Weide

The evolutionarily conserved apical Crumbs (CRB) complex, consisting of the core components CRB3a (an isoform of CRB3), PALS1 and PATJ, plays a key role in epithelial cell-cell contact formation and cell polarization. Recently, we observed that deletion of one Pals1 allele in mice results in functional haploinsufficiency characterized by renal cysts. Here, to address the role of PALS1 at the cellular level, we generated CRISPR/Cas9-mediated PALS1-knockout MDCKII cell lines. The loss of PALS1 resulted in increased paracellular permeability, indicating an epithelial barrier defect. This defect was associated with a redistribution of several tight junction-associated proteins from bicellular to tricellular contacts. PALS1-dependent localization of tight junction proteins at bicellular junctions required its interaction with PATJ. Importantly, reestablishment of the tight junction belt upon transient F-actin depolymerization or upon Ca2+ removal was strongly delayed in PALS1-deficient cells. Additionally, the cytoskeleton regulator RhoA was redistributed from junctions into the cytosol under PALS1 knockout. Together, our data uncover a critical role of PALS1 in the coupling of tight junction proteins to the F-actin cytoskeleton, which ensures their correct distribution along bicellular junctions and the formation of tight epithelial barrier.

2024-03-01·Osteoarthritis and cartilage open

Investigation of the association of long-term NSAID use with radiographic hip osteoarthritis over four to five years: Data from the OAI and CHECK studies.

Article

作者: Zubeyir Salis

Objective:

To examine the relationship between long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) and the incidence and progression of radiographic hip osteoarthritis (RHOA), as well as the degeneration of individual radiographic features.

Methods:

We analyzed data from the Osteoarthritis Initiative (OAI) and the Cohort Hip and Cohort Knee (CHECK) study. Our exposure was the number of years of NSAID use over a 4-to-5-year follow-up period. Our outcomes were the incidence and progression of RHOA over a 4-to-5-year follow-up as assessed using a modified Croft grade in OAI and the Kellgren-Lawrence (K/L) grade in CHECK. The incidence of RHOA was defined as having RHOA (grade ≥2) at follow-up and investigated in "incidence cohorts" of hips without RHOA at baseline (grade <2). The progression of RHOA was defined as an increase of ≥1 grade at follow-up from baseline and investigated in "progression cohorts" of hips with RHOA at baseline (grade ≥2). Additionally, we assessed the degeneration of nine specific radiographic features, such as joint space narrowing and osteophytes, defined by a grade increase of ≥1 at follow-up from baseline, in all cohorts.

Results:

In the incidence cohorts, there were 5153 hips in OAI and 1011 in CHECK; in the progression cohorts, there were 285 and 106 hips, respectively. There was no association between NSAID use and the outcomes investigated.

Conclusion:

Over 4-to-5 years, long-term NSAID use showed no association with the incidence or progression of RHOA, or with the degeneration of individual radiographic features.

项与 RHOA 相关的新闻（医药）

2024-03-20

·生物谷

Nature子刊：肖瑞平团队发现，癌症导致的体重减轻或由乳酸驱动

该研究明确了乳酸在肿瘤和脂肪分解代谢以及随后的肌肉质量损失之间的必要和充分联系，揭示了乳酸-GPR81信号通路作为癌症恶病质这种危及生命的癌症并发症的潜在治疗靶点。北京大学未来技术学院肖瑞平教授、胡新立副研究员等在 Nature Metabolism 期刊发表了题为：Activation of GPR81 by lactate drives tumour-induced cachexia 的研究论文。这项包含小鼠和人类数据的研究表明，乳酸可能是癌症发病后恶病质的驱动因素，揭示了乳酸-GPR81信号通路作为癌症恶病质这种危及生命的癌症并发症的潜在治疗靶点。脂肪和肌肉质量的减少是恶病质的主要表现，多种炎症因子，例如肿瘤坏死因子（TNF）、白细胞介素-6（IL-6）、转化生长因子-β，及干扰素γ（IFN-γ），已被证实与癌细胞的旺盛生长所引起的脂肪和肌肉重塑有关，它们被认为是癌症恶病质发病的主要驱动因素。然而，多个抗炎治疗的临床试验结果令人失望，这表明针对炎症因子治疗不足以治愈癌症恶病质。到目前为止，在癌症生物学和医学领域仍然存在一个基本的知识缺口，即肿瘤与宿主代谢失调之间的联系。在这项研究中，研究团队旨在确定连接肿瘤与脂肪组织和骨骼肌代谢和结构重塑的因果因素。研究团队通过对癌症恶病质患者和小鼠模型血液中代谢物的无偏筛查，结合遗传学和药理学方法，发现乳酸水平与体重减轻呈正相关，而乳酸灌注本身足以以剂量依赖的方式在无瘤小鼠中引发恶病质表型。该研究进一步证明了脂肪组织特异性的G蛋白偶联受体GPR81的敲除，类似于全身GPR81敲除，改善了乳酸诱导或肿瘤诱导的雄性小鼠的脂肪和肌肉质量损失，揭示了脂肪GPR81是乳酸代谢效应的主要介质，乳酸通过与GPR81结合，激活细胞信号增加脂肪组织的代谢活动，导致脂肪和肌肉质量损失，最终导致体重减轻。而阻断GPR81可限制小鼠的肿瘤生长。从机制上讲，乳酸/GPR81诱导的恶病质发生独立于已知的蛋白激酶A代谢途径，而是由一个信号级联顺序激活Gi-Gβγ-RhoA/ROCK1-p38的信号级联介导。总的来说，该研究明确了乳酸在肿瘤和脂肪分解代谢以及随后的肌肉质量损失之间的必要和充分联系，揭示了乳酸-GPR81信号通路作为癌症恶病质这种危及生命的癌症并发症的潜在治疗靶点。

2024-02-14

·生物探索

Cell Reports Medicine | 上海交通大学赵维莅团队通过多组学方法揭示外周T细胞淋巴瘤不同的分子和微环境亚型

引言外周T细胞淋巴瘤(PTCL)是一种异质性的非霍奇金淋巴瘤，其临床、表型和遗传特征各不相同。PTCL的分子发病机制和肿瘤微环境在PTCL中的作用尚不清楚，用于遗传分型和靶向治疗的生物标志物有限。2024年2月12日，上海交通大学赵维莅团队在Cell Reports Medicine在线发表题为“Genomic and transcriptomic profiling of peripheral T cell lymphoma reveals distinct molecular and microenvironment subtypes”的研究论文，该研究通过对221例PTCL患者的综合基因组和转录组学研究，描绘了PTCL的遗传景观，实现了分子和微环境分类。根据RHOA、TET2、组蛋白修饰和免疫相关基因的突变状态，PTCL分为4个分子亚型，基因表达模式离散，生物学畸变，对靶向药物易感性。研究人员还对微环境转录特征进行了无监督聚类，并根据致癌途径的特征性激活和免疫群落的组成将PTCL分为4种淋巴瘤微环境亚型。该研究强调了针对PTCL分子和微环境改变的未来精准医疗策略的潜在临床依据。外周T细胞淋巴瘤(PTCL)，占所有侵袭性非霍奇金淋巴瘤的15%-20%，其特点是胸腺后淋巴细胞的恶性增殖和异质性的临床病理表现。最常见的亚型包括未另行指定的PTCL (PTCL-NOS;35%)，血管免疫母细胞T细胞淋巴瘤(AITL;15% - 42%)，间变性大细胞淋巴瘤(ALCL;15%)，可进一步分为间变性淋巴瘤激酶(ALK)融合阳性ALCL (ALK+ ALCL)和ALK融合阴性ALCL (ALK ALCL)。2,3除ALK+ ALCL外，PTCL对标准蒽环类环磷酰胺、阿霉素、长春新碱和强龙(CHOP)化疗反应较差，导致大多数病理亚型的5年生存率低于30%。因此，有效的靶向治疗是这种致命疾病的迫切需要，长期以来，由于缺乏对PTCL遗传景观的了解，这种疾病一直受到阻碍。先前的研究表明，PTCL的异质性存在复杂的病理生物学基础。多种内在“罪魁祸首”失调成熟T细胞的基本途径，从而促进恶性转化在AITL中检测到与表观基因组(如TET2、DNMT3A和IDH2)和T细胞受体(TCR)信号通路(如RHOA)相关的频繁基因突变，并伴有TCR和磷脂酰肌醇3-激酶(PI3K)-AKT通路的激活。在PTCL-NOS中，通常观察到组蛋白修饰基因，主要是甲基化和乙酰化ALK+ ALCL是由NPM1-ALK融合蛋白定义的，伴随着缺氧诱导因子α (HIF1-a)和白细胞介素-10 (IL-10)相关基因的表达增加，而ALK+ALCL代表了一种病理上独特但遗传上异质性的疾病组，均表达三种基因：TNFRSF8、BATF3和TMOD1。至于细胞起源(COO)，基因表达谱揭示了AITL中T滤泡辅助(Tfh)细胞特征的显著富集。在PTCL-NOS中，已经描述了两个主要的分子亚群，PTCL-TBX21和PTCL-GATA3，分别以高表达Th1和Th2细胞分化调节因子为特征。最近，一种起源于Tfh的PTCL-NOS亚型被发现与AITL5高度相似，并且含有频繁的Tfh相关突变。模式图（Credit: Cell Reports Medicine）除了固有缺陷外，越来越多的证据表明，淋巴瘤微环境(LME)中细胞和非细胞成分的外在刺激对PTCL的肿瘤细胞行为和临床表现至关重要。在AITL中，基因表达谱揭示了B细胞和浆细胞的富集以及参与各种免疫过程的复杂细胞因子环境，表明复杂的免疫网络。IL-4、IL-6和IL-21的高表达与B细胞和浆细胞的扩增有关，可能导致高γ球蛋白血症和自身免疫现象。肿瘤相关巨噬细胞的积累和血管内皮生长因子(VEGF)、转化生长因子β (TGF-β)和IL-10的过度表达与免疫抑制和频繁的EB病毒(EBV)感染有关。在临床上，B细胞关联与良好预后显著相关，而VEGF高表达与AITL的肿瘤进展相关。在PTCL-NOS中，TBX21表达呈Th1驱动亚群，其免疫细胞浸润丰富，尤其是巨噬细胞极化，从而导致不良预后。相比之下，在Th2起源的PTCLGATA3亚群中检测到最低限度炎症微环境，其预后甚至更差。另一项研究揭示了PTCL-NOS的微环境分类基于肿瘤浸润免疫细胞的基因表达特征，其中同时具有B细胞和树突状细胞(DC)特征的亚型预后较好，而不具有任何特征的亚型预后最差。在巨噬细胞富集的病例中，观察到免疫检查点基因(包括PD-L1和IDO1)的表达升高，这意味着免疫检查点抑制剂(ICIs)可能在该亚型中使用。该研究通过整合221名PTCL患者的全外显子组测序(WES)、靶向测序和RNA-seq，描绘了一个全面的突变基因组景观，并建立基于遗传特征、生物学改变和治疗反应的分子分层，提出PTCL的四个不同的分子亚群。此外，还定义了一种微环境分层，源自浸润免疫细胞和基质成分的基因表达足迹，这也反映了不同的生物学特征和临床特性。该研究是一项利用PTCL大队列的RNA-seq数据的多组学研究，揭示了一系列癌症和微环境生物标志物，为PTCL患者的个性化治疗提供了理论依据。原文链接https://doi.org/10.1016/j.xcrm.2024.101416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Science最新发布：全世界最前沿的125个科学问题热文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Nature | 癌症与神经系统的致命舞蹈

免疫疗法临床结果临床研究

2023-12-20

·生物谷

低水平RhoA活性是连接小胶质细胞炎症反应和存活所必需的

小胶质细胞以其在中枢神经系统中的免疫和保护作用而闻名。这些功能需要小胶质感觉体的协调响应，其中细胞表面的模式识别受体(PRRs)识别病原体相关分子模式(PAMPs)和组织损伤相关分子模式(DAMPs) 小胶质细胞以其在中枢神经系统中的免疫和保护作用而闻名。这些功能需要小胶质感觉体的协调响应，其中细胞表面的模式识别受体(PRRs)识别病原体相关分子模式(PAMPs)和组织损伤相关分子模式(DAMPs)是最关键的参与者。PAMPs，如nod样受体(NLRs)和toll样受体(TLRs)，通常识别存在于各种病原体中的结构保守分子。受损细胞释放的DAMPs(如ATP、谷氨酸、DNA、RNA)通常与将小胶质细胞吸引到受损部位有关。图片来源：https://doi.org/10.1038/s41419-023-06217-w 近日，来自波尔图大学的研究者们在Cell Death Dis.杂志上发表了题为“RhoA balances microglial reactivity and survival during neuroinflammation”的文章，该研究表明在神经炎症期间，最低水平的RhoA活性是连接小胶质细胞炎症反应和存活所必需的。小胶质细胞是大脑中最大的髓系细胞群。在损伤、疾病或炎症期间，小胶质细胞采取不同的功能状态，主要参与恢复大脑稳态。然而，持续或加剧的小胶质细胞炎症反应可导致脑损伤。动态细胞骨架重组与外部信号驱动的小胶质细胞反应性改变相关，而控制细胞骨架重组的蛋白质，如Rho GTPase RhoA，在损伤、疾病或炎症期间可以很好地改善或调节小胶质细胞的功能状态。在这里，研究者使用基于多生物传感器的活细胞成像方法和小鼠组织特异性条件基因消融来了解RhoA在小胶质细胞对炎症反应中的作用。研究者发现RhoA活性的降低是小胶质细胞代谢重编程和炎症反应性的绝对要求。然而，如果没有RhoA，炎症会破坏Ca2+和pH稳态，抑制线粒体功能，恶化小胶质细胞坏死，并引发小胶质细胞凋亡。小胶质细胞对神经炎症的反应需要严格控制RhoA活性图片来源：https://doi.org/10.1038/s41419-023-06217-w 综上所述，降低RhoA活性(在一定程度上)是实现足够的小胶质细胞炎症能力所必需的。然而，维持最低水平的RhoA活性对于炎症期间小胶质细胞的存活至关重要。因此，微调RhoA信号以平衡小胶质细胞的反应性可能有利于在涉及神经炎症的脑疾病中保持神经元的可塑性。(生物谷 Bioon.com）参考文献 Renato Socodato et al. Cell Death Dis. RhoA balances microglial reactivity and survival during neuroinflammation. 2023 Oct 20;14(10):690. doi: 10.1038/s41419-023-06217-w.