Advances in biological regulation最新文献_第4页

Norepinephrine mediates adrenergic receptor transcription and oncogenic gene expression in pancreatic ductal adenocarcinoma 去甲肾上腺素介导胰腺导管腺癌中肾上腺素能受体转录和致癌基因表达

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-05-05 DOI: 10.1016/j.jbior.2025.101097

Henry H. Brak, Noelle R.J. Thielman

Adrenergic stimulation of β₂ receptors has shown to increase pancreatic ductal adenocarcinoma (PDAC) proliferation and migration in an in vitro setting; however, the role of α₁ receptors in these adrenergic signaling pathways is unclear. Previous research has suggested that the MAPK signaling pathway is upregulated in response to β-adrenergic signaling, but other signaling pathways and downstream targets of mutant KRAS have yet to be investigated. This study investigates the role of adrenergic signaling through α₁ and β-receptors in two human-derived PDAC cell lines, examining proliferation, wound healing, and protein expression after treatment with norepinephrine (NE) and in the presence of β and α₁-receptor antagonism. Using RT-qPCR, the expression of adrenergic receptors and downstream KRAS effector proteins was evaluated. We found that NE has varying effects on proliferation and wound healing in different PDAC cell lines. Moreover, adrenergic receptor expression is under negative feedback control through α₁ signaling in both cell lines. Furthermore, NE decreases expression of MMP9 while also affecting expression of VIM, CCND1, mTOR, and rhoA. We demonstrate genotype dependent effects of adrenergic stimulation on downstream molecular signaling pathways in PDAC that are important for oncogenicity. Based on our findings, genotypic characterization of cell signaling pathways in PDAC may aid further research in effective therapeutics for PDAC.

在体外环境中，肾上腺素能刺激β2受体可增加胰腺导管腺癌（PDAC）的增殖和迁移；然而，α1受体在这些肾上腺素能信号通路中的作用尚不清楚。先前的研究表明，MAPK信号通路响应β-肾上腺素能信号而上调，但突变体KRAS的其他信号通路和下游靶点尚未被研究。本研究探讨了肾上腺素能信号通过α1和β-受体在两种人源性PDAC细胞系中的作用，检测了去甲肾上腺素（NE）处理后以及β和α -受体拮抗剂存在下的增殖、伤口愈合和蛋白表达。RT-qPCR检测肾上腺素能受体和KRAS下游效应蛋白的表达。我们发现NE对不同PDAC细胞系的增殖和伤口愈合有不同的影响。此外，肾上腺素能受体的表达在两种细胞系中均受α1信号的负反馈控制。此外，NE降低MMP9的表达，同时也影响VIM、CCND1、mTOR和rhoA的表达。我们证明了肾上腺素能刺激对PDAC下游分子信号通路的基因型依赖性作用，这对致癌性很重要。基于我们的发现，PDAC细胞信号通路的基因型表征可能有助于进一步研究PDAC的有效治疗方法。

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引用次数: 0

Lipin phosphatidic acid phosphatases: Structure, function, regulation, and disease association 脂质磷脂酸磷酸酶：结构、功能、调节和疾病关联。

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-05-01 DOI: 10.1016/j.jbior.2025.101082

Franceine S. Welcome, Taisha C.M. Elizaire, Michael V. Airola

Lipids play essential roles as structural barriers in cell membranes, long-term energy storage, and as signaling molecules. One class of enzymes involved in lipid synthesis are lipins. Lipins are magnesium-dependent phosphatidic acid phosphatases that produce diacylglycerol, playing key roles in TAG synthesis, de novo phospholipid synthesis and metabolism. Here, we review recent advances on the structure, function, and regulation of lipins with a particular focus on the structural impacts of missense mutations associated with rhabdomyolysis, Majeed syndrome and neuropathies. Structural insights reveal that while some disease-associated mutations directly disrupt catalysis, many missense mutations are not near the active site, but still play a key role in PAP activity. With the resolved crystal structure of a lipin homolog Tt Pah2, AlphaFold, and AlphaMissense it has become increasingly possible to predict the pathogenicity and structural contributions of individual residues and mutations. Going forward, this structural information can be used to predict and understand new mutations as they arise.

脂质作为细胞膜的结构屏障、长期能量储存和信号分子发挥着重要作用。参与脂质合成的一类酶是脂质酶。脂质是镁依赖性磷脂酸磷酸酶，产生二酰基甘油，在TAG合成、新生磷脂合成和代谢中起关键作用。在这里，我们回顾了最近在脂质结构、功能和调控方面的进展，特别关注与横纹肌溶解、马吉德综合征和神经病变相关的错义突变的结构影响。结构洞察揭示，虽然一些疾病相关突变直接破坏催化，但许多错义突变不在活性位点附近，但仍在PAP活性中发挥关键作用。随着脂质同源物Tt Pah2、AlphaFold和AlphaMissense的晶体结构的解析，预测单个残基和突变的致病性和结构贡献变得越来越可能。展望未来，这些结构信息可以用来预测和理解新突变的出现。

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引用次数: 0

Lysophosphatidic acid (LPA) receptor signaling modulates cellular functions of colon cancer cells under cobalt chloride-induced hypoxic conditions 溶血磷脂酸（LPA）受体信号在氯化钴诱导的缺氧条件下调节结肠癌细胞的细胞功能

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-05-01 DOI: 10.1016/j.jbior.2025.101098

Mao Yamamoto, Miwa Takai, Narumi Yashiro, Moemi Tamura, Yuka Kusumoto, Shion Nagano, Anri Taniguchi, Nanami Shimomura, Toshifumi Tsujiuchi

In the tumor microenvironment (TME), hypoxia is critical in promoting tumor invasiveness and progression. Cobalt chloride (CoCl₂) mimics hypoxia by inducing comparable cellular responses. Lysophosphatidic acid (LPA) receptors (LPA₁ to LPA₆) play key roles in regulating cancer cell functions. In this study, we investigated the impact of LPA receptor signaling on malignant properties of colon cancer DLD-1 cells under hypoxic condition induced by CoCl₂. LPAR1 and LPAR2 expression levels were elevated in DLD-1 cells treated with CoCl₂. CoCl₂ treatment also stimulated DLD-1 cell motility. This enhanced motility induced by CoCl₂ was reduced with LW6 (HIF-1 inhibitor). Additionally, the motility of CoCl₂-treated DLD-1 cells was suppressed by AM966 (LPA₁ antagonist) and enhanced by GRI-977143 (LPA₂ agonist). Conversely, CoCl₂ treatment decreased DLD-1 cell invasion. While AM966 further inhibited cell invasion, GRI-977143 elevated it. The cell viability to fluorouracil (5-FU) was higher in CoCl₂-treated DLD-1 cells. This increased viability to 5-FU was further enhanced by both AM966 and GRI-977143. When CoCl₂-treated DLD-1 cells were cultured in low-glucose media, LPAR1 expression was upregulated compared to high-glucose media, while LPAR2 expression was downregulated. Additionally, motility and invasion in CoCl₂-treated DLD-1 cells were further stimulated under low-glucose conditions. These results suggest that LPA receptor signaling contributes to the malignant potential of DLD-1 cells in a hypoxic environment induced by CoCl₂ treatment.

在肿瘤微环境（TME）中，缺氧是促进肿瘤侵袭和进展的关键。氯化钴（CoCl2）通过诱导类似的细胞反应来模拟缺氧。溶血磷脂酸（LPA）受体（LPA1 ~ LPA6）在调节癌细胞功能中起关键作用。在本研究中，我们研究了在CoCl2诱导的缺氧条件下LPA受体信号传导对结肠癌DLD-1细胞恶性特性的影响。在CoCl2处理的DLD-1细胞中，LPAR1和LPAR2表达水平升高。CoCl2处理也刺激了DLD-1细胞的运动。CoCl2诱导的这种增强的运动性被LW6 （HIF-1抑制剂）所降低。此外，cocl2处理的DLD-1细胞的运动性被AM966 （LPA1拮抗剂）抑制，而被GRI-977143 （LPA2激动剂）增强。相反，CoCl2处理降低了DLD-1细胞的侵袭。AM966进一步抑制细胞侵袭，而GRI-977143则提高细胞侵袭。cocl2处理的DLD-1细胞对氟尿嘧啶（5-FU）的存活率较高。AM966和GRI-977143进一步增强了对5-FU的活性。当cocl2处理的DLD-1细胞在低糖培养基中培养时，与高糖培养基相比，LPAR1表达上调，而LPAR2表达下调。此外，在低糖条件下，cocl2处理的DLD-1细胞的运动性和侵袭性进一步受到刺激。这些结果表明，在CoCl2诱导的缺氧环境下，LPA受体信号传导有助于DLD-1细胞的恶性潜能。

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引用次数: 0

Solid pancancer analysis reveals immune and hematopoietic stem cell and DNA damage repair signatures to distinguish different cancer subtypes 实体胰腺癌分析揭示了免疫和造血干细胞和DNA损伤修复特征，以区分不同的癌症亚型

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-05-01 DOI: 10.1016/j.jbior.2025.101090

Nayila Abulimiti , Rongzhuo Long , Yin He , Junze Dong , Xiaosheng Wang

Purpose

Immunity, stemness, and DNA damage repair (DDR) are crucial for cancer development and therapy resistance. With advancements in multiomics technology, the exploration of cancers related to immunity, stemness, and the DDR has triggered interest, but the combination of these levels for analyzing multiple cancers remains insufficient.

Methods

In this study, 9906 solid tumor samples from 31 TCGA cancer types were clustered on the basis of the enrichment levels of 13 gene sets associated with stemness, immunity, and DDR. Moreover, a soft ensemble model was constructed on the basis of the enrichment levels of these 13 gene sets to predict cancer subtypes via other omics data.

Results

We identified four pancancer subtypes, termed C1, C2, C3, and C4, which presented distinct molecular and clinical features, including the immune microenvironment, stemness, genome instability, intratumor heterogeneity, methylation levels, tumor progression, sensitivity to chemotherapy and immunotherapy, and survival prognosis. The soft ensemble model validated this subtyping method in two breast cancer datasets (gene expression level), a pancancer proteomic dataset (protein expression level), and a pancancer cell line dataset (cell line gene expression level).

Conclusion

Our findings indicate that immune, stemness, and DDR signature-based subtyping offers new perspectives on cancer biology and holds promise for improving the clinical management of cancers.

目的免疫、干细胞和DNA损伤修复（DDR）是肿瘤发生和耐药的关键。随着多组学技术的进步，对与免疫、干细胞和DDR相关的癌症的探索引发了人们的兴趣，但将这些水平结合起来分析多种癌症仍然不足。方法基于13个与干性、免疫和DDR相关的基因集的富集水平，对31种TCGA肿瘤类型的9906个实体瘤样本进行聚类。此外，基于这13个基因集的富集水平，构建了一个软集合模型，通过其他组学数据预测癌症亚型。结果我们确定了四种胰腺癌亚型，分别为C1、C2、C3和C4，它们具有不同的分子和临床特征，包括免疫微环境、干性、基因组不稳定性、肿瘤内异质性、甲基化水平、肿瘤进展、对化疗和免疫治疗的敏感性以及生存预后。软集成模型在两个乳腺癌数据集（基因表达水平）、一个胰腺癌蛋白质组学数据集（蛋白质表达水平）和一个胰腺癌细胞系数据集（细胞系基因表达水平）中验证了这种亚型方法。结论基于免疫、干性和DDR特征的亚型为研究癌症生物学提供了新的视角，并有望改善癌症的临床管理。

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引用次数: 0

Fructose 1,6-bisphosphatase as a promising target of anticancer treatment 果糖-1,6-二磷酸酶有望成为抗癌治疗的靶点。

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-01-01 DOI: 10.1016/j.jbior.2024.101057

Agnieszka Gizak, Bartosz Budziak, Aleksandra Domaradzka, Łukasz Pietras, Dariusz Rakus

Fructose 1,6-bisphosphatase (FBP) is a regulatory enzyme of gluconeogenesis that also influences in a non-catalytic manner – via protein-protein interactions – cell cycle-dependent events, mitochondria biogenesis and polarization, synaptic plasticity and even cancer progression. FBP reduces glycolytic capacity of cells via blocking HIF-1α transcriptional activity and modulating NF-κB action, and influences oxidative metabolism by binding to c-MYC. Because FBP limits the energy-producing potential of cells and because a reduction of FBP amounts is observed in cancer cells, FBP is considered to be an anti-oncogenic protein. This is supported by the observation that cancer cells overexpress aldolase A (ALDOA), a pro-oncogenic protein that can bind to FBP and potentially block its anti-oncogenic activity. Interestingly, only the muscle isozyme of FBP (FBP2) interacts strongly with ALDOA, whereas the binding of the liver isozyme (FBP1) to ALDOA is more than an order of magnitude weaker.

Here, we briefly review the most important evidence supporting the anti-oncogenic function of FBP and discuss what structural properties of the two FBP isozymes allow FBP2, rather than FBP1, to exert more flexible anticancer functions.

果糖-1,6-二磷酸酶（FBP）是葡萄糖生成的一种调节酶，它还通过蛋白质之间的相互作用，以非催化的方式影响细胞周期依赖性事件、线粒体生物生成和极化、突触可塑性甚至癌症进展。FBP 通过阻断 HIF-1α 的转录活性和调节 NF-κB 的作用来降低细胞的糖酵解能力，并通过与 c-MYC 结合来影响氧化代谢。由于 FBP 限制了细胞产生能量的潜力，而且在癌细胞中观察到 FBP 数量减少，因此 FBP 被认为是一种抗癌蛋白。癌细胞过量表达醛缩酶 A（ALDOA）也证明了这一点，醛缩酶 A 是一种促癌蛋白，可与 FBP 结合，并有可能阻断其抗癌活性。有趣的是，只有 FBP 的肌肉同工酶（FBP2）与 ALDOA 有强烈的相互作用，而肝脏同工酶（FBP1）与 ALDOA 的结合力要弱一个数量级以上。在此，我们简要回顾了支持 FBP 抗癌功能的最重要证据，并讨论了两种 FBP 同工酶的哪些结构特性使 FBP2 而不是 FBP1 能够发挥更灵活的抗癌功能。

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引用次数: 0

A budding yeast-centric view of oxysterol binding protein family function 以芽殖酵母为中心的氧甾醇结合蛋白家族功能的观点。

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-01-01 DOI: 10.1016/j.jbior.2024.101061

Xiaohan Yu , Carl J. Mousley , Vytas A. Bankaitis , Prasanna Iyer

The Trans Golgi Network (TGN)/endosomal system is a sorting center for cargo brought via the anterograde secretory pathway and the endocytic pathway that internalizes material from the plasma membrane. As many of the cargo that transit this central trafficking hub are components of key homeostatic signaling pathways, TGN/endosomes define a critical signaling hub for cellular growth control. A particularly interesting yet incompletely understood aspect of regulation of TGN/endosome function is control of this system by two families of lipid exchange/lipid transfer proteins. The phosphatidylinositol transfer proteins promote pro-trafficking phosphoinositide (i.e. phosphatidylinositol-4-phosphate) signaling pathways whereas proteins of the oxysterol binding protein family play reciprocal roles in antagonizing those arms of phosphoinositide signaling. The precise mechanisms for how these lipid binding proteins execute their functions remain to be resolved. Moreover, information regarding the coupling of individual members of the oxysterol binding protein family to specific biological activities is particularly sparse. Herein, we review what is being learned regarding functions of the oxysterol binding protein family in the yeast model system. Focus is primarily directed at a discussion of the Kes1/Osh4 protein for which the most information is available.

跨高尔基网络(TGN)/内体系统是通过顺行分泌途径和内化质膜物质的内吞途径带来的货物的分拣中心。由于许多经过这个中心运输枢纽的货物是关键稳态信号通路的组成部分，TGN/核内体定义了细胞生长控制的关键信号枢纽。TGN/内体功能调控的一个特别有趣但尚未完全了解的方面是脂质交换/脂质转移蛋白的两个家族对该系统的控制。磷脂酰肌醇转移蛋白促进前运输磷酸肌醇（即磷脂酰肌醇-4-磷酸）信号通路，而氧甾醇结合蛋白家族的蛋白质在拮抗磷酸肌醇信号通路中发挥相互作用。这些脂质结合蛋白如何执行其功能的确切机制仍有待解决。此外，关于氧甾醇结合蛋白家族的个体成员与特定生物活性的偶联的信息尤其稀少。在此，我们回顾了酵母模型系统中关于氧甾醇结合蛋白家族功能的研究进展。重点主要集中在Kes1/Osh4蛋白的讨论上，这是可获得信息最多的蛋白。

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引用次数: 0

Sixty-fifth international symposium on biological regulation and enzyme activity in normal and neoplastic tissues 第65届正常和肿瘤组织的生物调控和酶活性国际研讨会

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-01-01 DOI: 10.1016/j.jbior.2025.101077

引用次数: 0

The perinucleolar compartment and the oncogenic super-enhancers are part of the same phase-separated structure filled with phosphatidylinositol 4,5-bisphosphate and long non-coding RNA HANR 核仁周围区室和致癌超增强子是同一相分离结构的一部分，充满磷脂酰肌醇4,5二磷酸和长链非编码RNA HANR。

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-01-01 DOI: 10.1016/j.jbior.2024.101069

Ana Miladinović , Ludovica Antiga , Tomáš Venit , Andrea Bayona-Hernandez , Jakub Červenka , Rajendra Kumar Labala , Michal Kolář , Enrique Castaño , Martin Sztacho , Pavel Hozák

The liquid-liquid phase separation in the cell nucleus regulates various processes such as gene regulation and transcription control, chromatin organization, and DNA repair. A plethora of proteins and RNAs contribute to the formation of biomolecular condensates and recently, several nuclear phosphoinositides were shown to be a part of these membrane-less complexes within the nucleus as well. Here we lipid-interacting RNA sequencing (LIPRNAseq) and confocal microscopy to uncover the RNA-binding capacity and localization of phosphatidylinositol 4,5 bisphosphate (PIP2). We discovered the consensus PIP2-binding AU-rich RNA motif and identified long non-coding RNA HANR (lncHANR) to colocalize with PIP2 in the proximity to the nucleolus in the perinucleolar compartment (PNC). Colocalization studies with different nuclear markers reveal that PIP2-HANR presence in the PNC correlates with oncogenic super-enhancers, and both PNC and oncogenic enhancers are part of the same structure. As lncHANR, PNC, and oncogenic super-enhancers are associated with cancer cell lines and tumors, we suggest that they can serve as interchangeable prognostic markers. Understanding of the interplay between lipid metabolism, and lncRNAs in subnuclear compartment phase separation can lead to future improvement in treatment strategies and personalized cancer management approaches.

细胞核中的液-液相分离调节着基因调控和转录控制、染色质组织和DNA修复等多种过程。过多的蛋白质和rna有助于生物分子凝聚物的形成，最近，几种核磷酸肌苷也被证明是核内这些无膜复合物的一部分。在这里，我们通过脂质相互作用RNA测序（LIPRNAseq）和共聚焦显微镜来揭示磷脂酰肌醇4,5二磷酸（PIP2）的RNA结合能力和定位。我们发现了一致的PIP2结合富au RNA基序，并鉴定了长链非编码RNA HANR （lncHANR）与PIP2共定位在核仁周围室（PNC）的核仁附近。不同核标记的共定位研究表明，PIP2-HANR在PNC中的存在与致癌超增强子相关，PNC和致癌增强子都是同一结构的一部分。由于lncHANR、PNC和致癌超级增强子与癌细胞系和肿瘤相关，我们认为它们可以作为可互换的预后标志物。了解脂质代谢和lncrna在亚核室相分离中的相互作用可以改善治疗策略和个性化癌症管理方法。

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引用次数: 0

Signaling pathways and bone marrow microenvironment in myelodysplastic neoplasms 骨髓增生异常肿瘤的信号通路和骨髓微环境。

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-01-01 DOI: 10.1016/j.jbior.2024.101071

Eleonora Ceneri , Alessia De Stefano , Irene Casalin , Carlo Finelli , Antonio Curti , Stefania Paolini , Sarah Parisi , Federica Ardizzoia , Gianluca Cristiano , Jaqueline Boultwood , James A. McCubrey , Pann-Ghill Suh , Giulia Ramazzotti , Roberta Fiume , Stefano Ratti , Lucia Manzoli , Lucio Cocco , Matilde Y. Follo

Key signaling pathways within the Bone Marrow Microenvironment (BMM), such as Notch, Phosphoinositide-Specific Phospholipase C (PI-PLCs), Transforming Growth Factor β (TGF-β), and Nuclear Factor Kappa B (NF-κB), play a vital role in the progression of Myelodysplastic Neoplasms (MDS). Among the various BMM cell types, Mesenchymal Stromal Cells (MSCs) are particularly central to these pathways. While these signaling routes can independently affect both MSCs and Hematopoietic Stem Cells (HSCs), they most importantly alter the dynamics of their interactions, leading to abnormal changes in survival, differentiation, and quiescence. Notch and PI-PLC signaling facilitate intercellular communication, TGF-β promotes quiescence and suppresses hematopoiesis, and NF-κB-driven inflammatory responses foster an environment detrimental to normal hematopoiesis. This review highlights the role of these pathways within the MDS microenvironment, driving the development and progression of the disease and paving the way for new possible therapeutic strategies.

骨髓微环境（BMM）中的关键信号通路，如Notch、磷酸肌苷特异性磷脂酶C （pi - plc）、转化生长因子β (TGF-β)和核因子κB (NF-κB)，在骨髓增生异常肿瘤（MDS）的进展中发挥重要作用。在各种BMM细胞类型中，间充质基质细胞（MSCs）在这些途径中尤其重要。虽然这些信号通路可以独立影响MSCs和造血干细胞（hsc），但它们最重要的是改变它们相互作用的动力学，导致生存、分化和静止的异常变化。Notch和PI-PLC信号通路促进细胞间通讯，TGF-β促进静止和抑制造血，NF-κ b驱动的炎症反应营造了一个不利于正常造血的环境。这篇综述强调了这些通路在MDS微环境中的作用，推动了疾病的发展和进展，并为新的可能的治疗策略铺平了道路。

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引用次数: 0

Making PI3K superfamily enzymes run faster 让 PI3K 超家族酶跑得更快

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-01-01 DOI: 10.1016/j.jbior.2024.101060

Grace Q. Gong , Madhangopal Anandapadamanaban , Md Saiful Islam , Iain M. Hay , Maxime Bourguet , Saulė Špokaitė , Antoine N. Dessus , Yohei Ohashi , Olga Perisic , Roger L. Williams

The phosphoinositide 3-kinase (PI3K) superfamily includes lipid kinases (PI3Ks and type III PI4Ks) and a group of PI3K-like Ser/Thr protein kinases (PIKKs: mTOR, ATM, ATR, DNA-PKcs, SMG1 and TRRAP) that have a conserved C-terminal kinase domain. A common feature of the superfamily is that they have very low basal activity that can be greatly increased by a range of regulatory factors. Activators reconfigure the active site, causing a subtle realignment of the N-lobe of the kinase domain relative to the C-lobe. This realignment brings the ATP-binding loop in the N-lobe closer to the catalytic residues in the C-lobe. In addition, a conserved C-lobe feature known as the PIKK regulatory domain (PRD) also can change conformation, and PI3K activators can alter an analogous PRD-like region. Recent structures have shown that diverse activating influences can trigger these conformational changes, and a helical region clamping onto the kinase domain transmits regulatory interactions to bring about the active site realignment for more efficient catalysis. A recent report of a small-molecule activator of PI3Kα for application in nerve regeneration suggests that flexibility of these regulatory elements might be exploited to develop specific activators of all PI3K superfamily members. These activators could have roles in wound healing, anti-stroke therapy and treating neurodegeneration. We review common structural features of the PI3K superfamily that may make them amenable to activation.

磷酸肌酸 3-激酶（PI3K）超家族包括脂质激酶（PI3Ks 和 III 型 PI4Ks）和一组类似 PI3K 的 Ser/Thr 蛋白激酶（PIKKs：mTOR、ATM、ATR、DNA-PKcs、SMG1 和 TRRAP），它们都有一个保守的 C 端激酶结构域。该超家族的一个共同特点是，它们的基础活性很低，但可以通过一系列调节因子大大提高。激活因子会重新配置活性位点，使激酶结构域的 N-叶相对于 C-叶发生微妙的重新排列。这种重新排列使 N 环的 ATP 结合环更接近 C 环的催化残基。此外，被称为 PIKK 调节结构域（PRD）的保守的 C-lobe 特征也会改变构象，PI3K 激活剂也会改变类似的 PRD 区域。最近的结构显示，各种激活影响因素都能引发这些构象变化，而夹在激酶结构域上的螺旋区域则能传递调控相互作用，使活性位点重新排列，从而提高催化效率。最近一份关于应用于神经再生的 PI3Kα 小分子激活剂的报告表明，可以利用这些调节元件的灵活性来开发所有 PI3K 超家族成员的特异性激活剂。这些激活剂可在伤口愈合、抗中风治疗和治疗神经变性方面发挥作用。我们回顾了 PI3K 超家族的共同结构特征，这些特征可能使它们适于激活。

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引用次数: 0