Advances in biological regulation最新文献_第5页

Group photo 合影

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-01-01 DOI: 10.1016/j.jbior.2025.101078

引用次数: 0

Key to photograph of participants from left to right of the photo 从照片左至右依次为参与者的照片键

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-01-01 DOI: 10.1016/j.jbior.2025.101079

引用次数: 0

Upstream and downstream pathways of diacylglycerol kinase : Novel phosphatidylinositol turnover-independent signal transduction pathways 二酰甘油激酶的上游和下游途径：不依赖磷脂酰肌醇周转的新型信号转导途径。

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-01-01 DOI: 10.1016/j.jbior.2024.101054

Fumio Sakane , Chiaki Murakami , Hiromichi Sakai

Diacylglycerol kinase (DGK) phosphorylates diacylglycerol (DG) to produce phosphatidic acid (PA). Mammalian DGK comprise ten isozymes (α–κ) that regulate a wide variety of physiological and pathological events. Recently, we revealed that DGK isozymes use saturated fatty acid (SFA)/monosaturated fatty acid (MUFA)-containing and docosahexaenoic acid (22:6)-containing DG species, but not phosphatidylinositol (PI) turnover-derived 18:0/20:4-DG. For example, DGKδ, which is involved in the pathogenesis of type 2 diabetes, preferentially uses SFA/MUFA-containing DG species, such as 16:0/16:0- and 16:0/18:1-DG species, in high glucose-stimulated skeletal muscle cells. Moreover, DGKδ, which destabilizes the serotonin transporter (SERT) and regulates the serotonergic system in the brain, primarily generates 18:0/22:6-PA. Furthermore, 16:0/16:0-PA is produced by DGKζ in Neuro-2a cells during neuronal differentiation. We searched for SFA/MUFA-PA- and 18:0/22:6-PA-selective binding proteins (candidate downstream targets of DGKδ) and found that SFA/MUFA-PA binds to and activates the creatine kinase muscle type, an energy-metabolizing enzyme, and that 18:0/22:6-PA interacts with and activates Praja-1, an E3 ubiquitin ligase acting on SERT, and synaptojanin-1, a key player in the synaptic vesicle cycle. Next, we searched for SFA/MUFA-DG-generating enzymes upstream of DGKδ. We found that sphingomyelin synthase (SMS)1, SMS2, and SMS-related protein (SMSr) commonly act as phosphatidylcholine (PC)-phospholipase C (PLC) and phosphatidylethanolamine (PE)-PLC, generating SFA/MUFA-DG species, in addition to SMS and ceramide phosphoethanolamine synthase. Moreover, the orphan phosphatase PHOSPHO1 showed PC- and PE-PLC activities that produced SFA/MUFA-DG. Although PC- and PE-PLC activities were first described 70–35 years ago, their proteins and genes were not identified for a long time. We found that DGKδ interacts with SMSr and PHOSPHO1, and that DGKζ binds to SMS1 and SMSr. Taken together, these results strongly suggest that there are previously unrecognized signal transduction pathways that include DGK isozymes and generate and utilize SFA/MUFA-DG/PA or 18:0/22:6-DG/PA but not PI-turnover-derived 18:0/20:4-DG/PA.

二酰甘油激酶（DGK）将二酰甘油（DG）磷酸化，生成磷脂酸（PA）。哺乳动物的 DGK 由十种同工酶（α-κ）组成，可调节多种生理和病理事件。最近，我们发现 DGK 同工酶使用含饱和脂肪酸（SFA）/单不饱和脂肪酸（MUFA）和含二十二碳六烯酸（22:6）的 DG 物种，但不使用磷脂酰肌醇（PI）周转衍生的 18:0/20:4-DG。例如，参与 2 型糖尿病发病机制的 DGKδ在高葡萄糖刺激的骨骼肌细胞中优先使用含 SFA/MUFA 的 DG 物种，如 16:0/16:0- 和 16:0/18:1-DG 物种。此外，破坏血清素转运体（SERT）稳定性并调节大脑血清素能系统的 DGKδ 主要生成 18:0/22:6-PA。此外，在神经元分化过程中，DGKζ会在神经-2a细胞中产生16:0/16:0-PA。我们搜索了 SFA/MUFA-PA 和 18:0/22:6-PA 选择性结合蛋白（DGKδ 的候选下游靶标），发现 SFA/MUFA-PA 与肌酸激酶（一种能量代谢酶）结合并激活肌酸激酶，18:0/22:6-PA 与 Praja-1（一种作用于 SERT 的 E3 泛素连接酶）和突触囊泡循环中的关键角色突触素-1 相互作用并激活突触素-1。接下来，我们寻找了 DGKδ 上游的 SFA/MUFA-DG 生成酶。我们发现，鞘磷脂合成酶（SMS）1、SMS2和SMS相关蛋白（SMSr）通常作为磷脂酰胆碱（PC）-磷脂酶C（PLC）和磷脂酰乙醇胺（PE）-PLC，生成SFA/MUFA-DG物种，此外还有SMS和神经酰胺磷脂酰乙醇胺合成酶。此外，孤磷酸酶 PHOSPHO1 具有 PC- 和 PE-PLC 活性，可产生 SFA/MUFA-DG。虽然 PC- 和 PE-PLC 活性在 70-35 年前就已被首次描述，但其蛋白质和基因却长期未被确定。我们发现，DGKδ 与 SMSr 和 PHOSPHO1 相互作用，DGKζ 与 SMS1 和 SMSr 结合。综上所述，这些结果有力地表明，存在以前未认识到的信号转导途径，其中包括 DGK 同工酶，它们产生并利用 SFA/MUFA-DG/PA 或 18:0/22:6-DG/PA，但不利用 PI 转化产生的 18:0/20:4-DG/PA。

{"title":"Upstream and downstream pathways of diacylglycerol kinase : Novel phosphatidylinositol turnover-independent signal transduction pathways","authors":"Fumio Sakane , Chiaki Murakami , Hiromichi Sakai","doi":"10.1016/j.jbior.2024.101054","DOIUrl":"10.1016/j.jbior.2024.101054","url":null,"abstract":"<div><div>Diacylglycerol kinase (DGK) phosphorylates diacylglycerol (DG) to produce phosphatidic acid (PA). Mammalian DGK comprise ten isozymes (α–κ) that regulate a wide variety of physiological and pathological events. Recently, we revealed that DGK isozymes use saturated fatty acid (SFA)/monosaturated fatty acid (MUFA)-containing and docosahexaenoic acid (22:6)-containing DG species, but not phosphatidylinositol (PI) turnover-derived 18:0/20:4-DG. For example, DGKδ, which is involved in the pathogenesis of type 2 diabetes, preferentially uses SFA/MUFA-containing DG species, such as 16:0/16:0- and 16:0/18:1-DG species, in high glucose-stimulated skeletal muscle cells. Moreover, DGKδ, which destabilizes the serotonin transporter (SERT) and regulates the serotonergic system in the brain, primarily generates 18:0/22:6-PA. Furthermore, 16:0/16:0-PA is produced by DGKζ in Neuro-2a cells during neuronal differentiation. We searched for SFA/MUFA-PA- and 18:0/22:6-PA-selective binding proteins (candidate downstream targets of DGKδ) and found that SFA/MUFA-PA binds to and activates the creatine kinase muscle type, an energy-metabolizing enzyme, and that 18:0/22:6-PA interacts with and activates Praja-1, an E3 ubiquitin ligase acting on SERT, and synaptojanin-1, a key player in the synaptic vesicle cycle. Next, we searched for SFA/MUFA-DG-generating enzymes upstream of DGKδ. We found that sphingomyelin synthase (SMS)1, SMS2, and SMS-related protein (SMSr) commonly act as phosphatidylcholine (PC)-phospholipase C (PLC) and phosphatidylethanolamine (PE)-PLC, generating SFA/MUFA-DG species, in addition to SMS and ceramide phosphoethanolamine synthase. Moreover, the orphan phosphatase PHOSPHO1 showed PC- and PE-PLC activities that produced SFA/MUFA-DG. Although PC- and PE-PLC activities were first described 70–35 years ago, their proteins and genes were not identified for a long time. We found that DGKδ interacts with SMSr and PHOSPHO1, and that DGKζ binds to SMS1 and SMSr. Taken together, these results strongly suggest that there are previously unrecognized signal transduction pathways that include DGK isozymes and generate and utilize SFA/MUFA-DG/PA or 18:0/22:6-DG/PA but not PI-turnover-derived 18:0/20:4-DG/PA.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"95 ","pages":"Article 101054"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

TP53 gene status can promote sensitivity and resistance to chemotherapeutic drugs and small molecule signal transduction inhibitors TP53基因状态可促进对化疗药物和小分子信号转导抑制剂的敏感性和耐药性。

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-01-01 DOI: 10.1016/j.jbior.2024.101073

James A. McCubrey , Matilde Y. Follo , Stefano Ratti , Alberto M. Martelli , Lucia Manzoli , Giuseppa Augello , Melchiorre Cervello , Lucio Cocco

TP53 is normally a tumor suppressor. However, it is mutated in at least 50% of human cancers. Usually, we assume that mutation of the TP53 is associated with loss of sensitivity to various drugs as in most cases wild type (WT) TP53 activity is lost. This type of mutations is often dominant-negative (DN) mutations as they can interfere with the normal functions of WT-TP53 which acts as a tetramer. These mutations can result in altered gene expression patterns. There are some TP53 mutations which may lack some of the normal functions of TP53 but have additional functions; these types of mutations are called gain of function (GOF) mutations. There is another class of TP53 mutations, they are TP53 null mutations as the cells have deleted the TP53 gene (TP53-null). Although TP53 mutations were initially considered undruggable, other approaches have been developed to increase TP53 activity. One approach was to develop mouse double minute 2 homolog (MDM2) inhibitors as MDM2 suppresses TP53 activity. In addition, there have been mutant TP53 reactivators created, which will at least partially restore some of the critical growth suppressing effects of TP53. Some of these mutant TP53 reactivators have shown promise in clinical trial in certain types of cancer patients, especially myelodysplastic syndrome (MDS). In this review, we summarize the development of novel TP53 reactivators and MDM2 inhibitors. Both approaches are aimed at increasing or restoring TP53 activity. Attempts to increase TP53 activity in various TP53 mutant tumors could increase therapy of multiple deadly diseases.

TP53通常是一种肿瘤抑制因子。然而，它在至少50%的人类癌症中发生突变。通常，我们认为TP53的突变与对各种药物的敏感性丧失有关，因为在大多数情况下野生型（WT） TP53活性丧失。这种类型的突变通常是显性阴性（DN）突变，因为它们可以干扰作为四聚体的WT-TP53的正常功能。这些突变会导致基因表达模式的改变。有一些TP53突变可能缺乏TP53的一些正常功能，但具有额外的功能；这些类型的突变被称为功能增益（GOF）突变。还有一类TP53突变，它们是TP53 null突变，因为细胞已经删除了TP53基因（TP53-null）。虽然TP53突变最初被认为是不可药物治疗的，但已经开发了其他方法来增加TP53的活性。一种方法是开发小鼠双分钟2同源物（MDM2）抑制剂，因为MDM2抑制TP53活性。此外，已经产生了突变的TP53再激活因子，这将至少部分恢复一些关键的TP53生长抑制作用。其中一些突变的TP53再激活因子在某些类型的癌症患者，特别是骨髓增生异常综合征（MDS）的临床试验中显示出希望。本文综述了新型TP53再激活剂和MDM2抑制剂的研究进展。这两种方法都旨在增加或恢复TP53活性。尝试在各种TP53突变肿瘤中增加TP53活性可以增加多种致命疾病的治疗。

{"title":"TP53 gene status can promote sensitivity and resistance to chemotherapeutic drugs and small molecule signal transduction inhibitors","authors":"James A. McCubrey , Matilde Y. Follo , Stefano Ratti , Alberto M. Martelli , Lucia Manzoli , Giuseppa Augello , Melchiorre Cervello , Lucio Cocco","doi":"10.1016/j.jbior.2024.101073","DOIUrl":"10.1016/j.jbior.2024.101073","url":null,"abstract":"<div><div>TP53 is normally a tumor suppressor. However, it is mutated in at least 50% of human cancers. Usually, we assume that mutation of the TP53 is associated with loss of sensitivity to various drugs as in most cases wild type (WT) TP53 activity is lost. This type of mutations is often dominant-negative (DN) mutations as they can interfere with the normal functions of WT-TP53 which acts as a tetramer. These mutations can result in altered gene expression patterns. There are some TP53 mutations which may lack some of the normal functions of TP53 but have additional functions; these types of mutations are called gain of function (GOF) mutations. There is another class of TP53 mutations, they are TP53 null mutations as the cells have deleted the TP53 gene (TP53-null). Although TP53 mutations were initially considered undruggable, other approaches have been developed to increase TP53 activity. One approach was to develop mouse double minute 2 homolog (MDM2) inhibitors as MDM2 suppresses TP53 activity. In addition, there have been mutant TP53 reactivators created, which will at least partially restore some of the critical growth suppressing effects of TP53. Some of these mutant TP53 reactivators have shown promise in clinical trial in certain types of cancer patients, especially myelodysplastic syndrome (MDS). In this review, we summarize the development of novel TP53 reactivators and MDM2 inhibitors. Both approaches are aimed at increasing or restoring TP53 activity. Attempts to increase TP53 activity in various TP53 mutant tumors could increase therapy of multiple deadly diseases.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"95 ","pages":"Article 101073"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Hyperactivation of NF-κB signaling in splicing factor mutant myelodysplastic syndromes and therapeutic approaches 剪接因子突变型骨髓增生异常综合征中 NF-κB 信号的过度激活与治疗方法。

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-01-01 DOI: 10.1016/j.jbior.2024.101055

Andrea Pellagatti, Jacqueline Boultwood

The transcription factor NF-κB plays a critical role in the control of innate and adaptive immunity and inflammation. Several recent studies have demonstrated that the mutation of different splicing factor genes, including SF3B1, SRSF2 and U2AF1, in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) result in hyperactive NF-κB signaling through the aberrant splicing of different target genes. The presence of U2AF1 and SF3B1 mutations in the bone marrow cells of MDS and AML patients induces oncogenic isoforms of the target gene IRAK4, leading to hyperactivation of NF-κB signaling and an increase in the fitness of leukemic stem and progenitor cells (LSPCs). The potent IRAK4 inhibitor CA-4948 has shown efficacy in both pre-clinical studies and MDS clinical trials, with splicing factor mutant patients showing the higher response rates. Emerging data has, however, revealed that co-targeting of IRAK4 and its paralog IRAK1 is required to maximally suppress LSPC function in vitro and in vivo by inducing cellular differentiation. These findings provide a link between the presence of the commonly mutated splicing factor genes and activation of innate immune signaling pathways in myeloid malignancies and have important implications for targeted therapy in these disorders.

转录因子 NF-κB 在先天性和适应性免疫及炎症控制中起着至关重要的作用。最近的一些研究表明，骨髓增生异常综合征（MDS）和急性髓性白血病（AML）中不同剪接因子基因（包括 SF3B1、SRSF2 和 U2AF1）的突变会通过不同靶基因的异常剪接导致 NF-κB 信号的过度活跃。MDS和AML患者骨髓细胞中存在的U2AF1和SF3B1突变会诱导靶基因IRAK4的致癌异构体，从而导致NF-κB信号的过度激活以及白血病干细胞和祖细胞（LSPCs）数量的增加。强效IRAK4抑制剂CA-4948已在临床前研究和MDS临床试验中显示出疗效，剪接因子突变患者的反应率较高。然而，新的数据显示，要通过诱导细胞分化在体外和体内最大限度地抑制 LSPC 的功能，就必须同时靶向 IRAK4 及其同系物 IRAK1。这些发现提供了骨髓恶性肿瘤中常见突变剪接因子基因的存在与先天性免疫信号通路激活之间的联系，对这些疾病的靶向治疗具有重要意义。

{"title":"Hyperactivation of NF-κB signaling in splicing factor mutant myelodysplastic syndromes and therapeutic approaches","authors":"Andrea Pellagatti, Jacqueline Boultwood","doi":"10.1016/j.jbior.2024.101055","DOIUrl":"10.1016/j.jbior.2024.101055","url":null,"abstract":"<div><div>The transcription factor NF-κB plays a critical role in the control of innate and adaptive immunity and inflammation. Several recent studies have demonstrated that the mutation of different splicing factor genes, including <em>SF3B1</em>, <em>SRSF2</em> and <em>U2AF1</em>, in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) result in hyperactive NF-κB signaling through the aberrant splicing of different target genes. The presence of <em>U2AF1</em> and <em>SF3B1</em> mutations in the bone marrow cells of MDS and AML patients induces oncogenic isoforms of the target gene <em>IRAK4</em>, leading to hyperactivation of NF-κB signaling and an increase in the fitness of leukemic stem and progenitor cells (LSPCs). The potent IRAK4 inhibitor CA-4948 has shown efficacy in both pre-clinical studies and MDS clinical trials, with splicing factor mutant patients showing the higher response rates. Emerging data has, however, revealed that co-targeting of IRAK4 and its paralog IRAK1 is required to maximally suppress LSPC function <em>in vitro</em> and <em>in vivo</em> by inducing cellular differentiation. These findings provide a link between the presence of the commonly mutated splicing factor genes and activation of innate immune signaling pathways in myeloid malignancies and have important implications for targeted therapy in these disorders.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"95 ","pages":"Article 101055"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Lamins and chromatin join forces 鞣质和染色质联手

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-01-01 DOI: 10.1016/j.jbior.2024.101059

Baihui Wang, Qiang Luo, Ohad Medalia

The intricate interplay between lamins and chromatin underpins the structural integrity and functional organization of the eukaryotic nucleus. Lamins, type V intermediate filament proteins, form a robust meshwork beneath the inner nuclear membrane that is crucial for sustaining nuclear architecture through interactions with lamin-associated domains (LADs). LADs are predominantly heterochromatic regions in which compacted chromatin is enriched at the nuclear periphery, interacting with lamins and lamin-associated proteins. Disruptions of these interactions are implicated in a spectrum of diseases, including laminopathies, cancer, and age-related pathologies, highlighting the importance of lamin-LAD interactions. Thus, a detailed understanding of lamin-chromatin interactions may provide new insights into chromatin organization and shed light on the mechanism behind certain disease states. Here, we discuss the current state of knowledge of lamin-chromatin interactions from a biochemical and structural point of view.

片层蛋白和染色质之间错综复杂的相互作用是真核细胞核结构完整性和功能组织的基础。片层蛋白是一种 V 型中间丝蛋白，它在核内膜下形成一个坚固的网状结构，通过与片层相关结构域（LADs）的相互作用对维持核结构至关重要。LADs 主要是异染色质区域，其中核外围富含紧密染色质，与片层蛋白和片层相关蛋白相互作用。这些相互作用的破坏与一系列疾病有关，包括板层病、癌症和与年龄有关的病症，这凸显了板层-LAD 相互作用的重要性。因此，详细了解板层与染色质的相互作用可能会为染色质组织提供新的见解，并揭示某些疾病状态背后的机制。在此，我们将从生化和结构的角度讨论目前对片层-染色质相互作用的认识。

引用次数: 0

Molecular basis of JAK kinase regulation guiding therapeutic approaches: Evaluating the JAK3 pseudokinase domain as a drug target JAK激酶调控指导治疗方法的分子基础：评价JAK3假激酶结构域作为药物靶点。

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-01-01 DOI: 10.1016/j.jbior.2024.101072

Anniina Virtanen , Vivian Kettunen , Kirsikka Musta , Veera Räkköläinen , Stefan Knapp , Teemu Haikarainen , Olli Silvennoinen

Janus kinases (JAK1-3, TYK2) are critical mediators of cytokine signaling and their role in hematological and inflammatory and autoimmune diseases has sparked widespread interest in their therapeutic targeting. JAKs have unique tandem kinase structure consisting of an active tyrosine kinase domain adjacent to a pseudokinase domain that is a hotspot for pathogenic mutations. The development of JAK inhibitors has focused on the active kinase domain and the developed drugs have demonstrated good clinical efficacy but due to off-target inhibition cause also side-effects and carry a black box warning limiting their use. Our understanding of the regulatory function of the pseudokinase domain in physiological and pathological signaling has improved substantially. The pseudokinase domain maintains the inactive state of JAKs in the absence of cytokine stimulation but it has also a key role in physiological and mutation-driven activation process. Furthermore, the pseudokinase domain has favourable structural characteristics for selective targeting of cytokine signaling, such as unique mode of ATP-binding, and the first pseudokinase targeting inhibitor for TYK2 has been approved for clinical use. Here we describe the recent functional and structural knowledge of JAK signaling and their therapeutic targeting, and present data evaluating the druggability of the JAK3 pseudokinase domain.

Janus激酶（JAK1-3, TYK2）是细胞因子信号传导的关键介质，它们在血液学、炎症和自身免疫性疾病中的作用引起了人们对其治疗靶点的广泛兴趣。jak具有独特的串联激酶结构，由一个活跃的酪氨酸激酶结构域与一个假激酶结构域相邻组成，是致病突变的热点。JAK抑制剂的开发主要集中在活性激酶结构域，已开发的药物具有良好的临床疗效，但由于脱靶抑制也会产生副作用，并且带有限制使用的黑箱警告。我们对假激酶结构域在生理和病理信号传导中的调节功能的理解有了很大的提高。伪激酶结构域在缺乏细胞因子刺激的情况下维持JAKs的失活状态，但它在生理和突变驱动的激活过程中也起着关键作用。此外，伪激酶结构域具有选择性靶向细胞因子信号的良好结构特征，例如独特的atp结合模式，并且第一个针对TYK2的伪激酶靶向抑制剂已被批准用于临床使用。在这里，我们描述了JAK信号的最新功能和结构知识及其治疗靶向性，并提供了评估JAK3假激酶结构域的可药物性的数据。

{"title":"Molecular basis of JAK kinase regulation guiding therapeutic approaches: Evaluating the JAK3 pseudokinase domain as a drug target","authors":"Anniina Virtanen , Vivian Kettunen , Kirsikka Musta , Veera Räkköläinen , Stefan Knapp , Teemu Haikarainen , Olli Silvennoinen","doi":"10.1016/j.jbior.2024.101072","DOIUrl":"10.1016/j.jbior.2024.101072","url":null,"abstract":"<div><div>Janus kinases (JAK1-3, TYK2) are critical mediators of cytokine signaling and their role in hematological and inflammatory and autoimmune diseases has sparked widespread interest in their therapeutic targeting. JAKs have unique tandem kinase structure consisting of an active tyrosine kinase domain adjacent to a pseudokinase domain that is a hotspot for pathogenic mutations. The development of JAK inhibitors has focused on the active kinase domain and the developed drugs have demonstrated good clinical efficacy but due to off-target inhibition cause also side-effects and carry a black box warning limiting their use. Our understanding of the regulatory function of the pseudokinase domain in physiological and pathological signaling has improved substantially. The pseudokinase domain maintains the inactive state of JAKs in the absence of cytokine stimulation but it has also a key role in physiological and mutation-driven activation process. Furthermore, the pseudokinase domain has favourable structural characteristics for selective targeting of cytokine signaling, such as unique mode of ATP-binding, and the first pseudokinase targeting inhibitor for TYK2 has been approved for clinical use. Here we describe the recent functional and structural knowledge of JAK signaling and their therapeutic targeting, and present data evaluating the druggability of the JAK3 pseudokinase domain.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"95 ","pages":"Article 101072"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cellular responses to low nutrient conditions via activation of lysophosphatidic acid (LPA) receptor signaling in gastric cancer cells 胃癌细胞通过激活溶血磷脂酸（LPA）受体信号对低营养条件的细胞反应

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2024-11-30 DOI: 10.1016/j.jbior.2024.101068

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

In the center of the solid tumor, abnormal vascular architecture impedes sufficient blood supply, leading to continuous hypoxia and nutrient deprivation for the tumor cells. Lysophosphatidic acid (LPA) receptor signaling is known to drive a range of malignant behaviors in cancer cells. This study aimed to explore the impact of LPA receptors on cellular functions in gastric cancer AGS cells cultured under low nutrient conditions. When AGS cells were cultured in media containing low glucose (2000 mg/L), low glutamine (1 mM), or low amino acids (50 % content), LPA receptor expression levels were significantly altered. The growth activity of AGS cells cultured in low glucose- and low amino acid-containing media was suppressed by LPA. Conversely, LPA increased the growth activity of AGS cells cultured in low glutamine-containing media. AGS cell motility increased under low glucose and low glutamine conditions, while low amino acid conditions decreased cell motility. Additionally, the viability of AGS cells in response to cisplatin (CDDP) was enhanced under low glucose, low glutamine, and low amino acid conditions. The motility and viability of AGS cells in response to CDDP were significantly increased by AM966 (LPA₁ antagonist), GRI-977143 (LPA₂ agonist) and (2S)-OMPT (LPA₃ agonist). These results suggest that LPA receptor signaling is significantly implicated in regulating malignant properties in AGS cells under low nutrient conditions.

在实体瘤中心，异常的血管结构阻碍了充足的血液供应，导致肿瘤细胞持续缺氧和营养剥夺。已知溶血磷脂酸（LPA）受体信号传导可驱动癌细胞的一系列恶性行为。本研究旨在探讨低营养条件下LPA受体对胃癌AGS细胞功能的影响。当AGS细胞在低葡萄糖（2000 mg/L）、低谷氨酰胺（1 mM）或低氨基酸（50%含量）培养基中培养时，LPA受体表达水平显著改变。低糖低氨基酸培养基培养的AGS细胞生长活性受到LPA的抑制。相反，LPA能提高低谷氨酰胺培养基中AGS细胞的生长活性。低葡萄糖和低谷氨酰胺条件下AGS细胞运动增强，低氨基酸条件下细胞运动减弱。此外，在低葡萄糖、低谷氨酰胺和低氨基酸条件下，AGS细胞对顺铂（CDDP）的反应活性增强。AM966 （LPA1拮抗剂）、GRI-977143 （LPA2激动剂）和(2S)-OMPT （LPA3激动剂）显著提高了AGS细胞对CDDP反应的运动性和活力。这些结果表明，在低营养条件下，LPA受体信号显著参与调节AGS细胞的恶性特性。

{"title":"Cellular responses to low nutrient conditions via activation of lysophosphatidic acid (LPA) receptor signaling in gastric cancer cells","authors":"Narumi Yashiro, Miwa Takai, Mao Yamamoto, Yuka Kusumoto, Shion Nagano, Anri Taniguchi, Moemi Tamura, Toshifumi Tsujiuchi","doi":"10.1016/j.jbior.2024.101068","DOIUrl":"10.1016/j.jbior.2024.101068","url":null,"abstract":"<div><div>In the center of the solid tumor, abnormal vascular architecture impedes sufficient blood supply, leading to continuous hypoxia and nutrient deprivation for the tumor cells. Lysophosphatidic acid (LPA) receptor signaling is known to drive a range of malignant behaviors in cancer cells. This study aimed to explore the impact of LPA receptors on cellular functions in gastric cancer AGS cells cultured under low nutrient conditions. When AGS cells were cultured in media containing low glucose (2000 mg/L), low glutamine (1 mM), or low amino acids (50 % content), LPA receptor expression levels were significantly altered. The growth activity of AGS cells cultured in low glucose- and low amino acid-containing media was suppressed by LPA. Conversely, LPA increased the growth activity of AGS cells cultured in low glutamine-containing media. AGS cell motility increased under low glucose and low glutamine conditions, while low amino acid conditions decreased cell motility. Additionally, the viability of AGS cells in response to cisplatin (CDDP) was enhanced under low glucose, low glutamine, and low amino acid conditions. The motility and viability of AGS cells in response to CDDP were significantly increased by AM966 (LPA<sub>1</sub> antagonist), GRI-977143 (LPA<sub>2</sub> agonist) and (2S)-OMPT (LPA<sub>3</sub> agonist). These results suggest that LPA receptor signaling is significantly implicated in regulating malignant properties in AGS cells under low nutrient conditions.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"96 ","pages":"Article 101068"},"PeriodicalIF":0.0,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142759699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Sphingosine phosphate lyase insufficiency syndrome as a primary immunodeficiency state 作为原发性免疫缺陷状态的磷酸卵磷脂酶不足综合征。

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2024-10-22 DOI: 10.1016/j.jbior.2024.101058

Saber Gharagozlou , NicolaA.M. Wright , Luis Murguia-Favela , Juliette Eshleman , Julian Midgley , Seha Saygili , Georgie Mathew , Harry Lesmana , Nadia Makkoukdji , Melissa Gans , Julie D. Saba

Sphingosine phosphate lyase insufficiency syndrome (SPLIS) is a genetic disease associated with renal, endocrine, neurological, skin and immune defects. SPLIS is caused by inactivating mutations in SGPL1, which encodes sphingosine phosphate lyase (SPL). SPL catalyzes the irreversible degradation of the bioactive sphingolipid sphingosine-1-phosphate (S1P), a key regulator of lymphocyte egress. The SPL reaction represents the only exit point of sphingolipid metabolism, and SPL insufficiency causes widespread sphingolipid derangements that could additionally contribute to immunodeficiency. Herein, we review SPLIS, the sphingolipid metabolic pathway, and various roles sphingolipids play in immunity. We then explore SPLIS-related immunodeficiency by analyzing data available in the published literature supplemented by medical record reviews in ten SPLIS children. We found 93% of evaluable SPLIS patients had documented evidence of immunodeficiency. Many of the remainder of cases were unevaluable due to lack of available immunological data. Most commonly, SPLIS patients exhibited lymphopenia and T cell-specific lymphopenia, consistent with the established role of the S1P/S1P1/SPL axis in lymphocyte egress. However, low B and NK cell counts, hypogammaglobulinemia, and opportunistic infections with bacterial, viral and fungal pathogens were observed. Diminished responses to childhood vaccinations were less frequently observed. Screening blood tests quantifying recent thymic emigrants identified some lymphopenic SPLIS patients in the newborn period. Lymphopenia has been reported to improve after cofactor supplementation in some SPLIS patients, indicating upregulation of SPL activity. A variety of treatments including immunoglobulin replacement, prophylactic antimicrobials and special preparation of blood products prior to transfusion have been employed in SPLIS. The diverse immune consequences in SPLIS patients suggest that aberrant S1P signaling may not fully explain the extent of immunodeficiency. Further study will be required to fully elucidate the complex mechanisms underlying SPLIS immunodeficiency and determine the most effective prophylaxis against infection.

磷酸鞘氨醇酶不足综合征（SPLIS）是一种与肾脏、内分泌、神经、皮肤和免疫缺陷有关的遗传病。SPLIS是由编码磷酸鞘磷脂酶（SPL）的SGPL1发生失活突变引起的。SPL 催化生物活性鞘磷脂鞘磷脂-1-磷酸（S1P）的不可逆降解，S1P 是淋巴细胞排出的关键调节因子。SPL反应是鞘磷脂代谢的唯一出口，SPL不足会导致广泛的鞘磷脂失调，进而导致免疫缺陷。在此，我们回顾了 SPLIS、鞘脂代谢途径以及鞘脂在免疫中发挥的各种作用。然后，我们通过分析已发表文献中的数据，并通过查阅十名 SPLIS 患儿的病历资料，探讨了与 SPLIS 相关的免疫缺陷。我们发现，在可评估的 SPLIS 患者中，93% 有免疫缺陷的记录证据。由于缺乏可用的免疫学数据，其余的许多病例都无法进行评估。最常见的情况是，SPLIS 患者表现出淋巴细胞减少和 T 细胞特异性淋巴细胞减少，这与 S1P/S1P1/SPL 轴在淋巴细胞排出中的既定作用一致。不过，也观察到 B 细胞和 NK 细胞计数偏低、低丙种球蛋白血症以及细菌、病毒和真菌病原体的机会性感染。对儿童疫苗接种的反应减弱的情况较少出现。通过对近期胸腺移出者进行定量的血液筛查，发现了一些新生儿期淋巴细胞减少的 SPLIS 患者。据报道，一些 SPLIS 患者在补充辅助因子后淋巴细胞减少症有所改善，这表明 SPL 活性得到了上调。对 SPLIS 采用了多种治疗方法，包括免疫球蛋白替代、预防性抗菌药物和输血前血液制品的特殊制备。SPLIS 患者的免疫后果多种多样，这表明 S1P 信号的异常可能无法完全解释免疫缺陷的程度。要全面阐明 SPLIS 免疫缺陷的复杂机制并确定最有效的预防感染方法，还需要进一步的研究。

{"title":"Sphingosine phosphate lyase insufficiency syndrome as a primary immunodeficiency state","authors":"Saber Gharagozlou , NicolaA.M. Wright , Luis Murguia-Favela , Juliette Eshleman , Julian Midgley , Seha Saygili , Georgie Mathew , Harry Lesmana , Nadia Makkoukdji , Melissa Gans , Julie D. Saba","doi":"10.1016/j.jbior.2024.101058","DOIUrl":"10.1016/j.jbior.2024.101058","url":null,"abstract":"<div><div>Sphingosine phosphate lyase insufficiency syndrome (SPLIS) is a genetic disease associated with renal, endocrine, neurological, skin and immune defects. SPLIS is caused by inactivating mutations in <em>SGPL1</em>, which encodes sphingosine phosphate lyase (SPL). SPL catalyzes the irreversible degradation of the bioactive sphingolipid sphingosine-1-phosphate (S1P), a key regulator of lymphocyte egress. The SPL reaction represents the only exit point of sphingolipid metabolism, and SPL insufficiency causes widespread sphingolipid derangements that could additionally contribute to immunodeficiency. Herein, we review SPLIS, the sphingolipid metabolic pathway, and various roles sphingolipids play in immunity. We then explore SPLIS-related immunodeficiency by analyzing data available in the published literature supplemented by medical record reviews in ten SPLIS children. We found 93% of evaluable SPLIS patients had documented evidence of immunodeficiency. Many of the remainder of cases were unevaluable due to lack of available immunological data. Most commonly, SPLIS patients exhibited lymphopenia and T cell-specific lymphopenia, consistent with the established role of the S1P/S1P1/SPL axis in lymphocyte egress. However, low B and NK cell counts, hypogammaglobulinemia, and opportunistic infections with bacterial, viral and fungal pathogens were observed. Diminished responses to childhood vaccinations were less frequently observed. Screening blood tests quantifying recent thymic emigrants identified some lymphopenic SPLIS patients in the newborn period. Lymphopenia has been reported to improve after cofactor supplementation in some SPLIS patients, indicating upregulation of SPL activity. A variety of treatments including immunoglobulin replacement, prophylactic antimicrobials and special preparation of blood products prior to transfusion have been employed in SPLIS. The diverse immune consequences in SPLIS patients suggest that aberrant S1P signaling may not fully explain the extent of immunodeficiency. Further study will be required to fully elucidate the complex mechanisms underlying SPLIS immunodeficiency and determine the most effective prophylaxis against infection.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"94 ","pages":"Article 101058"},"PeriodicalIF":0.0,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Characterisation of molecular mechanisms for PLCγ2 disease-linked variants PLCγ2 疾病相关变体的分子机制特征。

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2024-09-19 DOI: 10.1016/j.jbior.2024.101053

Tom D. Bunney, Charis Kampyli , Ashley Gregory , Matilda Katan

The phospholipase C enzyme PLCγ2 is best characterised in the context of immune cell regulation. Furthermore, many mutations discovered in PLCγ2 have been linked to the development of complex immune disorders as well as resistance to ibrutinib treatment in chronic lymphocytic leukaemia. Importantly, it has also been found that a rare variant of PLCγ2 (P522R) has a protective role in Alzheimer's disease (AD). Despite initial characterisation of these disease-linked variants, a comprehensive understanding of their differences and underpinning molecular mechanisms, needed to facilitate therapeutic efforts, is lacking. Here, we used available structural insights for PLCγ enzymes to further analyse PLCγ2 M1141K mutation, representative for mutations in immune disorders and cancer resistance, and the AD-protective variant, PLCγ2 P522R. Together with several other mutations in the autoinhibitory interface, the PLCγ2 M1141K mutation was strongly activating in a cell-based assay, under basal and stimulated conditions. Measurements of PLC activity in various in vitro assays demonstrated enhanced activity of PLCγ2 M1141K while the activity of PLCγ2 P522R was not significantly different from the WT. Similar trends were observed in several other assays, including direct liposome binding. However, an enhanced rate of phosphorylation of a functionally important tyrosine by Btk in vitro was observed for PLCγ2 P522R variants. To further assess implications of these in vitro findings in a cellular context relevant for the PLCγ2 P522R variant, microglia (BV2) stable cell lines were generated and analysed under growth conditions. The PLC activity in cells expressing PLCγ2 P522R at physiologically relevant levels was clearly enhanced compared to the WT, and differences in cell morphology observed. These data, combined with the structural insights, suggest that the PLCγ2 P522R variant has subtle, localised structural changes that do not directly affect the PLC activity by compromising autoinhibition, as determined for PLCγ2 M1141K. It is also likely that in contrast to the PLCγ2 M1141K, the functional impact of the P522R substitution completely depends on further interactions with upstream kinases and other regulatory proteins in a relevant cellular context, where changes in the PLCγ2 P522R variant could facilitate processes such as phosphorylation and protein-protein interactions.

磷脂酶C酶PLCγ2在免疫细胞调控方面的特征最为明显。此外，在 PLCγ2 中发现的许多突变都与复杂免疫疾病的发生以及慢性淋巴细胞白血病患者对伊布替尼治疗的耐药性有关。重要的是，人们还发现 PLCγ2 的一种罕见变体（P522R）在阿尔茨海默病（AD）中具有保护作用。尽管对这些与疾病相关的变体进行了初步定性，但仍缺乏对它们的差异和基础分子机制的全面了解，而这正是促进治疗工作所需要的。在这里，我们利用对 PLCγ 酶结构的现有了解，进一步分析了 PLCγ2 M1141K 突变（免疫紊乱和抗癌突变的代表）和 AD 保护变体 PLCγ2 P522R。PLCγ2 M1141K 突变与自身抑制界面上的其他几个突变一起，在基于细胞的试验中，在基础和刺激条件下都具有强烈的激活作用。在各种体外试验中对 PLC 活性的测量表明，PLCγ2 M1141K 的活性增强了，而 PLCγ2 P522R 的活性与 WT 没有显著差异。在其他几项检测中也观察到类似的趋势，包括直接脂质体结合。不过，体外观察到 PLCγ2 P522R 变体提高了 Btk 对一个功能重要的酪氨酸的磷酸化率。为了进一步评估这些体外研究结果在与 PLCγ2 P522R 变体相关的细胞环境中的影响，我们生成了小胶质细胞（BV2）稳定细胞系，并在生长条件下进行了分析。与 WT 相比，表达 PLCγ2 P522R 的细胞在生理相关水平上的 PLC 活性明显增强，细胞形态也出现差异。这些数据以及对结构的深入研究表明，PLCγ2 P522R 变体具有微妙的局部结构变化，不会像 PLCγ2 M1141K 所确定的那样，通过损害自身抑制作用而直接影响 PLC 活性。此外，与 PLCγ2 M1141K 不同的是，P522R 取代的功能影响可能完全取决于在相关细胞环境中与上游激酶和其他调节蛋白的进一步相互作用，在这种环境中，PLCγ2 P522R 变体的变化可能会促进磷酸化和蛋白质-蛋白质相互作用等过程。

{"title":"Characterisation of molecular mechanisms for PLCγ2 disease-linked variants","authors":"Tom D. Bunney, Charis Kampyli , Ashley Gregory , Matilda Katan","doi":"10.1016/j.jbior.2024.101053","DOIUrl":"10.1016/j.jbior.2024.101053","url":null,"abstract":"<div><div>The phospholipase C enzyme PLCγ2 is best characterised in the context of immune cell regulation. Furthermore, many mutations discovered in PLCγ2 have been linked to the development of complex immune disorders as well as resistance to ibrutinib treatment in chronic lymphocytic leukaemia. Importantly, it has also been found that a rare variant of PLCγ2 (P522R) has a protective role in Alzheimer's disease (AD). Despite initial characterisation of these disease-linked variants, a comprehensive understanding of their differences and underpinning molecular mechanisms, needed to facilitate therapeutic efforts, is lacking. Here, we used available structural insights for PLCγ enzymes to further analyse PLCγ2 M1141K mutation, representative for mutations in immune disorders and cancer resistance, and the AD-protective variant, PLCγ2 P522R. Together with several other mutations in the autoinhibitory interface, the PLCγ2 M1141K mutation was strongly activating in a cell-based assay, under basal and stimulated conditions. Measurements of PLC activity in various <em>in vitro</em> assays demonstrated enhanced activity of PLCγ2 M1141K while the activity of PLCγ2 P522R was not significantly different from the WT. Similar trends were observed in several other assays, including direct liposome binding. However, an enhanced rate of phosphorylation of a functionally important tyrosine by Btk <em>in vitro</em> was observed for PLCγ2 P522R variants. To further assess implications of these <em>in vitro</em> findings in a cellular context relevant for the PLCγ2 P522R variant, microglia (BV2) stable cell lines were generated and analysed under growth conditions. The PLC activity in cells expressing PLCγ2 P522R at physiologically relevant levels was clearly enhanced compared to the WT, and differences in cell morphology observed. These data, combined with the structural insights, suggest that the PLCγ2 P522R variant has subtle, localised structural changes that do not directly affect the PLC activity by compromising autoinhibition, as determined for PLCγ2 M1141K. It is also likely that in contrast to the PLCγ2 M1141K, the functional impact of the P522R substitution completely depends on further interactions with upstream kinases and other regulatory proteins in a relevant cellular context, where changes in the PLCγ2 P522R variant could facilitate processes such as phosphorylation and protein-protein interactions.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"94 ","pages":"Article 101053"},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142306937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0