PIK3R2

更新于：2025-05-07

基本信息

别名

p85、P85B、Phosphatidylinositol 3-kinase 85 kDa regulatory subunit beta

+ [10]

简介

Regulatory subunit of phosphoinositide-3-kinase (PI3K), a kinase that phosphorylates PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Binds to activated (phosphorylated) protein-tyrosine kinases, through its SH2 domain, and acts as an adapter, mediating the association of the p110 catalytic unit to the plasma membrane. Indirectly regulates autophagy (PubMed:23604317). Promotes nuclear translocation of XBP1 isoform 2 in a ER stress- and/or insulin-dependent manner during metabolic overloading in the liver and hence plays a role in glucose tolerance improvement (By similarity).

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100 项与 PIK3R2 相关的临床结果

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100 项与 PIK3R2 相关的转化医学

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0 项与 PIK3R2 相关的专利（医药）

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263

项与 PIK3R2 相关的文献（医药）

2025-02-01·Life Sciences

Gestational diabetes mellitus-derived miR-7-19488 targets PIK3R2 mRNA to stimulate the abnormal development and maturation of offspring-islets

Article

作者: Zou, Linhai ; Ji, Lixia ; Jiang, Guohui ; Xu, Chunxue ; Cao, Xiangju ; Wang, Yuan ; Wang, Li ; Lv, Wenshan ; Jia, Xinyu

AIMSGestational diabetes mellitus (GDM) provides offspring with a hyper-metabolic intrauterine microenvironment. In this study, we aimed to identify key differential microRNAs in GDM-derived exosomes and explore the potential mechanisms of abnormal embryonic development of islets in offspring.MAIN METHODSExosomes were extracted from umbilical vein blood of GDM and non-GDM (NGDM) parturients for microRNA sequencing. Offspring islets were collected on E18.5 and P0 to detect the expression and location of key proteins by immunofluorescence. Target binding of miR-7-19488 and PIK3R2 mRNA was verified using a dual-luciferase reporter assay. The miR-7-19488-mimic, PI3K/mTOR inhibitors were used to treat primarily islet cells to explore the relationship among miR-7-19488, PI3K, and Akt-FoxO1/mTORC1 signaling. The miR-7-19488 agomir was synthesized for further in vivo validation.KEY FINDINGSGDM-derived exosomes caused the overdevelopment of offspring-islets at E18.5 with an increased production of insulin and glucagon co-staining cells, increased number of α cells synthesizing GLP-1, and stimulation of mTORC1 singling, which were more serious at birth. The up-regulated miR-7-19488 in GDM-exosomes targeted PIK3R2 mRNA, leading to translation stagnation of p85β and activation of PI3K-Akt singling in fetal islets. Importantly, the activated PI3K-Akt-FoxO1 singling promoted development and differentiation of α and β cells and enhanced the GLP-1/GLP-1R axis, which cooperates with miR-7-19488 to activate PI3K-Akt-FoxO1/mTORC1 signaling, leading to the early initiation of the functional maturation of overdeveloped β cells.SIGNIFICANCEmiR-7-19488 loaded in GDM-derived exosomes induce the abnormal overdevelopment and functional maturation of fetal islets, which is one of the contributors of high incidence of diabetes in adulthood.

2024-12-01·Pediatric Neurology

Rare CCND2 (p.Thr280Ile) Variant Associated With Infantile Spasms in a Patient With Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome

Article

作者: Mok, Kent M ; Herrada, Pamela ; Greene, Carol ; Mok, Kent M. ; Yazbek, Sandrine ; Carpenter, Jessica L. ; Carpenter, Jessica L ; Erdemir, Gozde

BACKGROUNDThis report describes a pediatric case of megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome, a rare neurodevelopmental disorder caused by pathogenic variants in the AKT3, CCND2, or PIK3R2 genes. We present a patient with a rare CCND2 variant (c.839C>T, p.Thr280Ile), associated with infantile spasms, ventriculomegaly, polymicrogyria, and intraventricular hemorrhage (IVH).METHODSA retrospective chart review and literature search were performed using PubMed.RESULTSOur patient was found to have ventriculomegaly, grade 3 IVH, bilateral polymicrogyria, and restricted diffusion in the caudate nuclei prenatally. No polydactyly was observed. The patient developed infantile spasms at age 5 months. While high-dose prednisone treatment failed to control the spasms, they resolved with topiramate. By age 2 years, the patient continued to have significant developmental delays, including having poor tone and being nonverbal.CONCLUSIONMPPH syndrome remains a rare and challenging diagnosis, with fewer than 100 cases reported. This case highlights the importance of early genetic testing and neuroimaging in the diagnosis and management of MPPH. The unique presentation of IVH and restricted diffusion warrants further investigation into the syndrome's variable phenotypic spectrum. Early intervention and targeted therapy may help manage seizure activity and improve outcomes.

2024-12-01·Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology

[Xinfeng Capsule alleviates RA-FLS-induced angiogenesis in HUVEC cells by inhibiting the lncRNA HOTAIR/PI3K/AKT pathway].

Article

作者: Sun, Yanqiu ; Huang, Dan ; Huang, Chuanbing ; Liu, Feifei ; Wang, Yuan ; Liu, Jian

Objective To investigate the effect of serum containing Xinfeng capsule (XFC) on the angiogenesis of human umbilical vein endothelial cells (HUVEC) induced by rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) and its mechanism of action. Methods An in vitro co-culture model of RA-FLS and HUVEC was established. Serum containing XFC was prepared by oral gavage of SD rats. CCK-8 was used to screen the optimal co-culture ratio and XFC serum concentration. The lncRNA HOTAIR overexpression plasmid (pcDNA3.1-lncRNA HOTAIR), along with the negative control group, were constructed and transfected into RA-FLS. The experiments were done in HUVEC control group, model group (co-culture of HUVEC and RA-FLS), XFC group (co-culture of RA-FLS treated with 200 mL/L XFC), HOTAIR negative control group (co-culture of RA-FLS transfected with pcDNA3.1-NC), HOTAIR overexpression group (co-culture of RA-FLS transfected with pcDNA3.1-lncRNA HOTAIR), and XFC-treated HOTAIR overexpression group (co-culture of RA-FLS transfected with pcDNA3.1-lncRNA HOTAIR and treated with 200 mL/L XFC). The proliferation ability of HUVEC was detected by CCK-8 method. The migration ability of HUVEC was detected by Transwell^TM method. The tube formation ability of HUVEC was detected by tubule formation assay. The expression of CD34 and CD105 in HUVEC was detected by flow cytometry. The expressions of lncRNA HOTAIR, miR-126-3p, phosphatidylinositol 3-kinase (PI3K), PI3K receptor 2 (PIK3R2), AKT, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) mRNA in HUVEC were detected by real-time quantitative PCR. The protein expressions of PI3K, AKT, p-AKT, VEGF, and bFGF in HUVEC were detected by Western blot and immunofluorescence technique. Results The results of CCK-8 method showed that the optimal treatment ratio and time of RA-FLS and HUVEC co-culture were 5:1 and 48 h respectively. The optimal intervention concentration and time of XFC were 200 mL/L and 48 h. Compared with the control group, the proliferation, migration, tube-forming ability and CD34 and CD105 levels of HUVEC in the model group were significantly improved, the expressions of lncRNA HOTAIR, PIK3R2, VEGF, bFGF, PI3K, AKT and p-AKT were significantly upregulated, and miR-126-3p was significantly downregulated. Compared with the model group, the proliferation, migration, tube-forming ability and CD34 and CD105 levels of HUVEC in the XFC group were significantly decreased, the expressions of lncRNA HOTAIR, PIK3R2, VEGF, bFGF, PI3K, AKT and p-AKT were significantly downregulated, while the expression of miR-126-3p was significantly upregulated. Compared with the HOTAIR negative control group, in the HOTAIR overexpression group, the proliferation, migration, tube-forming ability and CD34 and CD105 levels of HUVECs were significantly increased, the expressions of lncRNA HOTAIR, PIK3R2, VEGF, bFGF, PI3K, AKT and p-AKT were significantly upregulated, and the expression of miR-126-3p was significantly downregulated. Compared with the HOTAIR overexpression group, the proliferation, migration, tube-forming ability and CD34 and CD105 levels of HUVECs in the HOTAIR overexpression group treated with XFC were significantly downregulated, the expressions of lncRNA HOTAIR, PIK3R2, VEGF, bFGF, PI3K, AKT and p-AKT were significantly downregulated, and the expression of miR-126-3p was significantly upregulated. Conclusion XFC-containing serum may play a therapeutic role by inhibiting the expression of lncRNA HOTAIR/PI3K/AKT pathway, reducing the expression levels of VEGF and bFGF, and alleviating synovial angiogenesis induced by RA-FLS to exert therapeutic effect.

项与 PIK3R2 相关的新闻（医药）

2024-12-23

·今日头条

致瘤新机制！同济大学赵德平团队：发现肿瘤治疗潜在策略

【导读】胸腺上皮肿瘤（TETs）是一种罕见的恶性肿瘤，起源于前纵隔。TETs，尤其是胸腺癌（TC）的治疗选择仍然相对有限。 12月19日，同济大学赵德平研究团队在期刊《Journal of Experimental & Clinical Cancer Research》上发表了研究论文，题为“SNAI1 promotes epithelial-mesenchymal transition and maintains cancer stem cell-like properties in thymic epithelial tumors through the PIK3R2/p-EphA2 Axis”，本研究中，SNAI1被确定为TETs的中心转录因子，其与疾病侵袭性的正相关性得到证实。随后的实验表明，SNAI1的上调增强了TET细胞系的迁移、侵袭和上皮间质转化。此外，研究人员观察到SNAI1的过表达维持了癌干细胞样特性。单细胞RNA测序显示，SNAI1抑制剂抑制了巨噬细胞从M1表型向M2表型的转变，这一发现进一步通过多重免疫组织化学（mIHC）得到验证。研究人员通过CUT&Tag和RNA测序，识别出PIK3R2是SNAI1的下游靶点之一，这一发现通过ChIP-qPCR、CUT&RUN-qPCR、荧光素酶报告基因和免疫荧光分析得到验证。相关分析进一步证实PIK3R2直接与磷酸化的EphA2（p-EphA2）相互作用，促进下游GSK3β/β-连环蛋白信号通路。本研究初步验证了SNAI1通过PIK3R2/p-EphA2轴在TETs中的致瘤作用。抑制SNAI1可能是TETs潜在的治疗策略。 https://jeccr.biomedcentral.com/articles/10.1186/s13046-024-03243-0#Sec31 背景介绍 01 胸腺上皮肿瘤（TETs）起源于胸腺。尽管它是前纵隔常见的肿瘤之一，但TETs的发病率相对较低，约为每百万人1.5例。近年来，多组学技术的进步使研究人员对TETs有了更深入的了解。分子亚型分类与疾病的临床特征密切相关。随后的研究整合了基因组学、转录组学、表观遗传学和蛋白质组学测序的数据，进一步阐明了TETs的基因组景观。研究人员还利用质谱和单细胞RNA测序阐明了肿瘤微环境的特征。遗憾的是，尽管研究人员对TETs有了初步的认识，但对潜在治疗靶点的探索和药物开发仍处于初期阶段。最近的临床试验仅证实了舒尼替尼和仑伐替尼在化疗耐药性TETs治疗中的有效性。仅使用帕博利珠单抗和纳武利尤单抗作为复发或晚期TETs的非一线疗法的可行性已经得到证明。还需要进行更多的研究来深入了解肿瘤发生机制，并为TETs确定潜在的治疗靶点。上皮-间质转化（EMT）是一种生物学过程，它使上皮细胞转化为间质细胞。它在各种生理过程中起着至关重要的作用，包括组织重塑、伤口愈合和肿瘤发生。伴随着典型的形态学变化，基因、生理和代谢的改变共同促成了肿瘤细胞的肿瘤发生转变。它还被证实与癌细胞干性获得密切相关。SNAI1基因编码的Snail1蛋白是一种已广泛研究的转录因子，它可以直接促进EMT，因此被认为是EMT标志物之一。由于Snail1在EMT和维持癌细胞干性方面的关键作用，它也被认为是药物开发的有前途的治疗靶点。然而，Snail1在TETs中的肿瘤发生功能尚未得到充分验证。Snail1在促进EMT和促进TETs获得癌细胞干性方面的基本作用仍有待阐明。 SNAI1通过转录调控PIK3R2的表达，促进肿瘤进展 02 为了理解TETs的致瘤机制，研究人员进一步评估了SNAI1调控的靶基因。首先，采用CUT&Tag测序技术评估SNAI1与其下游靶基因的基因组相互作用。共鉴定出5301个靶基因的启动子区域。随后，通过RNA测序评估过表达SNAI1的TET细胞与对照细胞之间的DEGs。共鉴定出372个DEGs。之后，研究人员对重叠的105个SNAI1靶基因进行通路富集分析。KEGG分析揭示了几个明显的致瘤通路，尤其是PI3K/Akt信号通路。这与之前通过纤维细胞的scRNA-seq分析获得的结果一致。在这些致瘤通路中，PIK3R2被确定为关键基因。研究人员重新评估了CUT&Tag测序的结果，发现SNAI1的分布位点集中在PIK3R2的启动子区域附近。为了验证测序结果，研究人员在JASPAR数据库中进行了启动子扫描，并在PIK3R2启动子区域识别出高度可能的SNAI1结合位点。该位点与通过CUT&Tag识别的位点重叠。ChIP-qPCR分析进一步证实了SNAI1在Ty82细胞中直接与PIK3R2启动子结合。研究人员还进行了荧光素酶报告基因实验，以在体外验证SNAI1与PIK3R2启动子区域的结合，使用Ty82细胞。研究人员还进行了CUT&RUN分析，以证明SNAI1与PIK3R2 DNA的结合。此外，免疫荧光共定位实验显示，Snai1主要定位于细胞核中，而PIK3R2编码的p85β主要定位于TET细胞系的细胞质中。 SNAI1下游靶点的选择为了探讨PIK3R2在TETs中的临床意义，研究人员对获取的TC组织及其相邻的正常胸腺组织进行了IHC染色。结果显示，TC组织中PIK3R2的染色分值确实高于相应的正常对照组。此外，研究人员还证实，SNAI1的过表达可导致PIK3R2表达水平升高，而SNAI1的敲低则可逆转这一效应。 PIK3R2的敲低也逆转了SNAI1过表达对TET细胞增殖、迁移和侵袭能力的促进作用。在TET细胞中，PIK3R2敲低后，上皮间质转化(EMT)标志物的表达水平降低。相关实验进一步证实，PIK3R2敲低降低了肿瘤干性。PIK3R2敲低后，TET细胞的转移能力受到抑制。总之，这些结果表明，SNAI1功能性地调节PIK3R2的表达，从而促进肿瘤侵袭性。结论 03 综上，SNAI1已被确认为TETs中一种重要的转录因子。SNAI1的致瘤作用通过PIK3R2/p-EphA2轴介导。这些发现有助于更深入地了解TETs的肿瘤发生机制，并为开发新的治疗策略提供了启示。【参考资料】 https://jeccr.biomedcentral.com/articles/10.1186/s13046-024-03243-0#Sec31 【关于投稿】转化医学网（360zhyx.com）是转化医学核心门户，旨在推动基础研究、临床诊疗和产业的发展，核心内容涵盖组学、检验、免疫、肿瘤、心血管、糖尿病等。如您有最新的研究内容发表，欢迎联系我们进行免费报道（公众号菜单栏-在线客服联系），我们的理念：内容创造价值，转化铸就未来！转化医学网（360zhyx.com）发布的文章旨在介绍前沿医学研究进展，不能作为治疗方案使用；如需获得健康指导，请至正规医院就诊。热门推荐活动点击免费报名 🕓 线上｜2024年12月6日-2025年1月16日 ▶ 《我的2024》 🕓 全国｜2024年12月-2025年03月 ▶ 中国转化医学产业大会 🕓 上海｜2025年02月28日-03月01日 ▶ 第四届长三角单细胞组学技术应用论坛暨空间组学前沿论坛点击对应文字查看详情

临床结果临床1期

2024-05-14

·生物探索

Nature | 罗擎宇等人发现靶向非经典PI3Kγ信号和天然免疫治疗急性白血病

引言磷酸肌醇-3-激酶-γ (PI3Kγ)被认为是肿瘤相关巨噬细胞再极化和促进实体癌抗肿瘤免疫反应的靶标。然而，PI3Kγ在癌细胞中的内在作用尚不清楚。2024年5月8日，哈佛医学院罗擎宇等人在Nature 在线发表题为“Targetable leukaemia dependency on noncanonical PI3Kγ signalling”的研究论文，该研究通过整合无偏倚的全基因组CRISPR干扰筛选和急性白血病的功能分析，定义了高风险亚群(包括髓系、淋巴系和树突状谱系)对PI3Kγ复合物的选择性依赖。这种依赖性的特点是先天炎症信号和磷酸化肌苷激酶调节亚基5 (PIK3R5)的激活，PIK3R5编码PI3Kγ5的调节亚基并稳定活性酶复合物。p21 (RAC1)激活的激酶1 (PAK1)是PI3Kγ的非规范底物，介导这种细胞内在依赖性，并发现通过PI3Kγ抑制PAK1的去磷酸化会损害线粒体氧化磷酸化。选择性PI3Kγ抑制剂eganelisib治疗PIK3R5活化的白血病有效。此外，eganelisib和阿糖胞苷联合使用比单独使用任何一种药物都能延长生存期，即使在基线PIK3R5表达较低的患者源性白血病异种移植物中也是如此，因为阿糖胞苷治疗后的残留白血病细胞具有升高的G蛋白偶联嘌呤能受体活性和PAK1磷酸化。总之，该研究揭示了急性白血病患者对PI3Kγ-PAK1信号的可靶向依赖性，可用于近期评估。尽管最近针对某些急性白血病基因亚群的靶向治疗取得了进展，但许多疾病亚型缺乏机械靶向治疗，大多数患者的长期预后较差。急性髓性白血病(AML)和急性淋巴细胞白血病(ALL)是两种最常见的急性白血病类型。母浆细胞样树突状细胞肿瘤(BPDCN)是一种侵袭性血液系统恶性肿瘤，起源于浆细胞样树突状细胞谱系，与AML和ALL具有相同的临床和病理特征。针对细胞表面表达的CD123的治疗已被批准用于BPDCN，并已在包括AML在内的其他急性白血病中进行了测试，但它并不直接针对细胞内在的致癌途径。研究人员假设BPDCN和其他急性白血病之间的重叠特征可能表明血液系统恶性肿瘤的功能相关亚群具有共同的治疗脆弱性。哺乳动物PI3K家族包含几个类别的多个亚型。I类PI3Ks分为IA类和IB类，产生3-磷酸肌醇脂，激活信号转导途径，II类和III类PI3Ks是内吞膜运输的调节剂。IA类PI3Ks包括三个催化亚基α、β和δ(分别由PIK3CA、PIK3CB和PIK3CD编码)，调控亚基p85α、p55α、p50α、p85β和p55γ(由PIK3R1、PIK3R2和PIK3R3编码)5。IB类PI3K只有一个催化亚基p110γ(由PIK3CG编码)和两个调节亚基p101和p84(分别由PIK3R5和PIK3R6编码)，并通过异源三聚体和小G蛋白被G蛋白偶联受体(GPCRs)激活。几种癌症已经激活了IA类PI3K，许多通路抑制剂已被批准或正在开发中。相比之下，IB类PI3K成分(即酶促p110γ和调节亚基)受到的关注较少，治疗重点仅限于用PI3Kγ抑制剂对巨噬细胞进行重编程，用于实体瘤免疫治疗。PI3Kγ作为细胞内在癌症驱动因子的作用尚不清楚。白血病依赖于非规范PI3Kγ信号（Credit: Nature）该研究发现以先天炎症信号激活的PIK3R5为特征的白血病亚群对PI3Kγ抑制高度敏感。增加的PIK3R5和PIK3CG似乎形成了一个自稳定复合体，能够将PIK3R5的适度转录升高转化为PI3Kγ的实质性激活。出乎意料的是，白血病对PI3Kγ的内在依赖性与传统的PI3K底物AKT4无关，而是依赖于PAK1激酶的磷酸化。PI3Kγ抑制使RAC1失活并降低其与PAK1的相互作用，从而证明PI3Kγ - RAC1 - PAK1信号通路在该白血病亚群中存在。因此，该研究发现PAK1(S144)磷酸化与原发性AML样本中对eganelisib的反应显著相关。几种ATP竞争性和ATP非竞争性PAK变构抑制剂可用，这可能有助于解决这些问题，并提供针对该途径的另一个治疗节点。正如预测的那样，这种组合在PIK3R5升高的模型中发挥协同作用。联合用药对低基线PIK3R5的白血病也有效，可能与G蛋白偶联嘌呤能受体信号传导和糖胞苷持久性白血病细胞中的PAK1磷酸化有关。总之，该研究揭示了急性白血病患者对PI3Kγ-PAK1信号的可靶向依赖性，可用于近期评估。原文链接https://www.nature.com/articles/s41586-024-07410-3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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