AbstractIntegrin adaptor proteins, like tensin-2, are crucial for cell adhesion and signaling. However, the function of tensin-2 beyond localizing to focal adhesions remain poorly understood. We utilized proximity-dependent biotinylation and Strep-tag affinity proteomics to identify interaction partners of tensin-2 in Flp-In 293 T-REx cells.

摘要整合素衔接蛋白，如张力蛋白-2，对细胞粘附和信号传导至关重要。然而，除了定位于粘着斑之外，张力蛋白-2的功能仍然知之甚少。我们利用邻近依赖性生物素化和Strep标签亲和蛋白质组学来鉴定Flp-in 293 T-REx细胞中张力蛋白-2的相互作用伴侣。

Interactomics linked tensin-2 to known focal adhesion proteins and the dystrophin glycoprotein complex, while also uncovering novel interaction with the glycolytic enzyme GAPDH. We demonstrated that Y483-phosphorylation of tensin-2 regulates the glycolytic rate in Flp-In 293 T-REx and MEF cells and found that pY483 tensin-2 is enriched in adhesions in MEF cells.

Interactomics将tensin-2与已知的粘着斑蛋白和肌营养不良蛋白糖蛋白复合物联系起来，同时也揭示了与糖酵解酶GAPDH的新型相互作用。我们证明了张力蛋白-2的Y483磷酸化调节Flp-in 293 T-REx和MEF细胞的糖酵解速率，并发现pY483张力蛋白-2在MEF细胞的粘附中富集。

Our study unveils novel interaction partners for tensin-2 and further solidifies its speculated role in cell energy metabolism. These findings shed fresh insight on the functions of tensin-2, highlighting its potential as a therapeutic target for diseases associated with impaired cell adhesion and metabolism..

我们的研究揭示了张力蛋白-2的新型相互作用伙伴，并进一步巩固了其在细胞能量代谢中的推测作用。这些发现为张力蛋白2的功能提供了新的见解，突出了其作为与细胞粘附和代谢受损相关疾病的治疗靶点的潜力。。

IntroductionIntegrin adaptors, such as tensins, regulate the activation and signaling of integrins, affecting crucial cellular functions such as cell growth, survival and development. Also, integrin regulation often plays a role in disease outcome. For that, understanding the functions of integrin adaptors is of high importance.Tensins are a family of integrin adaptor proteins that are generally considered to interact with integrin cytoplasmic domains in the cell-ECM adhesions1.

引言整合素衔接子，如张力蛋白，调节整合素的激活和信号传导，影响细胞生长，存活和发育等关键细胞功能。此外，整合素调节通常在疾病结果中起作用。为此，了解整合素衔接子的功能非常重要。张力蛋白是整联蛋白衔接蛋白家族，通常被认为与细胞ECM粘附中的整联蛋白细胞质结构域相互作用1。

Tensin-2, also known as C1 domain containing protein with homology to tensin (C1-TEN) or tensin-like C1 domain-containing phosphatase (TENC1), is less studied member of the tensin protein family comprising of four proteins, with tensins 1–3 sharing high homology. Tensins are often collectively categorized as focal adhesion proteins1.

Tensin-2，也称为与张力蛋白（C1-TEN）或张力蛋白样C1结构域磷酸酶（TENC1）同源的C1结构域蛋白，是由四种蛋白质组成的张力蛋白家族中研究较少的成员，张力蛋白1-3具有高度同源性。张力蛋白通常统称为粘着斑蛋白1。

However, individual reports state that tensin-1 and tensin-3 are fibrillar adhesion proteins (tensin-1 located also in focal adhesions), whereas tensin-2 has been considered mostly as focal adhesion protein2,3.In focal adhesions, tensins are believed to connect the integrin tails and actin cytoskeleton via binding to both partners.

。

Tensin-2 PTB domain binds to integrin cytoplasmic domains of β3, β5, β7 and β1A, whereas β2 does not bind tensin-2 PTB4. The SH and PTB domains of tensin-2 are shown to bind receptor tyrosine kinase Axl5 , tumor suppressor proteins DLC16 and DLC27, DISC18, c-MpI9 and tyrosine kinase Syk10 (Fig. 1A).

张力蛋白-2 PTB结构域与β3，β5，β7和β1A的整联蛋白胞质结构域结合，而β2不结合张力蛋白-2 PTB4。显示张力蛋白-2的SH和PTB结构域结合受体酪氨酸激酶Axl5，肿瘤抑制蛋白DLC16和DLC27，DISC18，c-MpI9和酪氨酸激酶Syk10（图1A）。

Since phosphorylation is a common regulator of protein function, we took a look at the known phosphorylation sites catalogued in Phosphosite plus for tensin-211 and observed that Y483 is the most often phosphorylated residue of tensin-2 (Fig. 1B). The phosphorylation of this site has been previously reported to be mediated by Src12 and Axl kin.

由于磷酸化是蛋白质功能的常见调节剂，因此我们研究了在Phosphosite plus中针对张力蛋白211分类的已知磷酸化位点，并观察到Y483是张力蛋白2最常被磷酸化的残基（图1B）。先前已报道该位点的磷酸化是由Src12和Axl-kin介导的。

Table 1 Prediction of subcellular localization for tensin family proteins. Three different prediction algorithms were used. Nucl = Nucleus, Cyto = cytoplasmic, Cyto-nucl = protein which shuttle between the cytosol and nucleus, PM = plasma membrane.Full size tableTensin-2 shows high-to-medium expression levels in specialized tissues, with the highest level of protein expression found in kidneys (Human protein atlas29) (Supplementary Fig. 1B).

表1张力蛋白家族蛋白亚细胞定位的预测。使用了三种不同的预测算法。Nucl=细胞核，细胞质，细胞质，在细胞质和细胞核之间穿梭的蛋白质，质膜。全尺寸tableTensin-2在特定组织中显示出高至中等的表达水平，在肾脏中发现的蛋白质表达水平最高（人类蛋白质图谱29）（补充图1B）。

Gene-disease-association (GDA) score of tensin-2 is highest in nephrotic diseases according to DisGeNET30 (Supplementary Fig. 1C) and tensin-2 gene expression often decreases heavily in tumorous tissues as visible from GEPIA31 (Supplementary Fig. 1D). In line with this, downregulation of tensin-2 has been shown to enhance the tumorigenicity of A549 and HeLa cells32.One phosphorylation site (Y483) was highly enriched and reported in almost 1600 previous studies (Fig. 1B).

根据DisGeNET30（补充图1C），tensin-2的基因-疾病关联（GDA）评分在肾病中最高，并且从GEPIA31（补充图1D）可见，tensin-2基因表达在肿瘤组织中通常严重降低。与此相一致，已显示张力蛋白-2的下调可增强A549和HeLa细胞的致瘤性32。一个磷酸化位点（Y483）高度富集，并在近1600项先前的研究中报道（图1B）。

As these references were investigated more closely, 1576 associations were detected with MS analysis and only one using phospho-specific antibodies and Western blotting33. Closer inspection of the 1576 MS studies revealed that majority of the studies were associated with cancers (Supplementary Fig. 1E), mostly with lung and liver cancer studies (Supplementary Fig. 1F).Tensin-2 proximal interactome reveals associations with proteins from the cytoplasm, plasma membrane, nucleoplasm and focal adhesions in Flp-In 293 T-REx cellsIn order to gain understanding of the location and interaction partners of tensin-2 and the function of Y483 phosphorylation site, we performed a BioID proximal interactions analysis for Flp-In 293 T-REx cells stably expressing tensin-2 WT, phospho-mimicking (Y483E) and phosphorylation-negative (Y483F, Y483A) forms of the tensin-2.

随着这些参考文献的进一步研究，MS分析检测到1576个关联，只有一个使用磷酸特异性抗体和蛋白质印迹33。仔细检查1576项MS研究发现，大多数研究与癌症有关（补充图1E），主要与肺癌和肝癌研究有关（补充图1F）。Tensin-2近端相互作用组揭示了与Flp-in 293 T-REx细胞中细胞质，质膜，核质和粘着斑中蛋白质的关联为了了解Tensin-2的位置和相互作用伴侣以及Y483磷酸化位点的功能，我们对稳定表达Tensin-2 WT，磷酸化模拟（Y483E）和磷酸化阴性（Y483F，Y483A）形式的Flp-in 293 T-REx细胞进行了类生物近端相互作用分析。

BioID reveals .

BioID揭示。

Our study provides important insights into the cellular localization of tensin-2 and molecular mechanisms underlying the regulation of energy metabolism by the adhesion protein tensin-2. The comprehensive analysis of tensin-2 interactors identified novel interaction partners, shedding new light on the diverse functions of this important protein.

我们的研究为张力蛋白-2的细胞定位以及粘附蛋白张力蛋白-2调节能量代谢的分子机制提供了重要见解。对张力蛋白-2相互作用子的综合分析确定了新的相互作用伴侣，为这种重要蛋白质的多种功能提供了新的思路。

Both bioinformatic prediction and immunofluorescence analysis suggests that tensin-2, in addition to cell-ECM adhesions, also localizes into cell nucleus and Y483- phosphorylated form is specifically enriched in focal adhesions in MEF cells. The identification of novel interaction partners for tensin-2 provides new avenues for future research, as we work to unravel the complex regulatory networks that govern cellular processes.While the exact biological role of tensin-2 remains to be fully elucidated, our results opens possibility that the suggested tumor suppressor role of tensin-2 in human cancers32 could be linked to adhesion biology and cell energy metabolism.

生物信息学预测和免疫荧光分析均表明，张力蛋白-2除细胞-ECM粘附外，还定位于细胞核中，Y483磷酸化形式在MEF细胞的粘着斑中特异性富集。随着我们努力解开控制细胞过程的复杂调控网络，张力蛋白-2新型相互作用伙伴的鉴定为未来的研究提供了新的途径。虽然张力蛋白-2的确切生物学作用仍有待完全阐明，但我们的结果揭示了张力蛋白-2在人类癌症中的肿瘤抑制作用可能与粘附生物学和细胞能量代谢有关。

Overall, our study represents a significant advance in our understanding of the link between adhesion biology and energy metabolism, as summarized in Fig. 7.Figure 7Summary of the main findings. Tensin-2 has been shown to promote cell contractility via Rho-mediated mechanism3 and is an actin-binding protein.

总体而言，我们的研究代表了我们对粘附生物学和能量代谢之间联系的理解的重大进步，如图7所示。图7主要发现的总结。已显示张力蛋白-2通过Rho介导的机制3促进细胞收缩，并且是肌动蛋白结合蛋白。

Actin has been further shown to associate with GAPDH and to regulate glycolysis via different mechanisms38. Here we have shown that tensin-2 is associated with GAPDH and controls glycolysis via Y483 phosphorylation and actin dynamics.Full size imageMaterials and methodsPlasmidsFor protein expression plasmid backbone we used the MAC-tag-C44 (Addgene: #108077) where the tags have been embedded in the C-terminus of the bait protein.For tensin-2 constructs we used the .

肌动蛋白已被进一步证明与GAPDH相关，并通过不同的机制调节糖酵解38。在这里，我们已经证明张力蛋白-2与GAPDH相关，并通过Y483磷酸化和肌动蛋白动力学控制糖酵解。全尺寸成像材料和方法对于蛋白质表达质粒骨架，我们使用MAC-tag-C44（Addgene：#108077），其中标签已嵌入诱饵蛋白的C末端。对于tensin-2构建体，我们使用了。

Data availability

数据可用性

The mass spectrometry datasets discussed in this study is available at MassIVE database with dataset ID MSV000091836 (https://massive.ucsd.edu/ProteoSAFe/dataset.jsp?task=46fd29805ffc4843ad3c36db2420d3cc). The RNA-seq data discussed in this study have been deposited in NCBI's Gene Expression Omnibus (Edgar et al., 2002) and are accessible through GEO Series accession number GSE231782 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?&acc=GSE231782)..

本研究中讨论的质谱数据集可在MassIVE数据库中获得，数据集ID为MSV000091836(https://massive.ucsd.edu/ProteoSAFe/dataset.jsp?task=46fd29805ffc4843ad3c36db2420d3cc)。本研究中讨论的RNA-seq数据已保存在NCBI的Gene Expression Omnibus（Edgar等，2002）中，可通过GEO系列登录号GSE231782访问(https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?&acc=GSE231782)。。

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The authors acknowledge the Biocenter Finland and Tampere Imaging Facility (TIF) for the service. Ulla Kiiskinen and Niklas Kähkönen (Tampere University) are acknowledged for technical support.Author informationAuthors and AffiliationsFaculty of Medicine and Health Technology, Tampere University, Tampere, FinlandPaula Turkki, Latifeh Azizi & Vesa P.

作者感谢芬兰生物中心和坦佩雷成像设施（TIF）的服务。Ulla Kiiskinen和Niklas Kähkönen（坦佩雷大学）获得了技术支持。作者信息作者和附属机构坦佩雷大学医学与健康技术学院，坦佩雷，芬兰德拉·保拉·图尔基，拉蒂菲·阿齐兹和维萨·P。

HytönenFimlab Laboratories, Tampere, FinlandPaula Turkki & Vesa P. HytönenInstitute of Biotechnology, University of Helsinki, Helsinki, FinlandIftekhar Chowdhury, Tiina Öhman & Markku VarjosaloAuthorsPaula TurkkiView author publicationsYou can also search for this author in.

HytönenFimlab实验室，坦佩雷，芬兰德保拉·图尔基和维萨·P·Hytönen生物技术研究所，赫尔辛基大学，芬兰德夫特哈尔·乔杜里，蒂娜·奥曼和马克库·瓦尔乔萨洛AuthorsPaula TurkkiView作者出版物你也可以在中搜索这位作者。

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PubMed Google ScholarContributionsThe authors confirm contribution to the paper as follows: Study conception and design: Turkki P, Varjosalo M, Hytönen VP. data collection: Turkki P, Chowdhury I, Öhman T, Azizi L. Analysis and interpretation of results: Turkki P, Chowdhury I, Öhman T, Azizi L.

PubMed谷歌学术贡献作者确认对论文的贡献如下：研究概念和设计：Turkki P，Varjosalo M，Hytönen VP。数据收集：Turkki P，Chowdhury I，Öhman T，Azizi L.结果的分析和解释：Turkki P，Chowdhury I，Öhman T，Azizi L。

Draft manuscript preparation: Turkki P, Hytönen VP. All authors reviewed the results and approved the final version of the manuscript.Corresponding authorCorrespondence to.

草稿准备：Turkki P，Hytönen VP。所有作者都审查了结果并批准了稿件的最终版本。对应作者对应。

Vesa P. Hytönen.Ethics declarations

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Reprints and permissionsAbout this articleCite this articleTurkki, P., Chowdhury, I., Öhman, T. et al. Tensin-2 interactomics reveals interaction with GAPDH and a phosphorylation-mediated regulatory role in glycolysis.

转载和许可本文引用本文Turkki，P.，Chowdhury，I.，Öhman，T。等人。Tensin-2 interactomics揭示了与GAPDH的相互作用以及磷酸化介导的糖酵解调节作用。

Sci Rep 14, 19862 (2024). https://doi.org/10.1038/s41598-024-65787-7Download citationReceived: 20 April 2023Accepted: 24 June 2024Published: 27 August 2024DOI: https://doi.org/10.1038/s41598-024-65787-7Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

Sci Rep 1419862（2024）。https://doi.org/10.1038/s41598-024-65787-7Download引文接收日期：2023年4月20日接收日期：2024年6月24日发布日期：2024年8月27日OI：https://doi.org/10.1038/s41598-024-65787-7Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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