Cell Communication and Signaling最新文献

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Breast cancer cells utilize T3 to trigger proliferation through cellular Ca2+ modulation. 乳腺癌细胞利用 T3 通过细胞 Ca2+ 调节引发增殖。
IF 8.2 2区 生物学
Cell Communication and Signaling Pub Date : 2024-11-06 DOI: 10.1186/s12964-024-01917-y
Ines Tawfik, Katharina Schlick, Julian Ostaku, Doruntina Bresilla, Sonja Gabrijelčič, Benjamin Gottschalk, Alwin Sokolowski, Ernst Malle, Katarina Kalinova, Martin Hirtl, Corina T Madreiter-Sokolowski
{"title":"Breast cancer cells utilize T3 to trigger proliferation through cellular Ca<sup>2+</sup> modulation.","authors":"Ines Tawfik, Katharina Schlick, Julian Ostaku, Doruntina Bresilla, Sonja Gabrijelčič, Benjamin Gottschalk, Alwin Sokolowski, Ernst Malle, Katarina Kalinova, Martin Hirtl, Corina T Madreiter-Sokolowski","doi":"10.1186/s12964-024-01917-y","DOIUrl":"10.1186/s12964-024-01917-y","url":null,"abstract":"<p><p>High levels of thyroid hormones are linked to increased risk and advanced stages of breast cancer. Our previous work demonstrated that the biologically active triiodothyronine (T3) facilitates mitochondrial ATP production by upregulating Ca<sup>2+</sup> handling proteins, thereby boosting mitochondrial Ca<sup>2+</sup> uptake and Krebs cycle activity. In this study, different cell types were utilized to investigate whether T3 activates a Ca<sup>2+</sup>-induced signaling pathway to boost cancer cell proliferation. Using live-cell imaging, biochemical assays, and molecular profiling, differences in intracellular signaling among MCF7 and MDA-MB-468 breast cancer cells, non-cancerous breast cells hTERT-HME1, and PC3 prostate carcinoma cells, previously found to be insensitive to thyroid hormones in terms of proliferation, were investigated. Our findings revealed that T3 upregulates 1,4,5-trisphosphate receptor 3 via thyroid hormone receptor α. This boosts mitochondrial Ca<sup>2+</sup> uptake, reduction equivalent yield, and mitochondrial ATP production, supporting the viability and proliferation of breast cancer cells without affecting non-cancerous hTERT-HME1 or PC3 prostate carcinoma cells. Understanding the interplay between T3 signaling, organellar interaction, and breast cancer metabolism could lead to targeted therapies that exploit cancer cell vulnerabilities. Our findings highlight T3 as a crucial regulator of cancer metabolism, reinforcing its potential as a therapeutic target in breast cancer.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":null,"pages":null},"PeriodicalIF":8.2,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11539297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142591070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Atomoxetine suppresses radioresistance in glioblastoma via circATIC/miR-520d-5p/Notch2-Hey1 axis. 阿托莫西汀通过circATIC/miR-520d-5p/Notch2-Hey1轴抑制胶质母细胞瘤的放射抗性
IF 8.2 2区 生物学
Cell Communication and Signaling Pub Date : 2024-11-05 DOI: 10.1186/s12964-024-01915-0
Hyun Jeong Seok, Jae Yeon Choi, Dong Hyeon Lee, Incheol Shin, In Hwa Bae
{"title":"Atomoxetine suppresses radioresistance in glioblastoma via circATIC/miR-520d-5p/Notch2-Hey1 axis.","authors":"Hyun Jeong Seok, Jae Yeon Choi, Dong Hyeon Lee, Incheol Shin, In Hwa Bae","doi":"10.1186/s12964-024-01915-0","DOIUrl":"10.1186/s12964-024-01915-0","url":null,"abstract":"<p><strong>Background: </strong>Resistance acquired after radiotherapy is directly related to the failure of various cancer treatments, including GBM. Because the mechanism for overcoming radioresistance has not yet been clearly identified, the development of diagnostic and therapeutic markers to treat radioresistance is necessary. Since increased expression of stemness- and EMT-related markers are reported to be closely correlated with radioresistance, research is underway to develop new drugs targeting these factors.</p><p><strong>Methods: </strong>To develop an anticancer drug that overcomes radioresistance, a library of drugs already approved by the FDA was used. After treating radioresistant GBM cells with each drug, the expression of stemness- and EMT-related markers was confirmed by qRT-PCR, and as a result, Atomoxetine (ATX) was selected. It was confirmed that radioresistance-induced cell migratory, invasive, sphere formation abilities, and tumor growth using a xenograft mouse model were suppressed upon ATX treatment. Using a miRNA prediction tool, we discovered miR-520d-5p, which targets Notch2 and Hey1, key factors in radioresistance, and discovered circATIC targeting this miRNA, revealing its relationship with ATX. We demonstrated the expression regulation mechanism and signaling mechanism between circATIC, miR-520d-5p, Notch2, and Hey1 factors using a luciferase reporter assay. In addition, the results at the cellular level were clinically verified by confirming the correlation between radiation, miR-520d-5p, and circATIC using patient plasma by qRT-PCR.</p><p><strong>Results: </strong>ATX showed potential as a treatment for radioresistance by suppressing the malignant phenotype by regulating the circATIC/miR-520d-5p/Notch2-Hey1 signaling mechanism in vitro and in vivo using radioresistant GBM cells.</p><p><strong>Conclusions: </strong>This study revealed that ATX suppresses radioresistance through the circATIC/miR-520d-5p/Notch2-Hey1 signaling pathway. These results showed the potential of ATX as a new drug that can overcome radioresistance, a major challenge in cancer treatment, and the signaling factors identified in this mechanism suggest the possibility of use as potential targets for the diagnosis and treatment of radioresistance.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":null,"pages":null},"PeriodicalIF":8.2,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11536942/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142584950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Regulation of ADAM10 activity through microdomain-dependent intracellular calcium changes. 通过微域依赖性细胞内钙变化调节 ADAM10 的活性。
IF 8.2 2区 生物学
Cell Communication and Signaling Pub Date : 2024-11-04 DOI: 10.1186/s12964-024-01891-5
Federico Guillermo Gharzia, Ahmad Aljohmani, Andreas Beck, Stephan E Philipp, Daniela Yildiz
{"title":"Regulation of ADAM10 activity through microdomain-dependent intracellular calcium changes.","authors":"Federico Guillermo Gharzia, Ahmad Aljohmani, Andreas Beck, Stephan E Philipp, Daniela Yildiz","doi":"10.1186/s12964-024-01891-5","DOIUrl":"10.1186/s12964-024-01891-5","url":null,"abstract":"<p><p>A disintegrin and metalloproteinases (ADAMs) are transmembrane proteases that cleave other proteins close to the surface in a process called shedding. The prominent member ADAM10 has been linked to several pathologies such as Alzheimer's disease, bacterial infection, cancer development and metastasis. Although the regulation of the ADAM10 activity by calcium influx and calmodulin inhibition has been reported, the spatiotemporal regulation of Ca<sup>2+</sup>-dependent ADAM10 activation and the required source of Ca<sup>2+</sup> ions have not been thoroughly studied. In the present study, we observed the rapid Ca<sup>2+</sup>-dependent activation of ADAM10 in A549 lung carcinoma cells upon stimulation with ionomycin. The calmodulin-inhibitors trifluoperazine and ophiobolin A mediated delayed activation of ADAM10, which apparently did not depend on intracellular Ca<sup>2+</sup> in the case of trifluoperazine. Furthermore, the surface translocation and release of ADAM10 in extracellular vesicles exhibited different kinetics and were only partially linked to catalytic activation. Finally, ADAM10 activation was observed after the entry of Ca<sup>2+</sup> through certain channels, such as canonical members of transient receptor potential (TRP) channels. Therefore, the opening of particular channels for Ca<sup>2+</sup> entry points and subsequent Ca<sup>2+</sup> flux as well as the temporal aspects of the consequent increase in Ca<sup>2+</sup> levels, must be considered for future therapeutic options involving the increasing or decreasing ADAM10 activity.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":null,"pages":null},"PeriodicalIF":8.2,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11533308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142577158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Blue light-driven cell cycle arrest in thyroid cancer via Retinal-OPN3 complex. 蓝光通过视网膜-OPN3复合物驱动甲状腺癌细胞周期停滞。
IF 8.2 2区 生物学
Cell Communication and Signaling Pub Date : 2024-11-01 DOI: 10.1186/s12964-024-01908-z
Changrui Zhao, Jiaqiang Bo, Tianyu Li, Jiameng Tian, Tian Long, Yingying He, Siyu Chen, Chang Liu
{"title":"Blue light-driven cell cycle arrest in thyroid cancer via Retinal-OPN3 complex.","authors":"Changrui Zhao, Jiaqiang Bo, Tianyu Li, Jiameng Tian, Tian Long, Yingying He, Siyu Chen, Chang Liu","doi":"10.1186/s12964-024-01908-z","DOIUrl":"10.1186/s12964-024-01908-z","url":null,"abstract":"<p><strong>Background: </strong>Papillary thyroid carcinoma (PTC) is the most common type of thyroid malignancy, with a rising incidence. Traditional treatments, such as thyroidectomy and radiotherapy, often lead to significant side effects, including impaired thyroid function. Therefore, there is an urgent need for non-invasive therapeutic approaches. This study aims to explore the potential of photobiomodulation therapy (PBMT), a non-invasive treatment using specific wavelengths of light, in the management of PTC.</p><p><strong>Methods: </strong>We investigated the effects of blue light PBMT on PTC cells, focusing on the Retinal-OPSIN 3 (OPN3) complex's role in mediating cellular responses. Blue light exposure was applied to PTC cells, and subsequent changes in cellular proliferation, cell cycle progression, and protein expression were analyzed. Statistical tests, including one-way ANOVA and t-tests, were used to evaluate the significance of the findings.</p><p><strong>Results: </strong>Blue light exposure led to the dissociation of 11-cis-retinal from OPN3, resulting in the accumulation of all-trans retinal. This accumulation disrupted cellular proliferation pathways and induced G0/G1 cell cycle arrest in PTC cells. The Retinal-OPN3 complex was found to be a key mediator in these processes, demonstrating that thyroid cells can respond to specific light wavelengths and utilize their photoreceptive potential for therapeutic purposes.</p><p><strong>Conclusions: </strong>Our findings suggest that PBMT, through the modulation of the Retinal-OPN3 complex, offers a promising non-invasive approach for treating PTC. This study highlights the therapeutic potential of light signal transduction in non-ocular tissues and opens new avenues for non-invasive cancer therapies.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":null,"pages":null},"PeriodicalIF":8.2,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11531186/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142565096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
PIM1 kinase and its diverse substrate in solid tumors. PIM1 激酶及其在实体瘤中的多种底物。
IF 8.2 2区 生物学
Cell Communication and Signaling Pub Date : 2024-11-01 DOI: 10.1186/s12964-024-01898-y
Rituparna Choudhury, Chandan Kumar Bahadi, Ipsa Pratibimbita Ray, Pragyanshree Dash, Isha Pattanaik, Suman Mishra, Soumya R Mohapatra, Srinivas Patnaik, Kumar Nikhil
{"title":"PIM1 kinase and its diverse substrate in solid tumors.","authors":"Rituparna Choudhury, Chandan Kumar Bahadi, Ipsa Pratibimbita Ray, Pragyanshree Dash, Isha Pattanaik, Suman Mishra, Soumya R Mohapatra, Srinivas Patnaik, Kumar Nikhil","doi":"10.1186/s12964-024-01898-y","DOIUrl":"10.1186/s12964-024-01898-y","url":null,"abstract":"<p><p>The PIM kinase family, consisting of PIM1, PIM2, and PIM3, is a group of serine/threonine protein kinases crucial for cellular growth, immunoregulation, and oncogenesis. PIM1 kinase is often overexpressed in solid and hematopoietic malignancies, promoting cell survival, proliferation, migration, and senescence by activating key genes. In vitro and in vivo studies have established the oncogenic potential of PIM1 kinases. These kinases have been implicated in tumor progression, metastasis, and resistance to chemotherapy, underscoring their potential as a therapeutic target for cancer therapy. This review delves into the intricate molecular mechanisms through which PIM1 interacts with specific substrates in different tumor tissues, leading to diverse outcomes in various human cancers. Over the past decade, the inhibition of PIM1 in cancers has garnered significant attention as a potential standalone treatment. Various in vitro, in vivo, and early clinical trial data have provided support for this approach to varying extents. Novel compounds that inhibit PIM1 kinase have shown effectiveness and a favorable toxicity profile in preclinical studies. Several of these substances are now being studied in clinical trials due to their promising outcomes. This article provides a thorough examination of the PIM1 kinase pathways and the recent advancements in producing PIM1 kinase inhibitors for the treatment of cancer.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":null,"pages":null},"PeriodicalIF":8.2,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11531143/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142565098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Exosome-based immunotherapy as an innovative therapeutic approach in melanoma. 基于外泌体的免疫疗法是治疗黑色素瘤的一种创新方法。
IF 8.2 2区 生物学
Cell Communication and Signaling Pub Date : 2024-10-31 DOI: 10.1186/s12964-024-01906-1
Shabnam Babaei, Manouchehr Fadaee, Hajar Abbasi-Kenarsari, Dariush Shanehbandi, Tohid Kazemi
{"title":"Exosome-based immunotherapy as an innovative therapeutic approach in melanoma.","authors":"Shabnam Babaei, Manouchehr Fadaee, Hajar Abbasi-Kenarsari, Dariush Shanehbandi, Tohid Kazemi","doi":"10.1186/s12964-024-01906-1","DOIUrl":"10.1186/s12964-024-01906-1","url":null,"abstract":"<p><p>The malignant form of melanoma is one of the deadliest human cancers that accounts for almost all of the skin tumor-related fatalities in its later stages. Achieving an exhaustive understanding of reliable cancer-specific markers and molecular pathways can provide numerous practical techniques and direct the way toward the development of rational curative medicines to increase the lifespan of patients. Immunotherapy has significantly enhanced the treatment of metastatic and late-stage melanoma, resulting in an incredible increase in positive responses to therapy. Despite the increasing occurrence of melanoma, the median survival rate for patients with advanced, inoperable terminal disease has increased from around six months to almost six years. The current knowledge of the tumor microenvironment (TME) and its interaction with the immune system has resulted in the swift growth of innovative immunotherapy treatments. Exosomes are small extracellular vesicles (EVs), ranging from 30 to 150 nm in size, that the majority of cells released them. Exosomes possess natural advantages such as high compatibility with living organisms and low potential for causing immune reactions, making them practical for delivering therapeutic agents like chemotherapy drugs, nucleic acids, and proteins. This review highlights recent advancements in using exosomes as an approach to providing medications for the treatment of melanoma.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":null,"pages":null},"PeriodicalIF":8.2,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11526674/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Refractory testicular germ cell tumors are highly sensitive to the targeting of polycomb pathway demethylases KDM6A and KDM6B. 难治性睾丸生殖细胞肿瘤对靶向多聚酶途径去甲基化酶KDM6A和KDM6B高度敏感。
IF 8.2 2区 生物学
Cell Communication and Signaling Pub Date : 2024-10-31 DOI: 10.1186/s12964-024-01912-3
Doha Shokry, Mehwish W Khan, Christine Powell, Samantha Johnson, Brayden C Rennels, Raya I Boyd, Zhengyang Sun, Zeeshan Fazal, Sarah J Freemantle, Maryanna H Parker, Miranda D Vieson, Jonathan P Samuelson, Michael J Spinella, Ratnakar Singh
{"title":"Refractory testicular germ cell tumors are highly sensitive to the targeting of polycomb pathway demethylases KDM6A and KDM6B.","authors":"Doha Shokry, Mehwish W Khan, Christine Powell, Samantha Johnson, Brayden C Rennels, Raya I Boyd, Zhengyang Sun, Zeeshan Fazal, Sarah J Freemantle, Maryanna H Parker, Miranda D Vieson, Jonathan P Samuelson, Michael J Spinella, Ratnakar Singh","doi":"10.1186/s12964-024-01912-3","DOIUrl":"10.1186/s12964-024-01912-3","url":null,"abstract":"<p><p>Testicular germ cell tumors (TGCTs) can be treated with cisplatin-based therapy. However, a clinically significant number of cisplatin-resistant patients die from progressive disease as no effective alternatives exist. Curative cisplatin therapy results in acute and life-long toxicities in the young TGCT patient population providing a rationale to decrease cisplatin exposure. In contrast to genetic alterations, recent evidence suggests that epigenetics is a major driving factor for TGCT formation, progression, and response to chemotherapy. Hence, targeting epigenetic pathways with \"epidrugs\" is one potential relatively unexplored strategy to advance TGCT treatment beyond cisplatin. In this report, we demonstrate for the first time that targeting polycomb demethylases KDM6A and KDM6B with epidrug GSK-J4 can treat both cisplatin-sensitive and -resistant TGCTs. While GSK-J4 had minimal effects alone on TGCT tumor growth in vivo, it dramatically sensitized cisplatin-sensitive and -resistant TGCTs to cisplatin. We validated KDM6A/KDM6B as the target of GSK-J4 since KDM6A/KDM6B genetic depletion had a similar effect to GSK-J4 on cisplatin-mediated anti-tumor activity and transcriptome alterations. Pharmacologic and genetic targeting of KDM6A/KDM6B potentiated or primed the p53-dominant transcriptional response to cisplatin, with also evidence for basal activation of p53. Further, several chromatin modifier genes, including BRD4, lysine demethylases, chromodomain helicase DNA binding proteins, and lysine methyltransferases, were repressed with cisplatin only in KDM6A/KDM6B-targeted cells, implying that KDM6A/KDM6B inhibition sets the stage for extensive chromatin remodeling of TGCT cells upon cisplatin treatment. Our findings demonstrate that targeting polycomb demethylases is a new potent pharmacologic strategy for treating cisplatin resistant TGCTs that warrants clinical development.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":null,"pages":null},"PeriodicalIF":8.2,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11529429/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A non-catalytic role of IPMK is required for PLCγ1 activation in T cell receptor signaling by stabilizing the PLCγ1-Sam68 complex. 通过稳定 PLCγ1-Sam68 复合物,IPMK 在 T 细胞受体信号传导过程中的非催化作用是 PLCγ1 激活所必需的。
IF 8.2 2区 生物学
Cell Communication and Signaling Pub Date : 2024-10-30 DOI: 10.1186/s12964-024-01907-0
Sehoon Hong, Kyurae Kim, Young-Ri Shim, Jiyeon Park, Sung Eun Choi, Hyungyu Min, Seulgi Lee, Ji-Joon Song, Suk-Jo Kang, Won-Il Jeong, Rho Hyun Seong, Seyun Kim
{"title":"A non-catalytic role of IPMK is required for PLCγ1 activation in T cell receptor signaling by stabilizing the PLCγ1-Sam68 complex.","authors":"Sehoon Hong, Kyurae Kim, Young-Ri Shim, Jiyeon Park, Sung Eun Choi, Hyungyu Min, Seulgi Lee, Ji-Joon Song, Suk-Jo Kang, Won-Il Jeong, Rho Hyun Seong, Seyun Kim","doi":"10.1186/s12964-024-01907-0","DOIUrl":"10.1186/s12964-024-01907-0","url":null,"abstract":"<p><strong>Background: </strong>Phospholipase C gamma 1 (PLCγ1) is an important mediator of the T cell receptor (TCR) and growth factor signaling. PLCγ1 is activated by Src family kinases (SFKs) and produces inositol 1,4,5-triphosphate (InsP<sub>3</sub>) from phosphatidylinositol 4,5-bisphosphate (PIP<sub>2</sub>). Inositol polyphosphate multikinase (IPMK) is a pleiotropic enzyme with broad substrate specificity and non-catalytic activities that mediate various functional protein-protein interactions. Therefore, IPMK plays critical functions in key biological events such as cell growth. However, the contribution of IPMK to the activation of PLCγ1 in TCR signaling remains mostly unelucidated. The current study aimed to elucidate the functions of IPMK in TCR signaling and to uncover the mode of IPMK-mediated signaling action in PLCγ1 activation.</p><p><strong>Methods: </strong>Concanavalin A (ConA)-induced acute hepatitis model was established in CD4<sup>+</sup> T cell-specific IPMK knockout mice (IPMK<sup>ΔCD4</sup>). Histological analysis was performed to assess hepatic injury. Primary cultures of naïve CD4<sup>+</sup> T cells were used to uncover the role of mechanisms of IPMK in vitro. Western blot analysis, quantitative real-time PCR, and flow cytometry were performed to analyze the TCR-stimulation-induced PLCγ1 activation and the downstream signaling pathway in naïve CD4<sup>+</sup> T cells. Yeast two-hybrid screening and co-immunoprecipitation were conducted to identify the IPMK-binding proteins and protein complexes.</p><p><strong>Results: </strong>IPMK<sup>ΔCD4</sup> mice showed alleviated ConA-induced acute hepatitis. CD4<sup>+</sup> helper T cells in these mice showed reduced PLCγ1 Y783 phosphorylation, which subsequently dampens calcium signaling and IL-2 production. IPMK was found to contribute to PLCγ1 activation via the direct binding of IPMK to Src-associated substrate during mitosis of 68 kDa (Sam68). Mechanistically, IPMK stabilizes the interaction between Sam68 and to PLCγ1, thereby promoting PLCγ1 phosphorylation. Interfering this IPMK-Sam68 binding interaction with IPMK dominant-negative peptides impaired PLCγ1 phosphorylation.</p><p><strong>Conclusions: </strong>Our results demonstrate that IPMK non-catalytically promotes PLCγ1 phosphorylation by stabilizing the PLCγ1-Sam68 complex. Targeting IPMK in CD4<sup>+</sup> T cells may be a promising strategy for managing immune diseases caused by excessive stimulation of TCR.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":null,"pages":null},"PeriodicalIF":8.2,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11524019/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142549043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The multifaceted role of mitochondria in cardiac function: insights and approaches. 线粒体在心脏功能中的多方面作用:见解和方法。
IF 8.2 2区 生物学
Cell Communication and Signaling Pub Date : 2024-10-29 DOI: 10.1186/s12964-024-01899-x
Sriram Ravindran, Christoph D Rau
{"title":"The multifaceted role of mitochondria in cardiac function: insights and approaches.","authors":"Sriram Ravindran, Christoph D Rau","doi":"10.1186/s12964-024-01899-x","DOIUrl":"10.1186/s12964-024-01899-x","url":null,"abstract":"<p><p>Cardiovascular disease (CVD) remains a global economic burden even in the 21st century with 85% of deaths resulting from heart attacks. Despite efforts in reducing the risk factors, and enhancing pharmacotherapeutic strategies, challenges persist in early identification of disease progression and functional recovery of damaged hearts. Targeting mitochondrial dysfunction, a key player in the pathogenesis of CVD has been less successful due to its role in other coexisting diseases. Additionally, it is the only organelle with an agathokakological function that is a remedy and a poison for the cell. In this review, we describe the origins of cardiac mitochondria and the role of heteroplasmy and mitochondrial subpopulations namely the interfibrillar, subsarcolemmal, perinuclear, and intranuclear mitochondria in maintaining cardiac function and in disease-associated remodeling. The cumulative evidence of mitochondrial retrograde communication with the nucleus is addressed, highlighting the need to study the genotype-phenotype relationships of specific organelle functions with CVD by using approaches like genome-wide association study (GWAS). Finally, we discuss the practicality of computational methods combined with single-cell sequencing technologies to address the challenges of genetic screening in the identification of heteroplasmy and contributory genes towards CVD.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":null,"pages":null},"PeriodicalIF":8.2,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11523909/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142549045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Gelsolin regulates intestinal stem cell regeneration and Th17 cellular function. Gelsolin 可调节肠道干细胞再生和 Th17 细胞功能。
IF 8.2 2区 生物学
Cell Communication and Signaling Pub Date : 2024-10-29 DOI: 10.1186/s12964-024-01902-5
Jicong Du, Lan Fang, Yuedong Wang, Jianpeng Zhao, Zhenlan Feng, Yike Yu, Duo Fang, Daqian Huang, Xuanlu Zhai, Ying Cheng, Rui Min, Fu Gao, Cong Liu
{"title":"Gelsolin regulates intestinal stem cell regeneration and Th17 cellular function.","authors":"Jicong Du, Lan Fang, Yuedong Wang, Jianpeng Zhao, Zhenlan Feng, Yike Yu, Duo Fang, Daqian Huang, Xuanlu Zhai, Ying Cheng, Rui Min, Fu Gao, Cong Liu","doi":"10.1186/s12964-024-01902-5","DOIUrl":"10.1186/s12964-024-01902-5","url":null,"abstract":"<p><p>Intestinal stem cells (ISCs) are responsible for intestinal homeostasis and are important for the regeneration of damaged intestine. We established an ionizing radiation (IR)-induced intestinal injury model and observed that Gelsolin KO mice had increased radiosensitivity. The deletion of Gelsolin aggravated intestinal damage and reduced the number of ISCs after lethal IR. The intestinal organoid experiments showed that Gelsolin deletion inhibited ISCs function after IR. Notably, RNA sequencing and RT-PCR results showed IL-17 signaling pathway was down-regulated and Th17 cells differentiation was inhibited in Gelsolin KO mice. Moreover, recombinant IL-17 A ameliorated IR-induced intestinal injury and promoted ISCs regeneration. To figure out the role of Gelsolin in Th17 cells differentiation, flow cytometry was used and we found that Gelsolin targets Th17 cells functionality via the p-STAT3/RORγt axis. By establishing the co-culture system, we proved that Th17 cells promoted self-renewal and budding abilities in Gelsolin-deficient organoids. Finally, we found that Gelsolin was protective against DSS-induced colitis and that this protective effect was not specific or limited to the IR induced intestinal injury model. Based on these results, we proved Gelsolin maintained the regeneration of ISCs by sustaining Th17 cells functions via the p-STAT3/RORγt axis.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":null,"pages":null},"PeriodicalIF":8.2,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11520831/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142549044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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