Experimental cell research最新文献

{"title":"FBXL6 drives tumorigenesis in lung adenocarcinoma through ubiquitination and proteasomal degradation of CDKN1C","authors":"Guanzhong Dong,&nbsp;Ning Zhang,&nbsp;Dong Yang,&nbsp;Zibo Zhu,&nbsp;Yi He","doi":"10.1016/j.yexcr.2025.114872","DOIUrl":"10.1016/j.yexcr.2025.114872","url":null,"abstract":"<div><div>Lung adenocarcinoma (LUAD) is a highly prevalent and lethal malignancy. Although F-box and leucine-rich repeat protein 6 (FBXL6), an E3 ubiquitin ligase, has been implicated in tumor progression across certain cancers, its functional role in LUAD remains unclear. In this study, we investigated the oncogenic potential of FBXL6 in LUAD pathogenesis. Bioinformatics analysis of GEO, TCGA, and TNM datasets revealed significant upregulation of FBXL6 in LUAD tissues. Functional studies using FBXL6-knockdown (via shRNA in PC-9 cells) and FBXL6-overexpressing (via plasmid transfection in A549 cells) demonstrated that FBXL6 depletion suppressed cell proliferation, migration, and invasion, whereas its overexpression reversed these effects. In vivo experiments further confirmed that FBXL6 knockdown in PC-9 cells inhibited tumor growth and liver metastasis in BALB/c nude mice following subcutaneous or tail vein injection. Mechanistically, FBXL6 was found to physically interact with cyclin-dependent kinase inhibitor 1C (CDKN1C/p57Kip2) and promote its polyubiquitination and proteasomal degradation, thereby destabilizing this tumor suppressor. Rescue assays validated that CDKN1C mediates the pro-tumorigenic effects of FBXL6 on LUAD cell proliferation and metastasis. Collectively, our findings reveal that FBXL6 drives LUAD progression by ubiquitinating and degrading CDKN1C, highlighting its potential as a therapeutic target for LUAD.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"455 2","pages":"Article 114872"},"PeriodicalIF":3.5,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145827178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrin β1 contributes to acute pancreatitis by mediating macrophage adhesion and inflammatory cascades","authors":"Yansong Xu ,&nbsp;Yuansong Sun ,&nbsp;Chunlin Yin ,&nbsp;Fei Xie ,&nbsp;He Li","doi":"10.1016/j.yexcr.2025.114883","DOIUrl":"10.1016/j.yexcr.2025.114883","url":null,"abstract":"<div><div>Acute pancreatitis (AP) exhibits marked clinical heterogeneity. To investigate the molecular mechanisms involved in AP, we integrated bioinformatics analysis of public sequencing datasets, which identified differentially expressed genes (DEGs) significantly associated with AP. Subsequently, GO/KEGG enrichment analyses revealed robust involvement of these DEGs in cellular adhesion and MAPK signaling pathways. Protein-protein interaction (PPI) network analysis pinpointed integrin β1 (ITGB1) as the central hub gene, while single-gene gene set enrichment analysis (GSEA) across ontological databases confirmed its significant enrichment in pathways associated with adhesion and inflammation. These findings establish ITGB1 as a pivotal regulator coordinating cell adhesion and inflammatory responses in AP. In murine AP models, ITGB1 protein was significantly upregulated in the pancreas and co-localized specifically with macrophages. <em>In vitro</em> studies using bone marrow-derived macrophages (BMDMs) revealed that ITGB1 upregulation enhanced macrophage-endothelial adhesion and inflammatory cascades through p38 MAPK phosphorylation. Critically, clinical translation studies established the dual diagnostic value of ITGB1. The receiver operating characteristic (ROC) curve exhibited significant discriminatory power for distinguishing patients with AP from healthy controls, along with robust efficacy in stratifying disease severity. In conclusion, ITGB1 orchestrates macrophage-mediated inflammation through p38 MAPK-dependent mechanisms and can function as a biomarker for diagnosis and severity stratification in AP.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"455 2","pages":"Article 114883"},"PeriodicalIF":3.5,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145855157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The circ-GLG1/miR-346/KCNJ9 axis drives malignant progression of bladder cancer by modulating KCNJ9 expression","authors":"Kangjie He ,&nbsp;Chunxiao Lin ,&nbsp;Hengyou Wang ,&nbsp;Hongshen Wu ,&nbsp;Shanfeng Yin ,&nbsp;Chang Tao ,&nbsp;Xiang Yan","doi":"10.1016/j.yexcr.2026.114885","DOIUrl":"10.1016/j.yexcr.2026.114885","url":null,"abstract":"<div><div>Bladder cancer is a common malignant tumor of the urinary system, with its malignant progression mechanisms remaining unclear. In this study, a circular RNA (hsa_circ_0040457, hereinafter referred to as \"circ-GLG1″), which has been less characterized in bladder cancer, was identified. It is significantly overexpressed in bladder cancer tissues and cells, and closely associated with patients' pTNM stage and poor prognosis. Circ-GLG1 is formed by back-splicing of exons 23–26 of the GLG1 gene, with circular stability and IRES-dependent translational potential. Functional studies confirmed that silencing circ-GLG1 inhibits cellular malignant phenotypes and tumor formation in nude mice, while overexpression promotes progression by activating TGF-β, PI3K-AKT, and MAPK pathways. Mechanistically, transcriptome sequencing identified 555 differentially expressed genes, with GO/KEGG enrichment in cancer-related pathways. Combined with database prediction, KCNJ9 was identified as a key target. Luciferase assays confirmed that circ-GLG1 may sponge miR-346, relieving its inhibitory effect on KCNJ9's 3′UTR. Functional rescue experiments showed that KCNJ9 overexpression reversed the phenotypic and pathway inactivation induced by circ-GLG1 silencing, verifying the \"circ-GLG1/miR-346/KCNJ9″ regulatory axis. This study reveals that circ-GLG1 acts as a ceRNA to target KCNJ9, relieving miR-346-mediated post-transcriptional inhibition, with concurrent activation of TGF-β, PI3K-AKT, and MAPK pathways via KCNJ9 that are associated with bladder cancer progression.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"455 2","pages":"Article 114885"},"PeriodicalIF":3.5,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145905790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioinformatics analysis of PLAUR and its oncogenic role of promoting colorectal cancer progression through the AKT/p53 signaling","authors":"You Chen ,&nbsp;Rui Ma ,&nbsp;Chuyue Wang ,&nbsp;Zhiying Yang ,&nbsp;Ying Shi ,&nbsp;Yingying Zhao ,&nbsp;Xiaofen Pan ,&nbsp;Bo Wang ,&nbsp;Weili Wu ,&nbsp;Ping Yuan","doi":"10.1016/j.yexcr.2025.114850","DOIUrl":"10.1016/j.yexcr.2025.114850","url":null,"abstract":"<div><div>Cancer is a significant global health challenge, driving an urgent need to uncover novel therapeutic strategies, including for colorectal cancer (CRC). Elevated expression of the plasminogen activator, urokinase receptor (PLAUR) has been reported in several cancer types and is correlated with cancer progression. This study aims to evaluate the role of PLAUR in CRC and investigate its underlying mechanisms. We found that PLAUR expression was elevated across multiple cancer types, particularly in CRC, and consistently correlated with poor survival. Functional experiments <em>in vitro</em> and <em>in vivo</em> demonstrated that PLAUR knockdown inhibited tumor cell growth, triggering G1/S phase cell cycle arrest and apoptosis. Conversely, PLAUR overexpression facilitated malignant phenotypes. Mechanistically, PLAUR depletion activated the p53 pathway, which was associated with reduced phosphorylated AKT. PLAUR knockdown led to significant downregulation of phosphorylated AKT and upregulation of p53 and p21 in CRC cells, suggesting the involvement of the AKT/p53 pathway. Rescue experiments confirmed that PLAUR promotes malignant progression in colorectal cancer via the AKT/p53 pathway. In summary, these findings highlight the potential of PLAUR as a prospective prognostic indicator and a therapeutic target in CRC.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"455 2","pages":"Article 114850"},"PeriodicalIF":3.5,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145700082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GLRX5 is a prognostic marker in bladder cancer and correlates with activation of cancer-associated fibroblasts in the tumor microenvironment","authors":"Yini Wang ,&nbsp;Hongquan Liu ,&nbsp;Tianqi Wang ,&nbsp;Yingying Yang ,&nbsp;Xiaohong Ma ,&nbsp;Jitao Wu","doi":"10.1016/j.yexcr.2025.114884","DOIUrl":"10.1016/j.yexcr.2025.114884","url":null,"abstract":"<div><h3>Objective</h3><div>Investigate the function of glutathione reductase-associated protein 5 (GLRX5) and its prognostic significance, as well as its association with CAFs and the TME.</div></div><div><h3>Methods</h3><div>Based on data from TCGA and the GEO databases, this study investigates the expression of GLRX5 in BLCA and its association with clinical outcomes. Using the ssGSEA algorithm, we explored the association between functional features of GLRX5 and BLCA. We validated our findings using in vitro cellular functional assays. We explored the regulatory mechanisms associated with GLRX5 using GO, KEGG, and GSEA. Furthermore, based on single-cell and spatial transcriptomics data from bladder cancer, we analyzed the expression patterns and potential functions of GLRX5 in bladder cancer. The results of the above analyses were experimentally explored and validated.</div></div><div><h3>Results</h3><div>High expression of GLRX5 in BLCA correlates with malignant biological behavior and poor prognosis. Enrichment analysis indicates that GLRX5 is primarily associated with malignant functional characteristics in bladder cancer, and its expression levels are also linked to EMT, OXPHOS, and FAM. The above analyses have all been validated through in vitro experiments. Single-cell and spatial transcriptomics analyses indicate that GLRX5 is also expressed in CAFs and participates in metabolic pathways. Experiments demonstrated that GLRX5 promotes the activation of CAFs and may enhance tumor cell migration by influencing pathways within the TME.</div></div><div><h3>Conclusion</h3><div>High expression of GLRX5 in tumor cells promotes malignant biological behavior and predicts poor prognosis. At the same time, high expression of GLRX5 in CAFs promotes tumor cell migration by affecting the TME.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"455 2","pages":"Article 114884"},"PeriodicalIF":3.5,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145899569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"p38 MAPK-mediated suppression of Nrf2-MPC2 axis drives metabolic reprogramming which confers imatinib resistance in blast crisis phase of chronic myeloid leukemia","authors":"Manish Bhat ,&nbsp;Mythreyi Narasimhan ,&nbsp;Ashutosh Shelar ,&nbsp;Raghavendra Patwardhan ,&nbsp;Santosh Kumar Sandur ,&nbsp;Rukmini Govekar","doi":"10.1016/j.yexcr.2025.114870","DOIUrl":"10.1016/j.yexcr.2025.114870","url":null,"abstract":"<div><h3>Background</h3><div>Metabolic reprogramming is a hallmark of cancer and its role in tumour drug resistance is emerging. This study explored its role in resistance to tyrosine kinase inhibitors (TKIs) in the blast crisis (BC) phase of chronic myeloid leukemia (CML), which occurs despite inactivation of the oncogenic Bcr-Abl by TKIs. We previously reported that this Bcr-Abl-independent resistance is mimicked in TKI-resistant CML-BC cell line and is causally associated with p38MAPK, a known modulator of metabolism. Thus, we investigated whether p38MAPK-mediated metabolic rewiring caused resistance in CML-BC.</div></div><div><h3>Methods</h3><div>Imatinib sensitive and resistant CML-BC cell lines K562 and KU812 were analysed for metabolic proteins by Western blotting, metabolome by mass spectrometry, and apoptosis, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) by flow cytometry. Sequence of alterations was established by inhibition and knockdown studies.</div></div><div><h3>Results</h3><div>TKI-resistant cells exhibited enhanced glucose uptake, increased levels of GLUT1, glycolytic enzymes, and those of pyruvate and ATP which reduced upon inhibition of GLUT1, indicative of enhanced glycolysis as contributor of energy. In contrast, the cells displayed reduced NADH/NAD ratio, MMP, mitochondrial ROS which resulted in reduction in apoptotic population. Inhibition studies revealed that suppression of hyperphosphorylated p38MAPK-mediated activation of Nrf2, caused reduced mitochondrial pyruvate carrier (MPC2) expression. MPC2 inhibition in sensitive cells recapitulated the resistant phenotype with reduced MMP and ROS levels.</div></div><div><h3>Conclusion</h3><div>p38MAPK-mediated suppression of Nrf2/MPC2 axis abrogates mitochondrial function and ROS-mediated cell death while enhanced glycolysis generates ATP to sustain growth. The resultant pro-survival conditions allow leukemic cell survival under drug pressure causing resistance.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"455 2","pages":"Article 114870"},"PeriodicalIF":3.5,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145803318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MICA/B-driven NK cell dysfunction promotes cervical cancer via Toll signaling","authors":"Hatila Tuerxun ,&nbsp;JinQiu Li ,&nbsp;Qian Liu ,&nbsp;Mikrban Tursun ,&nbsp;Jin BaoXiao ,&nbsp;Chengwei Wang ,&nbsp;Ayshamgul Hasim","doi":"10.1016/j.yexcr.2025.114876","DOIUrl":"10.1016/j.yexcr.2025.114876","url":null,"abstract":"<div><div>The immune status is of crucial importance in the development of cervical cancer (CC). MICA/B, as a major histocompatibility complex Class I associated protein, mediates anti-tumor immunity by activating NK cell receptors. However, the precise mechanisms underlying MICA/B-mediated regulation of CC progression remain poorly understood. This study combined spatial transcriptome sequencing and bioinformatics analysis and found that MICA/B was significantly highly expressed in CC tissues and cells, accompanied by more NK cell infiltration. Flow cytometry and Cell Functional assays, Knockdown of MICA/MICB weakens the activation receptor efficacy of NK cells, enhances the inhibitory signal, leads to a decrease in cytotoxicity, and simultaneously upregulates Cyclin expression in CC cells while downregulating BCL-2/BAX. Tumor xenograft models indicated that tumors with MICA knockdown exhibited a growth tendency in the presence of natural killer (NK) cells. Mechanistically, MICA/B regulates inflammatory factors such as IL-6 and CXCL10/11 through the Toll-like signaling pathway, affecting the function of NK cells. Thus, MICA/B expression on cervical cancer cells plays a pivotal role in eliciting NK cell-mediated antitumor immunity. Their downregulation attenuates NK cell function, promoting cervical cancer cell proliferation and survival via the Toll signaling pathway. These findings highlight the potential of targeting MICA/B-NK cell interactions as a therapeutic strategy for cervical cancer.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"455 2","pages":"Article 114876"},"PeriodicalIF":3.5,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145877978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neutrophil extracellular traps promote epithelial-mesenchymal transition in COPD via the RAGE/PI3K/AKT pathway","authors":"Jiawei Zou ,&nbsp;Lin Chen ,&nbsp;Yang Yang ,&nbsp;Zengyu Huo ,&nbsp;Yuhong Liu ,&nbsp;Zhijuan Luo ,&nbsp;Siyi Ou ,&nbsp;Cunlai Xu ,&nbsp;Jing Bai","doi":"10.1016/j.yexcr.2025.114869","DOIUrl":"10.1016/j.yexcr.2025.114869","url":null,"abstract":"<div><div>Neutrophil extracellular traps (NETs) play a critical role in smoking-related chronic airway inflammation. However, it remains unknown whether NETs promote COPD progression by affecting epithelial-mesenchymal transition (EMT). This study aimed to investigate the correlation between serum biomarker profiles and pulmonary function in COPD patients, elucidate the relationship between NETs formation and EMT in COPD lung tissue, and explore the effect of cigarette smoke extract (CSE)-induced NETs on EMT in bronchial epithelial cells and its molecular mechanisms. We found that COPD patients showed decreased serum DNase-I and elevated IL-6, TNF-α, dsDNA, and MPO-DNA levels. COPD lung tissues exhibited increased NETs accumulation and altered EMT-related protein expression. In vitro, CSE-NETs treatment altered the gene expression profile of BEAS-2B cells, activating the RAGE/PI3K/AKT signaling pathway and promoting EMT. Inhibition of RAGE or PI3K attenuated CSE-NETs-induced EMT. In vivo, DNase-I and CI-amidine Attenuate Emphysema and EMT in Cigarette Smoke–Induced COPD Mice by Reducing NETs. This study reveals the critical role of CSE-induced-NETs in the pathogenesis of COPD and identifies the RAGE/PI3K/AKT signaling pathway as a potential therapeutic target, providing new insights for COPD treatment.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"455 2","pages":"Article 114869"},"PeriodicalIF":3.5,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SLBP promotes lung adenocarcinoma progression by inhibiting ferroptosis and reprogramming glutamine metabolism via FADS2 interaction","authors":"Wei Yan ,&nbsp;Pengfei Xu ,&nbsp;Dan Xiao ,&nbsp;Dong Hong ,&nbsp;Huiqun Liu ,&nbsp;Yigang Liu ,&nbsp;Yaqi Wang ,&nbsp;Tanxiu Chen ,&nbsp;Anwen Liu","doi":"10.1016/j.yexcr.2025.114849","DOIUrl":"10.1016/j.yexcr.2025.114849","url":null,"abstract":"<div><div>SLBP is significantly overexpressed in lung adenocarcinoma (LUAD) and correlates strongly with poor patient prognosis. Functional studies demonstrated that SLBP potently enhances proliferation, invasion, and metastasis of LUAD cells both <em>in vitro</em> and <em>in vivo</em>. Mechanistically, SLBP suppresses ferroptosis—a form of regulated cell death—by modulating key biochemical markers, including GSH, MDA, and Fe²⁺ levels, and it restores cell viability upon treatment with ferroptosis inducers. RNA-seq and biochemical analyses revealed that SLBP transcriptionally upregulates and stabilizes SLC7A11, a critical ferroptosis suppressor, thereby inhibiting lipid peroxidation and ferroptotic cell death. Additionally, immunopurification and mass spectrometry (IP-MS) identified FADS2 as a novel SLBP-interacting partner. SLBP binds to FADS2, promotes its expression, and drives metabolic reprogramming toward glutamine dependency, significantly altering choline and metal ion metabolism. This metabolic shift enhances cellular proliferation under nutrient stress. Crucially, SLBP-mediated proliferation was shown to be functionally dependent on FADS2, as FADS2 inhibition abrogates SLBP-driven growth without affecting SLBP levels. Collectively, these results uncover SLBP as a multifunctional oncoprotein that promotes LUAD progression through dual mechanisms: inhibiting ferroptosis via SLC7A11 and rewiring glutamine metabolism through FADS2, offering new potential targets for therapeutic intervention.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"455 1","pages":"Article 114849"},"PeriodicalIF":3.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145676801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phospholipase C δ1 affects integrin-mediated cell adhesion and migration by altering available phosphatidylinositol 4,5-bisphosphate levels","authors":"Atsuko Yoneda ,&nbsp;Ryosuke Fujinaka ,&nbsp;Natsuki Tsuchiya ,&nbsp;Saori Yaita ,&nbsp;Sachi Suzuki ,&nbsp;Yuu Kishi ,&nbsp;Yoshikazu Nakamura ,&nbsp;Reiko Satow ,&nbsp;Kiyoko Fukami","doi":"10.1016/j.yexcr.2025.114857","DOIUrl":"10.1016/j.yexcr.2025.114857","url":null,"abstract":"<div><div>Integrins are primary extracellular matrix receptors that play essential roles in homeostasis and development. Integrin activity is tightly regulated and is associated with conformational states. Although phosphatidylinositol 4,5-bisphosphate (PIP₂), produced by phosphatidylinositol 4-phosphate 5-kinases, is involved in integrin activation, it is unclear whether PIP₂-reducing enzymes affect integrin conformation and integrin-mediated cell behavior by altering PIP₂ levels. Herein, we showed that phospholipase C (PLC) δ1, a PIP₂-hydrolyzing enzyme, affected integrin-mediated cell adhesion and migration. In PLCδ1 null murine fibroblasts and PLCδ1 knockdown-human melanoma cells, integrin-mediated cell behavior and basal PIP₂ levels in the plasma membrane increased compared with those in control cells. PLCδ1 reduction led to increases in the extended conformation of integrin β1 ectodomain and the interaction between integrin and its activator/stabilizer talin in the absence of ligands. Overexpression of full-length-PLCδ1 or its pleckstrin homology domain but not their PIP₂-binding incompetent mutants inhibited the integrin-mediated cell behavior. To understand how altering plasma membrane PIP₂ levels affects integrin-mediated cell behavior, the catalytic domain of PIP₂ phosphatase was used. It reduced the basal levels of plasma membrane PIP₂, inhibited integrin-mediated cell migration, increased the closed conformation of the integrin β1 headpiece, and decreased integrin-talin interaction. These data suggested that the effects of PLCδ1 reduction were due to a PIP₂ increase and that the plasma membrane PIP₂ levels affected integrin conformation in the absence of ligands. Our results revealed that PLCδ1 finely tunes integrin-mediated cell adhesion and migration and integrin conformation by altering available PIP₂ levels in the plasma membrane.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"455 1","pages":"Article 114857"},"PeriodicalIF":3.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145755584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}