Cell Communication and Signaling最新文献

{"title":"Lysine 2-hydroxyisobutyrylation of HXK1 alters energy metabolism and K_ATP channel function in the atrium from patients with atrial fibrillation.","authors":"Hai-Tao Hou, Xiang-Chong Wang, Huan-Xin Chen, Jun Wang, Qin Yang, Guo-Wei He","doi":"10.1186/s12964-025-02108-z","DOIUrl":"10.1186/s12964-025-02108-z","url":null,"abstract":"<p><strong>Background: </strong>Atrial fibrillation (AF) is the most common form of arrhythmia and is a growing clinical problem. Post-translational modifications (PTMs) constitute crucial epigenetic mechanisms but modification of lysine 2-hydroxyisobutyrylation (K_hib) in AF is still unknown. This study aimed to investigate the role and mechanism of K_hib in AF.</p><p><strong>Methods: </strong>PTM proteomics was applied in the human atrial tissue from AF and sinus rhythm patients with heart valve disease during cardiac surgery to identify the K_hib sites. The functional changes of differential modification sites were further validated at the cellular level. Cellular electrophysiology was performed to record the ion channel current and action potential duration (APD).</p><p><strong>Results: </strong>The modification of 124 K_hib sites in 35 proteins and 67 sites in 48 proteins exhibited significant increase or decrease in AF compared to sinus rhythm. Ten K_hib sites were included in energy metabolism-related signaling pathways (HXK1, TPIS, PGM1, and ODPX in glycolysis; MDHC and IDH3A in tricarboxylic acid cycle; NDUS2, ETFB, ADT3, and ATPB in oxidative respiratory chain). Importantly, decreased HXK1 K418_hib regulated by HDAC2 attenuated the original chemical binding domain between HXK1 and glucose, inhibited the binding ability between HXK1 and glucose, and reduced catalytic ability of the enzyme, resulting in low production of glucose-6-phosphate and ATP. Further, it also increased Kir6.2 protein and the current of K_ATP channel, and decreased APD.</p><p><strong>Conclusions: </strong>This study demonstrates the importance of K_hib to catalysis of HXK1 and reveals molecular mechanisms of HXK1 K418_hib in AF, providing new insight into strategies of AF.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"117"},"PeriodicalIF":8.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11874433/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143544576","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}

{"title":"The alternative polyadenylation regulator CFIm25 promotes macrophage differentiation and activates the NF-κB pathway.","authors":"Srimoyee Mukherjee, Atish Barua, Luyang Wang, Bin Tian, Claire L Moore","doi":"10.1186/s12964-025-02114-1","DOIUrl":"10.1186/s12964-025-02114-1","url":null,"abstract":"<p><strong>Background: </strong>Macrophages are required for development and tissue repair and protect against microbial attacks. In response to external signals, monocytes differentiate into macrophages, but our knowledge of changes that promote this transition at the level of mRNA processing, in particular mRNA polyadenylation, needs advancement if it is to inform new disease treatments. Here, we identify CFIm25, a well-documented regulator of poly(A) site choice, as a novel mediator of macrophage differentiation.</p><p><strong>Methods: </strong>CFIm25 expression was analyzed in differentiating primary human monocytes and monocytic cell lines. Overexpression and depletion experiments were performed to assess CFIm25's role in differentiation, NF-κB signaling, and alternative polyadenylation (APA). mRNA 3' end-focused sequencing was conducted to identify changes in poly(A) site use of genes involved in macrophage differentiation and function. Cell cycle markers, NF-κB pathway components, and their targets were examined. The role of CFIm25 in NF-κB signaling was further evaluated through chemical inhibition and knockdown of pathway regulators.</p><p><strong>Results: </strong>CFIm25 showed a striking increase upon macrophage differentiation, suggesting it promotes this process. Indeed, CFIm25 overexpression during differentiation amplified the acquisition of macrophage characteristics and caused an earlier slowing of the cell cycle, a hallmark of this transition, along with APA-mediated downregulation of cyclin D1. The NF-κB signaling pathway plays a major role in maturation of monocytes to macrophages, and the mRNAs of null, TBL1XR1, and NFKB1, all positive regulators of NF-κB signaling, underwent 3'UTR shortening, coupled with an increase in the corresponding proteins. CFIm25 overexpression also elevated phosphorylation of the NF-κB-p65 transcription activator, produced an earlier increase in the NF-κB targets p21, Bcl-XL, ICAM1 and TNF-α, and resulted in greater resistance to NF-κB chemical inhibition. Knockdown of Tables 2 and TBL1XR1 in CFIm25-overexpressing cells attenuated these effects, reinforcing the mechanistic link between CFIm25-regulated APA and NF-κB activation. Conversely, depletion of CFIm25 hindered differentiation and led to lengthening of NFKB1, TAB2, and TBL1XR1 3' UTRs.</p><p><strong>Conclusions: </strong>Our study establishes CFIm25 as a key mediator of macrophage differentiation that operates through a coordinated control of cell cycle progression and NF-κB signaling. This linkage of mRNA processing and immune cell function also expands our understanding of the role of alternative polyadenylation in regulating cell signaling.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"115"},"PeriodicalIF":8.2,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11871739/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532144","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}

{"title":"Soluble E-cadherin contributes to inflammation in acute lung injury via VEGF/VEGFR2 signaling.","authors":"Lihong Yao, Zemin Chen, Sudan Gan, Chunlai Fu, Zhefan Xie, Hailing Zhang, Changyun Yang, Lin Fu, Ye Liu, Ming Luo, Daibin Kuang, Jingjing Cao, Guodong Hu, Shiyue Li, Liping Yang, Lingfeng Li, Xin Chen, Haixiong Tang","doi":"10.1186/s12964-025-02110-5","DOIUrl":"10.1186/s12964-025-02110-5","url":null,"abstract":"<p><p>As a gatekeeper of the airway epithelial cells, E-cadherin is not only a critical component for the maintenance of epithelial integrity, but also engaged in pathological processes through the release of a soluble form (sE-cadherin). This study was aimed to investigate the role of sE-cadherin in ALI/ARDS. Serum samples from patients with ARDS and healthy volunteers were collected for the detection of sE-cadherin. An LPS-induced mouse model was induced to analyze the expression of sE-cadherin, and a neutralizing antibody against sE-cadherin (DECMA-1) was given to the LPS-exposed mice. The effects of recombinant sE-cadherin were tested both in vitro and in vivo, and VEGFR2 inhibition was used to explore a possible mechanism for sE-cadherin-induced pulmonary inflammation. We observed an increased level of sE-cadherin in ARDS patients as well as in LPS-exposed mice. In vivo treatment of DECMA-1 significantly attenuated LPS-induced inflammation. In vitro, exogenous sE-cadherin can dramatically upregulate the expression of VEGF in THP1-derived macrophages and human primary macrophages. In addition, intratracheal instillation of recombinant sE-cadherin leads to significant increased infiltration of neutrophils as well as overproduction of IL-6 and IL1β, which could be attenuated by inhibition of VEGF/VEGFR2 signaling. While blockade of the VEGF/VEGFR2 pathway inhibited pulmonary inflammatory responses in LPS-exposed mice. Taken together, our data demonstrated that sE-cadherin contributes to lung inflammation in ALI/ARDS, which is related to activation of the VEGF/VEGFR2 pathway.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"113"},"PeriodicalIF":8.2,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866821/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143517458","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}

{"title":"Metabolic reprogramming of peritoneal mesothelial cells in peritoneal dialysis-associated fibrosis: therapeutic targets and strategies.","authors":"Fang Yu, Jia Chen, Xiaoyue Wang, Shihui Hou, Hong Li, Yaru Yao, Yani He, Kehong Chen","doi":"10.1186/s12964-025-02113-2","DOIUrl":"10.1186/s12964-025-02113-2","url":null,"abstract":"<p><p>Peritoneal dialysis (PD) is considered a life-saving treatment for end-stage renal disease. However, prolonged PD use can lead to the development of peritoneal fibrosis (PF), diminishing its efficacy. Peritoneal mesothelial cells (PMCs) are key initiators of PF when they become damaged. Exposure to high glucose‑based peritoneal dialysis fluids (PDFs) contributes to PF development by directly affecting highly metabolically active PMCs. Recent research indicates that PMCs undergo metabolic reprogramming when exposed to high-glucose PDFs, including enhanced glycolysis, impaired oxidative phosphorylation, abnormal lipid metabolism, and mitochondrial dysfunction. Although this metabolic transition temporarily compensates for the cellular damage and maintains energy levels, its long-term impact on peritoneal tissue is concerning. Multiple studies have identified a close association between this shift in energy metabolism and PF, and may promote the progression of PF through various molecular mechanisms. This review explores recent findings regarding the role and mechanism of PMC metabolic reprogramming in PF progression. Moreover, it provides a summary of potential therapeutic strategies aimed at various metabolic processes, including glucose metabolism, lipid metabolism, and mitochondrial function. The review establishes that targeting metabolic reprogramming in PMCs may be a novel strategy for preventing and treating PD-associated fibrosis.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"114"},"PeriodicalIF":8.2,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866825/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143525293","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}

{"title":"ApoE2 affects insulin signaling in the hippocampus and spatial cognition of aged mice in a sex-dependent manner.","authors":"Yu Wang, Hanchen Liu, Yijuan Ye, Wenting Fang, Anlan Lin, Xiaoman Dai, Qinyong Ye, Xiaochun Chen, Jing Zhang","doi":"10.1186/s12964-025-02093-3","DOIUrl":"10.1186/s12964-025-02093-3","url":null,"abstract":"<p><p>Apolipoprotein E (APOE) has garnered significant attention as one of the most influential genetic risk factors for Alzheimer's disease (AD). While the pathogenic role of APOE4 in sporadic AD has been extensively studied, research on the protective effects of the APOE2 genotype and its underlying mechanisms remains limited. Additionally, the existence of sex differences in the protective effects of ApoE2 continues to be a topic of debate. In this study, we utilized humanized ApoE2- and ApoE3- target replacement mice to examine the sex-specific effects of ApoE2 on cognition. Compared with female ApoE3 mice, we found significantly lower spatial cognitive ability and impaired hippocampal synaptic ultrastructure in aged female ApoE2 mice, accompanied by reduced insulin signaling of the hippocampus. Further analyses by target metabolomics and transcriptomic analyses revealed that female ApoE2 mice exhibit an age-related decline in hippocampal inositol levels, and that alterations in inositol levels lower insulin signaling. Importantly, inositol supplementation was found to alleviate peripheral glucose intolerance, enhance insulin signaling, and ultimately improve cognitive function. Interestingly, these differences were not observed between male ApoE2 and ApoE3 mice. The research findings not only provide new insights into the impact of ApoE2 on cognition but also offer a new strategy for cognitive improvement through inositol supplementation in older women.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"112"},"PeriodicalIF":8.2,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866816/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143517405","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}

{"title":"Regulation of CXCR4 function by S1P₁ through heteromerization.","authors":"Hyun-Tae Kim, Jae-Yeon Jeong, Won-Ki Huh","doi":"10.1186/s12964-025-02099-x","DOIUrl":"10.1186/s12964-025-02099-x","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;The trafficking of immune cells between lymphoid organs and circulation depends on gradients of CXCL12 and sphingosine-1-phosphate (S1P), mediated through their cognate receptors C-X-C chemokine receptor type 4 (CXCR4) and S1P receptor type 1 (S1P&lt;sub&gt;1&lt;/sub&gt;). S1P&lt;sub&gt;1&lt;/sub&gt; facilitates the egress of hematopoietic stem cells and lymphocytes by counteracting CXCR4-mediated retention signals. However, the molecular mechanisms underlying this interplay remain poorly understood. In this study, we uncover CXCR4-S1P&lt;sub&gt;1&lt;/sub&gt; heteromerization and explore their functional interactions.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Bimolecular fluorescence complementation (BiFC) assay, proximity ligation assay (PLA), and quantitative bioluminescence resonance energy transfer (BRET) assay were employed to detect CXCR4-S1P&lt;sub&gt;1&lt;/sub&gt; heteromerization. Functional properties of the heteromers were assessed using cAMP assay, G protein activation, β-arrestin recruitment, ligand binding, calcium mobilization, and transwell migration assays. S1P&lt;sub&gt;1&lt;/sub&gt;-overexpressing Jurkat T cells were generated via lentiviral transduction, while S1P&lt;sub&gt;1&lt;/sub&gt;-deficient KARPAS299 cells and β-arrestin1/2-deficient HEK293A cells were constructed using the CRISPR/Cas9 system.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;CXCR4-S1P&lt;sub&gt;1&lt;/sub&gt; heteromerization was observed in HEK293A cells overexpressing both receptors. The S1P/S1P&lt;sub&gt;1&lt;/sub&gt; axis interfered with CXCR4-mediated signaling, while CXCR4 did not affect S1P&lt;sub&gt;1&lt;/sub&gt;-mediated signaling, indicating a unidirectional modulation of CXCR4 by S1P&lt;sub&gt;1&lt;/sub&gt;. CXCL12 binding to CXCR4 remained unchanged in the presence of S1P&lt;sub&gt;1&lt;/sub&gt;, and interference of CXCL12-induced Gα&lt;sub&gt;i&lt;/sub&gt; activation by S1P&lt;sub&gt;1&lt;/sub&gt; was observed in β-arrestin1/2-deficient cells. BRET analysis revealed that S1P&lt;sub&gt;1&lt;/sub&gt; interfered with CXCR4-Gα&lt;sub&gt;i&lt;/sub&gt; pre-association and CXCR4 oligomerization, both of which are critical for CXCR4 function. Domain-swapping experiments identified transmembrane domain 3 of S1P&lt;sub&gt;1&lt;/sub&gt; as essential for this modulation. In Jurkat T cells overexpressing S1P&lt;sub&gt;1&lt;/sub&gt;, CXCR4-mediated signaling and cell migration were diminished, whereas these functions were enhanced in S1P&lt;sub&gt;1&lt;/sub&gt;-deficient KARPAS299 cells. Co-activation of S1P&lt;sub&gt;1&lt;/sub&gt; attenuated CXCL12-induced migration, while pretreatment with S1P or FTY720-phosphate increased CXCR4-mediated migration by downregulating surface S1P&lt;sub&gt;1&lt;/sub&gt; in KARPAS299 cells. In primary T cells, PLA confirmed CXCR4-S1P&lt;sub&gt;1&lt;/sub&gt; heteromerization, and S1P interfered with CXCL12-induced migration.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;This study identifies CXCR4-S1P&lt;sub&gt;1&lt;/sub&gt; heteromers and demonstrates a unidirectional modulation of CXCR4 by S1P&lt;sub&gt;1&lt;/sub&gt;. S1P&lt;sub&gt;1&lt;/sub&gt; affects CXCR4 function by disrupting its G protein pre-association and oligomerization. These findings underscore the regulatory role of the S1P/S1P&lt;sub&gt;1&lt;/sub&gt; axis i","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"111"},"PeriodicalIF":8.2,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11863771/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143517451","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}

{"title":"CXXC5 function blockade promotes diabetic wound healing through stimulating fibroblast and vascular endothelial cell activation.","authors":"Yutong Chen, Xiaofeng Ding, Zhouji Ma, Shuai Shao, Heyan Huang, Yumeng Huang, Beizhi Wang, Hao Zhang, Qian Tan","doi":"10.1186/s12964-025-02097-z","DOIUrl":"10.1186/s12964-025-02097-z","url":null,"abstract":"<p><strong>Background: </strong>Extracellular matrix (ECM) and angiogenesis are critical controls of wound regeneration, and their dysfunction delays diabetes recovery. CXXC5 belongs to the CXXC protein family that can regulate the function of human dermal fibroblasts (HDFs) and human umbilical vein endothelial cells (HUVECs); However, awareness of its functional role remains limited.</p><p><strong>Methods: </strong>Mice were divided into control (CON), diabetic (DM), diabetic + KY19382 (DM + KY19382), and diabetic + vehicle (DM + Vehicle) groups. HDFs and HUVECs were stimulated under different CXXC5 conditions and mice were treated with KY19382, followed by the application of assays including Western blotting (WB), immunofluorescence (IF) and quantitative reverse transcription-PCR (qRT-PCR) to assess wound healing and molecular signaling.</p><p><strong>Results: </strong>Mice in DM had fewer blood vessels, a slower wound healing rate, and more disrupted collagen than CON. Application of KY19382 improved these conditions, which promoted fibroblast activation and vascularization in high glucose environments and DM. Mechanistically, blocking CXXC5 promotes Wnt/β-catenin-mediated stabilization by reducing the binding of the deterrent factor CTBP1 to β-catenin, which induces dermal fibroblast activation and facilitates HUVECs tube formation and migration via VEGFA/VEGFR2 and NFκB signaling pathways. KY19382 promotes HUVECs activation by blocking CTBP1 transcription to activate the NFκB signaling pathway, thus wound re-vascularization.</p><p><strong>Conclusion: </strong>CXXC5 is an essential regulatory factor of wound healing and a prospective therapeutic target for treating chronic wound damage in diabetes.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"108"},"PeriodicalIF":8.2,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11863911/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143506202","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}

{"title":"LRSAM1 mediated the degradation of intracellular Vibrio through the ubiquitination-autophagy-lysosome pathway in oyster.","authors":"Wenwen Yang, Jiejie Sun, Qiuyan Guo, Wei Wang, Jinyuan Leng, Lingling Wang, Linsheng Song","doi":"10.1186/s12964-025-02111-4","DOIUrl":"10.1186/s12964-025-02111-4","url":null,"abstract":"<p><p>The leucine rich repeat and sterile alpha motif containing 1 (LRSAM1) as E3 ligase recognizes bacteria and generates a ubiquitin signal to initiate the autophagy process. In the present study, LRSAM1 was identified from the Pacific oyster Crassostrea gigas (designed as CgLRSAM1), which was able to recognize various pathogen-associated molecular patterns and bacteria and directly ubiquitinate Vibrio splendidus. V. splendidus was co-localized with CgLRSAM1 and ubiquitin after invading haemocytes, and the ubiquitinated V. splendidus was then internalized into haemocyte lysosomes by p62-LC3-mediated autophagy. In haemocytes of CgLRSAM1-RNAi oysters, the activation of CgLC3 was enhanced after V. splendidus stimulation. While the co-localization values of V. splendidus with ubiquitin, CgLC3 and lysosomes all decreased significantly after V. splendidus stimulation. These results indicated that CgLRSAM1 functioned as E3 ligase responsible for anti-Vibrio-associated ubiquitination and regulated the degradation of bacteria through the ubiquitination-autophagy-lysosome pathway.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"110"},"PeriodicalIF":8.2,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11863841/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143506205","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}

{"title":"Emerging functions of Plakophilin 4 in the control of cell contact dynamics.","authors":"Lisa Müller, Mechthild Hatzfeld","doi":"10.1186/s12964-025-02106-1","DOIUrl":"10.1186/s12964-025-02106-1","url":null,"abstract":"<p><p>Plakophilin 4 (PKP4, also called p0071) is a unique armadillo family protein localized at adherens junctions that acts as a scaffold protein capable of clustering cadherins. PKP4 also regulates cadherin recycling which is vital to enable junction dynamics. In addition, PKP4 controls the mechanical properties of cells by regulating actin filament organization through small Rho-GTPases. In this setting, PKP4 controls the localization and activity of specific guanine exchange factors (GEFs) and of their opponents, the GTPase activating proteins (GAPs). Through the formation of multiprotein complexes with Rho-GTPases, their regulators and their effectors, PKP4 controls the spatio-temporal activity of Rho signaling to regulate cell adhesion and cell mechanics. In keratinocytes, PKP4 prevents differentiation and at the same time dampens proliferation. This is, in part achieved through an interaction with the Hippo pathway, which controls the activity of the transcriptional co-factors YAP and TAZ. In a feedback loop, YAP/TAZ modulate PKP4 localization and function. Here, we review the various functions of PKP4 in cell signaling, cell mechanics, cell adhesion and growth control. We discuss how these functions converge in the regulation of cell adhesion dynamics to allow cells to adapt to their changing environment and enable proliferation, delamination but, at the same time, guarantee cell barrier function.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"109"},"PeriodicalIF":8.2,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11863852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143506204","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}

{"title":"Targeting A2M-LRP1 reverses uterine spiral artery remodeling disorder and alleviates the progression of preeclampsia.","authors":"Zhengrui Huang, Ping Zhang, Ruiping Chen, Lu Sun, Jingyun Wang, Ruiling Yan, Mengyuan Liu, Yuzhen Ding, Jian Wang, Jiachun Wei, Wanchang Yin, Xinyao Lu, Guang Wang, Xuesong Yang, Ruiman Li","doi":"10.1186/s12964-025-02060-y","DOIUrl":"10.1186/s12964-025-02060-y","url":null,"abstract":"<p><strong>Background: </strong>Patients with early-onset preeclampsia (EOPE) have a most severe disease state. a2-macroglobulin (A2M) play a crucial role in the pathogenesis of EOPE, but its molecular basis and therapeutic potential remain unclear. This study aimed to elucidate the mechanisms of A2M in EOPE progression and explore the potential of A2M in the treatment of EOPE.</p><p><strong>Methods: </strong>A2M-Low Density Lipoprotein Receptor-Related Protein 1 (LRP1) blocker Receptor-associated protein (RAP) were utilized to alleviate the disease symptom of lipopolysaccharide (LPS) induced preeclampsia rat model. RNA-seq data sourced from public databases and morphological experiments were utilized to examine the relationship between the main fate of smooth muscle cell (SMC) during uterine spiral artery remodeling (SPA-REM) and A2M. Proteomic sequencing analysis of A2M overexpression rat placenta was used to identify the underlying mechanism. Further, LC-MS/MS analysis combined with Co-immunoprecipitation (Co-IP) was used to examine the interacting between A2M and underlying mechanism.</p><p><strong>Results: </strong>Single-cell analysis and morphological experimental results suggest that SMC phenotype switching disorder is the main fate of SMC in the pathological of SPA-REM disorder, and A2M has a causal relationship with this process. Proteomic sequencing data suggest that A2M participates in this process through the RhoA-GTPase pathway, further experimental data provide evidences that A2M can directly upregulate RhoA-GTPase. Cytological and explant experiments suggest that RAP has better efficacy than A2M knockdown AAV vector, finally the efficacy of RAP was verified in the rat model of preeclampsia.</p><p><strong>Conclusion: </strong>SMC A2M promotes the progression of preeclampsia by directly upregulating RhoA-GTPase. Our findings also reveal that A2M serve as a potential target for EOPE and provide a preliminary therapy for inhibit the combination of A2M-LRP1.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"107"},"PeriodicalIF":8.2,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11852582/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143493972","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}