Cell Communication and Signaling最新文献

{"title":"Revealing the role of RAB27 in HER receptor family expression and signaling in melanoma cells.","authors":"Katarzyna Horodecka, Liliana Czernek, Łukasz Pęczek, Magdalena Klink","doi":"10.1186/s12964-025-02064-8","DOIUrl":"10.1186/s12964-025-02064-8","url":null,"abstract":"<p><strong>Background: </strong>Alterations in signalling pathways fuel the growth and progression of melanoma. Therefore, understanding these processes is essential for developing effective treatment strategies. RAB27A and RAB27B are known to possess oncogenic effects by modulating cancer cell proliferation, invasion and drug resistance in various types of cancer, including melanoma. These proteins are mostly acknowledged as coordinators of the vesicular trafficking, however, their function in cellular signaling is less recognized. Therefore we aimed to investigate the relationship between RAB27 and oncogenic or signalling proteins in melanoma cells.</p><p><strong>Methods: </strong>We generated RAB27A knockout (KO) in SkMel28, A375, and patient-derived DMBC12 melanoma cell lines. Additionally, a double RAB27A/B knockout (dKO) A375 cell line was created. Firstly, we applied the Proteome Profiler array to identify proteins differentially expressed upon RAB27A/B loss. Subsequently, we picked selected specific proteins for a further in-depth analysis using RT-PCR, Western blot, and flow cytometry.</p><p><strong>Results: </strong>We found that silencing RAB27 markedly decreased the levels of various intracellular proteins linked with proliferation, invasion, angiogenesis, adhesion, or EMT at a cell-line dependent level. Among others, we observed a link between the expression of RAB27 and EGFR, HER2 and HER3. Altered levels of HER receptors disturbed the downstream signaling pathways by reducing the phosphorylation of AKT and ERK1/2 proteins.</p><p><strong>Conclusions: </strong>Our findings present novel, previously unpublished data on the relationship between HER family receptor expression and potential activity, and the involvement of RAB27 in melanoma cells.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"118"},"PeriodicalIF":8.2,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11877929/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143558884","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 role of IGF1R and IR expression and localisation in adrenocortical carcinomas.","authors":"Rosa Catalano, Emma Nozza, Barbara Altieri, Emanuela Esposito, Giorgio A Croci, Anna Maria Barbieri, Donatella Treppiedi, Sonia Di Bari, Otilia Kimpel, Mario Detomas, Mariangela Tamburello, Marc P Schauer, Sabine Herterich, Anna Angelousi, Michaela Luconi, Letizia Canu, Gabriella Nesi, Constanze Hantel, Sandra Sigala, Laura-Sophie Landwehr, Guido Di Dalmazi, Elisa Cassinotti, Ludovica Baldari, Serena Palmieri, Alessandra Mangone, Emanuele Ferrante, Cristina L Ronchi, Giovanna Mantovani, Erika Peverelli","doi":"10.1186/s12964-025-02115-0","DOIUrl":"10.1186/s12964-025-02115-0","url":null,"abstract":"<p><strong>Background: </strong>The insulin-like growth factor 2 (IGF2) is overexpressed in 90% of adrenocortical carcinomas (ACC) and promotes cell proliferation via IGF1R and isoform A of insulin receptor (IRA). However, IGF2 role in ACC tumourigenesis has not been completely understood yet, and the contribution of IGF1R and IRA in mediating ACC cell growth has been poorly explored. This study aimed to investigate IGF1R and IR expression and localisation, including the expression of IR isoforms, in ACC and adrenocortical adenomas (ACA), and their role in IGF2-driven proliferation.</p><p><strong>Methods: </strong>Immunohistochemistry staining of IGF1R and IR was performed on 118 ACC and 22 ACA to evaluate their expression and cellular localisation and statistical analyses were carried out to assess correlations with clinicopathological data. The expression of IRA and IRB in ACC and ACA tissues, ACC cell lines and ACC and ACA primary cultures was determined by RT-qPCR. To appraise the specific role of IGF1R and IR in mediating IGF2 mitogenic pathway, single and double silencing of receptors and their inhibition in 2 ACC cell lines derived from primary tumours (H295R and JIL-2266) and 2 derived from metastatic tumours (MUC-1 and TVBF-7) as well as in ACC and ACA primary cultures were performed.</p><p><strong>Results: </strong>We found a higher IGF1R plasma membrane localisation in ACC compared to ACA. In ACC this localisation was associated with higher Ki67 and Weiss score. IR was expressed in about half of ACC and in all ACA but, in ACC, it was associated with higher Ki67 and Weiss score. RT-qPCR revealed that the prevalent isoform of IR was IRA in ACC and ACA, but not in normal adrenals. In ACC cell lines, double IGF1R + IR silencing reduced cell proliferation in JIL-2266, MUC-1 and TVBF-7 but not in H295R. In ACC, but not ACA, primary cultures, cell proliferation was reduced after IR but not IGF1R knockdown.</p><p><strong>Conclusions: </strong>Overall, these data suggest that IGF1R localisation and IR expression represent new biomarkers predicting tumour aggressiveness, as well as possible molecular markers useful to patients' stratification for more individualized IGF1R-IR targeted therapies or for novel pharmacological approaches specifically targeting IRA isoform.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"119"},"PeriodicalIF":8.2,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11877998/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143558883","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":"Sos1 ablation alters focal adhesion dynamics and increases Mmp2/9-dependent gelatinase activity in primary mouse embryonic fibroblasts.","authors":"Pilar Liceras-Boillos, Rósula Garcia-Navas, Clara Llorente-González, L Francisco Lorenzo-Martin, Luis Luna-Ramírez, Rocío Fuentes-Mateos, Nuria Calzada, Francisco M Vega, Mark R Holt, Anne J Ridley, Xose R Bustelo, Miguel Vicente-Manzanares, Eugenio Santos, Fernando C Baltanás","doi":"10.1186/s12964-025-02122-1","DOIUrl":"10.1186/s12964-025-02122-1","url":null,"abstract":"<p><strong>Background: </strong>Sos1 and Sos2 are guanine-nucleotide exchange factors for Ras and Rac small GTPases, which are involved in a wide range of cellular responses including proliferation and migration. We have previously shown that Sos1 and Sos2 have different effects on cell migration, but the underlying mechanisms are not clear.</p><p><strong>Methods: </strong>Using a 4-hydroxytamoxifen-inducible conditional Sos1^KO mutation, here we evaluated the functional specificity or redundancy of Sos1 and Sos2 regarding the control of cell migration and dynamics of focal adhesions (FAs) in primary mouse embryonic fibroblasts (MEFs).</p><p><strong>Results: </strong>Functional analysis of the transcriptome of primary Sos1/2^WT, Sos1^KO, Sos2^KO and Sos1/2^DKO-MEFs revealed a specific, dominant role of Sos1 over Sos2 in transcriptional regulation. Sos1^KO MEFs had an increased number and stability of focal adhesions (FAs) and curbed protrusion and spreading. Conversely, Sos2^KO MEFs displayed unstable FAs with increased protrusion. Interestingly, Sos1, but not Sos2, ablation reduced the levels of GTP-bound Rac at the leading edge. In 3D, however, only Sos1/2^KO MEFs showed increased invasion and matrix degradative capacity, which correlated with increased expression of the Mmp2 and Mmp9 gelatinases. Moreover, increased matrix degradation in Sos1/2^KO MEFs was abrogated by treatment with Mmp2/9 inhibitors.</p><p><strong>Conclusions: </strong>Our data demonstrate that Sos1 and Sos2 have different functions in FAs distribution and dynamics in 2D whereas in 3D they act together to regulate invasion and unveil a previously undescribed mechanistic connection between Sos1/2 and the regulation of Mmp2/9 expression in primary MEFs.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"116"},"PeriodicalIF":8.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11874121/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143544577","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":"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}