Cell Communication and Signaling最新文献

{"title":"Targeting cytokine and chemokine signaling pathways for enhancing chemo-sensitivity in colorectal cancer.","authors":"Shisen Li, Mianjiao Xie, Yongtao Du, Zhaobang Tan","doi":"10.1186/s12964-025-02235-7","DOIUrl":"10.1186/s12964-025-02235-7","url":null,"abstract":"<p><p>Chemo-resistance is one of the main obstacles in the treatment of colorectal cancer. Many studies have been performed to identify the mechanisms associated with chemo-resistance in colorectal cancer cells, and it has been found that increasing the activity of ABC family transporters, enhancing DNA repair, weakening apoptosis, strengthening stemness, and EMT are among the most important of these mechanisms. Inflammation and cytokines have been linked to colorectal cancer, and there is even a type of colorectal cancer that is caused by chronic inflammation in patients with inflammatory bowel disease. However, the association between cytokines and chemo-resistance in colorectal cancer cells is not yet clear. Various studies have shown that chemotherapy drugs, by affecting the tumor microenvironment, can enhance the recruitment of some immune cells and the production of some cytokines. These cytokines have a variety of effects on various chemo-resistance mechanisms in colorectal cancer cells. Some of them can strengthen chemo-resistance and others weaken chemo-resistance. IL-6, TNFα, IFN, IL1, IL8, IL-17, IL-10, and IL-22 are among the most important cytokines whose effects on chemo-resistance mechanisms in colorectal cancer cells are known. In this article, we will have a comprehensive overview of the effects of these cytokines on chemo-resistance mechanisms in colorectal cancer cells.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"369"},"PeriodicalIF":8.2,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12341088/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144838648","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":"Activation of integrin signaling up-regulates pro-inflammatory cytokines in JAK2-V617F positive hematopoietic cells.","authors":"Conny K Baldauf, Corinna Fahldieck, Alexa Angenstein, Sönke Weinert, Mariam Hakobyan, Daniel B Lipka, Tobias R Haage, Vikas Bhuria, Martin Böttcher, Dimitrios Mougiakakos, Burkhart Schraven, Thomas Fischer","doi":"10.1186/s12964-025-02358-x","DOIUrl":"10.1186/s12964-025-02358-x","url":null,"abstract":"<p><strong>Background: </strong>The JAK2-V617F mutation is the most frequent driver mutation in a group of malignant hematopoietic disorders called myeloproliferative neoplasms (MPN). JAK2-V617F is a somatic mutation originating in a hematopoietic stem cell and results in constitutively activated JAK-STAT signaling. High levels of pro-inflammatory cytokines in the blood are a hallmark of MPN patients and are a key factor in the severe clinical symptoms seen in these patients. The molecular mechanisms underlying the up-regulation of inflammatory cytokines in JAK2-V617F mutated hematopoietic cells remain to be elucidated.</p><p><strong>Methods: </strong>32D myeloid progenitor cells expressing JAK2-wildtype (WT) and JAK2-V617F, respectively were employed. In addition, primary hematopoietic cells from the JAK2-V617F knock-in MPN mouse model were investigated. Integrin outside-in signaling upon binding of cells to the adhesion molecules VCAM-1/ICAM-1 was characterized by Western blotting of phosphorylated FAK, STAT3, p65, SYK and JNK. Regulation of mRNA and protein expression of IL-1α, IL-1β, IL-6, TNF and CXCL10 was measured by qPCR and ELISA. RNAseq and DNA methylation analysis in primary mouse JAK2-V617F granulocytes was performed. In JAK2-V617F knock-in mice, anti-integrin treatment was applied to evaluate the impact of activated integrin signaling on IL-1 blood levels in vivo.</p><p><strong>Results: </strong>Integrin stimulation via the adhesion molecules VCAM-1/ICAM-1 activated integrin outside-in signaling including FAK, SYK, NFκB, and JNK. This induced strong mRNA expression of IL-1α, IL-1β, IL-6, TNF and CXCL10. In 32D cells, the presence of the JAK2-V617F mutation further increased VCAM-1/ICAM-1-induced mRNA and protein levels of IL-1α and IL-1β, and active caspase 1 expression. In primary granulocytes, integrin stimulation resulted in an activated mRNA signature of inflammatory cytokines. Consistent with the mRNA results, adhesion to VCAM-1/ICAM-1 induced an increase in intracellular IL-1α and IL-1β protein levels in 32D cells. However, in primary hematopoietic cells, up-regulation of inflammatory cytokines was not observed at the protein level in vitro, whereas, in vivo, blocking of integrin binding to VCAM-1/ICAM-1 was sufficient to reduce elevated IL-1α levels in the blood of JAK2-V617F mice.</p><p><strong>Conclusions: </strong>We conclude that integrin stimulation via the adhesion molecules VCAM-1/ICAM-1 activates integrin outside-in signaling, leading to the up-regulation of pro-inflammatory cytokines in both JAK2-mutated and non-mutated mouse hematopoietic cells.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"368"},"PeriodicalIF":8.2,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12337553/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144823197","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":"Characterization of a pathogenic gain-of-function mutation in the N-terminal domain of STAT1 which is reported to be associated with eosinophilic esophagitis.","authors":"Kristin Annawald, Anke Gregus, Oliver Wirths, Thomas Meyer","doi":"10.1186/s12964-025-02330-9","DOIUrl":"10.1186/s12964-025-02330-9","url":null,"abstract":"<p><p>The pathophysiology of eosinophilic esophagitis (EoE), a chronic allergic disease characterized by eosinophilic infiltration of the esophageal mucosa, is largely unknown. Recently, a case report described a gain-of-function (GOF) mutation in the STAT1 (signal transducer and activator of transcription 1) protein (D65A) to be associated with this disease. In the present paper, we investigated in more detail the molecular mechanisms of this missense mutation and, in addition, characterized a second aspartic acid-to-alanine substitution (D66A) in the N-terminal domain of STAT1. Results showed that, upon stimulation of cells with cytokines, the two mutants had increased levels of tyrosine phosphorylation compared to the wild-type (WT) protein. The altered phosphorylation kinetics led to an elevated and prolonged phase of nuclear accumulation, which was in line with an increased concentration of DNA-bound complexes observed by means of electrophoretic mobility shift assays. However, the dissociation rate from a single high-affinity DNA-binding site did not differ between the WT and the two mutants. A promoter-specific higher transcriptional activation was observed for reporter gene constructs and the majority of the tested endogenous STAT1 target genes. In summary, the two N-terminal point mutations showed characteristic features of a GOF phenotype, as indicated by a gene-specific, rather than a global upregulation of cytokine-driven gene expression. A model is proposed suggesting that the equilibrium between antiparallel, tetrameric complexes and parallel dimer complexes is shifted to the transcriptionally active latter ones as the underlying mechanistic basis of these N-terminal STAT1 mutations.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"367"},"PeriodicalIF":8.2,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12329892/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144800983","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":"Extracellular domain shedding of NOTCH3 during endocytosis associated with heterogeneity between different CADASIL mutant activation mechanisms.","authors":"Samira Hosseini-Alghaderi, Martin Baron","doi":"10.1186/s12964-025-02362-1","DOIUrl":"10.1186/s12964-025-02362-1","url":null,"abstract":"<p><strong>Background: </strong>Mutations in NOTCH3 cause CADASIL, a dominantly inherited condition, linked to recurrent stroke and vascular dementia and associated with accumulation of the ECD of NOTCH3. The latter has a toxic effect on VSMCs. Misregulated signalling may also play a role in disease progression. ECD detachment is an obligatory step in NOTCH3 activation, but some CADASIL mutants prevent ligand-induced activation and so ligand interactions are not a common underlying requirement. Here we investigated whether basal NOTCH3 endocytosis that is associated with ligand-independent activation mechanisms can be source of ECD shedding in CADASIL mutants.</p><p><strong>Methods: </strong>We used transient transfection of hTERT-RPE1 cells to express WT, R90C, C212Y and C455R mutant NOTCH3 constructs. Internalisation of NOTCH3 was followed using a pulse-chase endocytic uptake assay after surface NOTCH3 labelling of live cells. Immunolocalisation of NOTCH3 ECD and ICD was used to define the subcellular localisation of expressed NOTCH3 in the secretory and endocytic pathway of transfected cells, and endogenous NOTCH3 in MCF7 cells and VSMCs derived from human ES cells. To investigate NOTCH3 signalling we used a luciferase reporter assay under control of a NOTCH-responsive reporter element.</p><p><strong>Results: </strong>Both WT and CADASIL NOTCH3 proteins are endocytosed before ECD shedding and then undergo dissociation and independent trafficking of the ECD and ICD in the endosome. The relative amount of ICD compared to ECD that colocalised with endosomal markers increases as NOTCH3 progresses through the endosomal trafficking pathway from early endosome to lysosome. The R90C mutant showed earlier separation of ECD compared to WT or other CADASIL mutants tested. All WT and mutant constructs activated downstream signalling when expressed in hTERT-RPE1 cells, and these basal signalling levels were not affected by the C455R mutation which removes ligand-activated signalling. R90C showed distinctly different requirements for activation being less sensitive to metalloprotease inhibition and more sensitive to inhibition of the lysosomal protein TRPML.</p><p><strong>Conclusions: </strong>Basal NOTCH3 endocytosis and signalling is a potential source of ECD shedding and accumulation in CADASIL. Different mechanisms may apply to different CADASIL mutants and understanding the variety of mechanisms by which NOTCH3 signalling and ECD shedding occur will inform new targeted approaches to treatments of small vessel disease. Tuning NOTCH3 activity through modulation of the endocytic pathway may offer better tolerated approaches than direct targeting of NOTCH3 signalling.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"366"},"PeriodicalIF":8.2,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12326875/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144790782","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":"Wnt5a suppresses colorectal cancer progression via TGF-β/NOTUM/OLFM4 axis in patient-derived organoids.","authors":"Yewei Huang, Jiahao Huang, Jiazi Yu, Songlin Zhuang, Ming Liu","doi":"10.1186/s12964-025-02364-z","DOIUrl":"10.1186/s12964-025-02364-z","url":null,"abstract":"<p><strong>Background: </strong>Wnt5a, a noncanonical Wnt ligand, exhibits dual roles in cancer progression, but its tumor-suppressive mechanisms in colorectal cancer (CRC) remain poorly defined. Stromal-derived signals in the tumor microenvironment (TME) are increasingly recognized as critical modulators of CRC behavior, yet their interplay with therapeutic resistance is unclear.</p><p><strong>Methods: </strong>Using patient-derived CRC organoids (PDOs) and functional assays, we investigated the role of stromal-secreted Wnt5a. Mechanistic studies combined RNA sequencing, pharmacological inhibition, and immunofluorescence to dissect the Wnt5a/TGF-β/NOTUM/OLFM4 axis. Drug sensitivity assays evaluated the synergy between Wnt5a and 5-fluorouracil (5-FU).</p><p><strong>Results: </strong>Wnt5a was predominantly stromal-derived and suppressed CRC organoid growth by activating TGF-β/Smad2 signaling, which upregulated the Wnt inhibitor NOTUM and downregulated the stemness marker OLFM4. RNA-seq revealed NOTUM induction as the key mediator. Combining Wnt5a with 5-FU synergistically enhanced organoid growth inhibition and cell death, reversing 5-FU-driven NOTUM downregulation.</p><p><strong>Conclusions: </strong>Our study identifies a novel stromal-TME crosstalk mechanism wherein Wnt5a restrains CRC progression via TGF-β/NOTUM/OLFM4 signaling. The combinatorial efficacy of Wnt5a and 5-FU highlights a promising strategy to overcome chemoresistance. These findings emphasize the therapeutic potential of targeting stromal-derived pathways in CRC.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"365"},"PeriodicalIF":8.2,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12323272/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144790735","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":"Biophysical and biochemical signatures of pancreatic stellate cell activation: insights into mechano-metabolic signalling from atomic force microscopy and Raman spectroscopy.","authors":"Jacek J Litewka, Monika A Jakubowska, Marta Targosz-Korecka, Ewelina Wiercigroch, Jakub Dybas, Natalia Cisak, Zbigniew Madeja, Pawel E Ferdek","doi":"10.1186/s12964-025-02354-1","DOIUrl":"10.1186/s12964-025-02354-1","url":null,"abstract":"<p><strong>Background: </strong>Pancreatic fibrosis is a key pathological feature of chronic pancreatitis and pancreatic cancer, driven by the persistent activation of pancreatic stellate cells. These cells, normally quiescent, undergo profound phenotypic changes in response to environmental cues, yet the interplay between mechanical forces and metabolic reprogramming during this transition remains poorly understood. As the stromal microenvironment actively communicates with epithelial and vascular compartments, understanding this mechano-metabolic signalling axis is critical for uncovering novel mechanisms of tissue remodelling.</p><p><strong>Methods: </strong>To investigate the biomechanical and biochemical alterations during stellate cell activation, we employed atomic force microscopy and Raman spectroscopy to measure changes in cell stiffness, morphology, and molecular composition. These data were complemented by transcriptomic analyses to evaluate gene expression profiles related to lipid metabolism and autophagy. Quantitative statistical tests, including ANOVA and Kruskal-Wallis tests with appropriate post hoc corrections, were applied.</p><p><strong>Results: </strong>Activation of human pancreatic stellate cells led to progressive cytoskeletal remodelling, increased cellular stiffness, and a flattened morphology. Raman spectroscopy revealed an expansion of the cytoplasmic area, changes in nucleic acid signal, and significant increases in lipid content, particularly in unsaturated lipids and triacylglycerols. Gene expression analysis demonstrated upregulation of lipid elongation and desaturation pathways, along with enhanced autophagy, suggesting a coordinated metabolic adaptation. These changes support the myofibroblast-like phenotype and may influence intercellular signalling by altering extracellular matrix composition, mechanical tension, and the release of signalling molecules that affect the surrounding microenvironment.</p><p><strong>Conclusions: </strong>Our findings reveal that pancreatic stellate cell activation involves a tightly coupled shift in mechanical and metabolic states, highlighting an integrated signalling process that may modulate stromal-vascular and stromal-epithelial communication. This mechano-metabolic axis represents a potential therapeutic target in fibrotic and neoplastic pancreatic diseases, where aberrant stromal signalling contributes to disease progression.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"363"},"PeriodicalIF":8.2,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12320368/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144786004","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":"Lactylation modification of HIF-1α enhances its stability by blocking VHL recognition.","authors":"Chengyu Li, Chen Fu, Wenhan Zhou, Hongmin Li, Zhaojun Liu, Gang Wu, Tong He, Ming Shen, Honglin Liu","doi":"10.1186/s12964-025-02366-x","DOIUrl":"10.1186/s12964-025-02366-x","url":null,"abstract":"<p><p>Hypoxia-inducible factor 1α (HIF-1α) is a master regulator of cellular adaptation to hypoxia. Although prolyl hydroxylation-mediated degradation via the von Hippel-Lindau (VHL) ubiquitination complex is a well-established regulatory mechanism, the role of lactate-induced posttranslational modifications in HIF-1α stabilization remains incompletely understood. Here, we demonstrate that lactate induces lysine lactylation of HIF-1α at distinct residues across species-specifically, K644 in mice and K12 in humans and pigs-to increase protein stability by impairing VHL recognition. Mass spectrometry and mutagenesis analyses revealed that lactylation at these sites reduces K48-linked ubiquitination and proteasomal degradation, even when HIF-1α is hydroxylated. Structural modeling and functional assays revealed that lactylation sterically hinders VHL binding without affecting hydroxylation. Notably, lactylated HIF-1α exhibited increased transcriptional activity, as evidenced by increased promoter occupancy and upregulation of hypoxia-responsive genes (Vegfa, Glut1). Cross-species comparisons highlighted evolutionary divergence in lactylation sites while preserving the functional conservation of this modification. Our findings reveal that lactylation is a universal regulatory mechanism that overrides classical hydroxylation-dependent degradation, expanding our understanding of metabolic control over hypoxic signaling.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"364"},"PeriodicalIF":8.2,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12323271/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144786005","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 crucial role of intercellular calcium wave propagation triggered by influenza A virus in promoting infection.","authors":"Fumiya Kozawa, Tomokazu Tamura, Naoki Takahashi, Taishi Kakizuka, Taro Ichimura, Rumi Shimada, Yasuyuki Hashimoto, Hironoshin Onizuska, Sayaka Kashiwagi, Tomoko Kamasaki, Maho Amano, Takeharu Nagai, Takasuke Fukuhara, Yoichiro Fujioka, Yusuke Ohba","doi":"10.1186/s12964-025-02357-y","DOIUrl":"10.1186/s12964-025-02357-y","url":null,"abstract":"<p><strong>Background: </strong>Influenza A viruses (IAVs) initially infect a few host cells before spreading to neighboring cells. However, the molecular mechanisms underlying this dissemination remain unclear. We have previously demonstrated that intracellular Ca²⁺ plays a crucial role in facilitating IAV infection. This study aims to clarify the connections between intracellular Ca²⁺ dynamics and spread of IAV infection.</p><p><strong>Methods: </strong>Madin-Darby canine kidney (MDCK) cells stably expressing a Ca²⁺ indicator for optical imaging were established. Cells were cultured in Matrigel to form monolayers, and cell-to-cell Ca²⁺ dynamics within IAV-infected cells were analyzed using fluorescence microscopy.</p><p><strong>Results: </strong>IAV infection upregulated the frequency of intercellular calcium wave propagations (iCWPs), facilitating viral spread. ADP released from initially infected cells mediated iCWPs via the P2Y₁ receptor. P2Y₁ antagonist suppressed both the generation of iCWPs and spread of viral infection. Enhanced endocytosis by the surrounding cells that received ADP signaling upregulated viral entry. Expression of IAV matrix protein 2 (M2) in initially infected cells triggered iCWPs through ADP diffusion, thereby increasing infection. Conversely, an ion permeability-deficient mutation of M2 or inhibition of its ion channel activity suppressed iCWPs.</p><p><strong>Conclusions: </strong>Intercellular calcium signaling plays a crucial role in the early expansion and establishment of IAV infection, presenting a potential target for IAV prophylaxis.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"361"},"PeriodicalIF":8.2,"publicationDate":"2025-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12317542/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144769384","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 Notch signaling by multiple Ankyrin repeat containing protein Mask.","authors":"Bappi Sarkar, Jyoti Singh, Dipti Verma, Mousumi Mutsuddi, Ashim Mukherjee","doi":"10.1186/s12964-025-02190-3","DOIUrl":"10.1186/s12964-025-02190-3","url":null,"abstract":"<p><strong>Background: </strong>Notch pathway is an evolutionarily conserved, highly pleiotropic signaling system that governs diverse developmental processes. Its diverse functions are attributed to the intricate regulatory mechanisms that finely tune the pathway. While several known elements contribute to maintaining cellular homeostasis by modulating Notch signaling, many unidentified components likely play significant roles in its regulation, necessitating further exploration.</p><p><strong>Methods: </strong>To identify novel regulators of Notch-intracellular domain (Notch-ICD), we carried out a yeast two-hybrid screen and identified Multiple Ankyrin repeat single KH domain containing protein (Mask) as an interacting partner of Notch-ICD. Physical interaction between these two proteins was further validated by co-immunoprecipitation experiments. Moreover, cellular studies using immunocytochemistry reveals that Mask plays important role in Notch turnover and protect from degradation. To inhibit lysosomal degradation, chloroquine was introduced in the food at a concentration of 1 mg/ml.</p><p><strong>Results: </strong>Immunocytochemical analyses revealed that Notch and Mask co-localised within the same subcellular compartments. Different alleles of mask showed strong genetic interactions with Notch pathway components in transheterozygous combinations. Loss- and gain-of-function studies of Mask demonstrated that it plays a regulatory role in Notch signaling. Specifically, the absence of Mask results in downregulation of Notch target genes, although it does not significantly affect endogenous Notch protein levels. Our data suggest that Mask positively regulates Notch signaling by stabilizing Notch-ICD and protecting it from lysosomal degradation. Treatment with 1 mg/ml chloroquine can mitigate the Mask loss-mediated Notch intracellular domain degradation. This study presents a novel mode of Notch signaling regulation mediated by the Ankyrin repeat-containing protein Mask.</p><p><strong>Conclusion: </strong>Here we provide evidence that Mask physically binds with Notch-ICD and positively regulates Notch signaling pathway by protecting it from degradation. Mask genetically interacts with Notch and Notch pathway components and absence of Mask affects the Notch signaling pathway thus it may control the hyper activation of the signaling.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"358"},"PeriodicalIF":8.2,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12309132/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144755187","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":"Role of adiponectin and its receptors AdipoR1/2 in inflammatory bowel disease.","authors":"Qiuyan Zhu, Xiaoli Jia, Shupeng Li, Jinxing Feng","doi":"10.1186/s12964-025-02359-w","DOIUrl":"10.1186/s12964-025-02359-w","url":null,"abstract":"<p><p>Intake of nutrients and water from diet to maintain life, a typical physiological function of gut, is highly dependent on the extensive immune network, whose imbalance is easy to induce inflammatory bowel disease (IBD) including Crohn's disease (CD) and ulcerative colitis (UC). Clinical strategies to completely cure IBD are poor, so it is urgent to develop novel drugs or targets. Adiponectin (APN), an adipokine from adipocytes, regulates energy metabolism and immune response. High levels APN are inversely associated with CD severity UC colonic fibrosis. However, the mechanism by which APN interferes with IBD remains unclear. This review aims to analyze correlation and molecular mechanism between APN and IBD. APN and AdipoR2 proteins are highly expressed in colon which is a primary organ of IBD, and the target intersection of APN and IBD is huge. APN may interfere with lipid metabolism in IBD individuals through AdipoR1/2, but regulates neural and peripheral immune by AdipoR1 but not AdipoR2 and mediates nutritional and energy homeostasis through AdipoR2 rather than AdipoR1. Besides, APN mediates CRP and IL-6 through AdipoR1/2, AMPK and TNF-α through AdipoR1 and PI3K-Akt, PPARA and PPARG through AdipoR2 to affect IBD progression, which depends on direct interaction between APPL1 and AdipoR1/2. Unexpectedly, AMPK and TNF-α may also interact directly with AdipoR1. APN regulates CD through AdipoR1/2-metabolism process and UC through AdipoR1-inflammation axis or AdipoR2-fibrosis process. APN analogues or AdipoRon which is a dual agonist of AdipoR1/2 potentially reduces colonic fibrosis in UC and fistulae in CD, promotes mucosal healing, repairs intestinal microbiota homeostasis and increases autophagy to alleviate IBD symptoms by weakening TNF-α, IL-6, NLRP3, TGFB1 activities and aggrandizing P-AKT, PPARA, PPARG, INS, IRS1/2, IGF-1, TIMP1, NOD2, SIRT1 levels.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"356"},"PeriodicalIF":8.2,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12297855/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144719190","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}