Cell Communication and Signaling最新文献

{"title":"RAS pathway mutations orchestrate chromatin reconfiguration and transcriptional rewiring in colorectal cancer.","authors":"Zhangjingyi Gao, Snehangshu Kundu, Pengwei Xing, Eric Cruz Davila, Vamsi Krishna Polavarapu, Ece Akcan, Xingqi Chen, Tobias Sjöblom","doi":"10.1186/s12964-026-03305-0","DOIUrl":"10.1186/s12964-026-03305-0","url":null,"abstract":"<p><strong>Background: </strong>RAS pathway mutations occur in ~ 40% of colorectal cancers (CRCs), with KRAS- and BRAF- mutant tumors exhibiting distinct mutational, transcriptional, and epigenetic landscapes. Advances in next-generation sequencing enable integrated analyses of multi-omics data, providing insight into their regulatory relationships. To define the molecular programs driven by RAS pathway mutations, we generated isogenic CRC cell models and profiled chromatin accessibility using ATAC-seq.</p><p><strong>Methods: </strong>We performed ATAC-seq in isogenic HCT116 and RKO models. Mutation-associated changes in genes, regulatory elements, and signaling pathways were identified, together with inferred transcription factor (TF) binding activity. Clinical datasets were analyzed to assess whether features identified in the cell models were recapitulated in patient tumors and whether they were associated with clinical outcomes.</p><p><strong>Results: </strong>Isogenic CRC models segregated by RAS pathway mutation status at both epigenetic and transcriptomic levels. Mutation alterations modulated WNT signaling, accompanied by changes in RUNX2 and TCF7L2 expression and binding activity. Comparison between the HCT116 and RKO models identified 85 genes, eight of which displayed reproducible expression patterns across three independent clinical cohorts. TCF7L2 were associated with RAS pathway mutations in patient tumors, with elevated expression level predicting worse overall survival independent of cofactors.</p><p><strong>Conclusion: </strong>We identified RAS pathway mutation-driven regulatory reprogramming with convergent effects on WNT signaling. TCF7L2 emerged as a key TF, with elevated expression in BRAF-mutant tumors independently associated with poor clinical outcomes. These findings highlight a clinically relevant epigenetic mechanism linking RAS pathway mutations to CRC cell survival maintenance.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"24 1","pages":""},"PeriodicalIF":11.6,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13663232/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149186283","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":"Neuroimmune-oligovascular signaling shapes oligodendrocyte precursor cell fate and repair after ischemic stroke.","authors":"Bin Li, Ruixi Ming, Zijun Wu, Shifeng Pan","doi":"10.1186/s12964-026-03299-9","DOIUrl":"10.1186/s12964-026-03299-9","url":null,"abstract":"<p><strong>Background: </strong>Ischemic stroke causes neuronal and oligodendroglial injury, axonal and myelin damage, and neurovascular unit dysfunction. Oligodendrocyte precursor cells (OPCs) are lifelong progenitors that generate oligodendrocytes while receiving and transmitting signals within neural, immune, and vascular microenvironments. This review examines how neuroimmune-oligovascular communication and intracellular signaling shape OPC survival, recruitment, state transitions, differentiation, and remyelination after ischemic stroke.</p><p><strong>Main body: </strong>We first define OPC lineage identity, functional heterogeneity, and signaling interfaces with neurons, microglia/macrophages, astrocytes, endothelial cells, and pericytes. We then examine how excitotoxic, metabolic, redox, inflammatory, vascular, extracellular-matrix, and regulated cell-death signals converge on OPCs across lesion compartments and disease phases. Severe core ischemia depletes the progenitor pool, whereas partially perfused peri-infarct tissue permits reactive proliferation and migration. During the subacute phase, intercellular signals within the post-ischemic niche influence whether recruited OPCs adopt inflammatory, angiogenic, differentiation-competent, or arrested states. Long-term repair ultimately depends on lineage completion and stable myelin formation rather than OPC accumulation alone. The strongest causal evidence supports signaling from the surrounding niche as a regulator of OPC differentiation and demonstrates that OPC-derived myelin repair contributes to neuronal preservation and functional recovery. By contrast, evidence that endogenous OPCs themselves substantially regulate post-stroke inflammation, angiogenesis, blood-brain barrier integrity, or synaptic reconstruction remains less complete and often derives from culture, conditioned-medium, pharmacological, or transplantation paradigms. Therapeutic strategies are therefore organized according to the signaling and lineage bottleneck they target, including acute OPC preservation, niche remodeling, lineage completion, oligovascular reconstruction, and cell-based interventions.</p><p><strong>Conclusions: </strong>OPC fate after ischemic stroke is determined by the interaction of cell-intrinsic signaling competence with temporally and spatially changing neuroimmune-oligovascular cues. Translation will require lineage-resolved causal studies, human spatial and longitudinal validation, signaling-linked target-engagement measures, and treatment strategies matched to lesion phase, compartment, and repair bottleneck. A cell-communication framework may therefore provide a more mechanistically testable basis for OPC-centered white-matter repair after stroke.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"24 1","pages":""},"PeriodicalIF":11.6,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13663253/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149186227","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":"Correction: Distinct roles of centriole distal appendage proteins in ciliary assembly and disassembly.","authors":"Su-Yeon Je, Hyuk Wan Ko","doi":"10.1186/s12964-026-03285-1","DOIUrl":"10.1186/s12964-026-03285-1","url":null,"abstract":"","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"24 1","pages":""},"PeriodicalIF":11.6,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13663178/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149186296","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":"Junctional plakoglobin regulates intestinal epithelial cell proliferation via MAPK/ERK signaling.","authors":"Marius Hörner, Natalie Burkard, Friedrich Forchel, Andre Schmidt, Catherine Kollmann, Christoph Otto, Aarushi Mukherjee, Stefanie Schmidt, Christoph-Thomas Germer, Sven Flemming, Timo Kohler, Matthew Penner, Franziska Vielmuth, Daniela Kugelmann, Kai Kretzschmar, Brenda Gerull, Babak Saravi, Nicolas Schlegel, Matthias Kelm","doi":"10.1186/s12964-026-03256-6","DOIUrl":"https://doi.org/10.1186/s12964-026-03256-6","url":null,"abstract":"<p><p>Junctional plakoglobin (JUP) is a desmosomal protein essential for epithelial tissue integrity and epithelial-immune cell crosstalk. Although JUP has been implicated in inflammatory processes, its role in intestinal epithelial repair remains unclear. In vitro, loss of JUP in Caco-2 monolayers and non-transformed intestinal organoids markedly accelerated wound closure, driven by enhanced epithelial cell migration and proliferation. RNA sequencing-based pathway analysis of organoids revealed activation of MAPK/ERK signaling following JUP deficiency. This effect was corroborated by increased ERK phosphorylation in Western blot analyses. In line with that, pharmacological inhibition of ERK abrogated the accelerated wound closure, confirming that MAPK/ERK signaling is critical for the phenotype. To further examine the relevance in vivo, we used an inducible, intestine-specific JUP knockout mouse model (iVilCreER^T2Jup^fl/fl). Following biopsy-induced intestinal injury, JUP deletion significantly enhanced mucosal repair, accompanied by increased cell proliferation and MAPK signaling, thereby confirming the in vitro results. Collectively, these findings establish JUP as a previously unrecognized regulator of epithelial cell dynamics and repair through MAPK/ERK signaling.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"24 1","pages":""},"PeriodicalIF":11.6,"publicationDate":"2026-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13633646/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149119012","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":"CDK2/9 blockade remodels chromatin and drives phenotypic plasticity in glioblastoma organoids.","authors":"Philipp Kaps, Anne Sophie Hieltscher, Andrea Auditore, Christoph Kamper, Sophie-Charlotte Nelz, Jacqueline Heskamp, Paul Meißner, Annabell Wolff, Katharina Richter, Jakob Brandstetter, Piotr Grabarczyk, Sascha Troschke-Meurer, Burkhard Hinz, Felix Wittig, Daniel Dubinski, Florian Gessler, Thomas M Freiman, Susanne Stählke, Philipp-Kjell Ficht, Lars Boeckmann, Christian Polley, Carl-Friedrich Classen, Christian Junghanss, Claudia Maletzki","doi":"10.1186/s12964-026-03272-6","DOIUrl":"https://doi.org/10.1186/s12964-026-03272-6","url":null,"abstract":"<p><strong>Background: </strong>Glioblastoma (GBM) remains a highly lethal brain tumor with limited therapeutic options and pervasive resistance to standard treatments. Cyclin-dependent kinases (CDKs), key regulators of cell cycle progression and transcription, are frequently dysregulated in GBM and contribute to tumor pathogenesis.</p><p><strong>Methods: </strong>We employed a range of preclinical GBM models-including 2D cultures, 3D spheroids, patient-derived organoids (PDOs), and multicellular 3D bioprints-to evaluate the effects of the CDK2/9 inhibitor fadraciclib in comparison to the standard-of-care temozolomide. Endpoints included cell viability, stress responses, immune-modulatory effects, and transcriptomic reprogramming.</p><p><strong>Results: </strong>Fadraciclib robustly reduces cell viability and invasion in all patient-specific 2D- and 3D models. This effect was independent of O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, demonstrating superior efficacy to temozolomide. Mechanistically, fadraciclib disrupted lysosomal, mitochondrial, and endoplasmic reticulum integrity and increased γH2AX levels, indicating enhanced DNA double-strand breaks. Seahorse analysis demonstrated impaired mitochondrial bioenergetics following fadraciclib treatment. In a triple-culture blood-brain barrier (BBB) model, fadraciclib demonstrated effective BBB penetration and antitumoral activity against GBM cells, while exhibiting minor cytotoxicity toward brain-specific normal cells. In semi-autologous co-culture systems, fadraciclib inhibited GBM invasion, promoted intercellular communication via Connexin 43 upregulation in microglia, and activated peripheral T cells. Transcriptomic analyses of treated patient-derived organoids revealed widespread transcriptional reprogramming, including downregulation of oncogenic long non-coding RNAs (MALAT1, POM121L9), suppression of immune-related pathways, and upregulation of the tumor suppressor LZTS1. Increased histone-associated gene expression suggests chromatin remodeling and induction of a quiescent tumor cell state. Subtype analysis indicated a shift toward a proneural molecular signature. Notably, the antitumoral effects of fadraciclib were preserved in multicellular biomimetic bioprints, whereas nonmalignant astrocytes and microglia were not affected. Therapeutic activity also coincided with altered secretion profiles of extracellular vesicles (EV). EVs from reactive astrocytes contained higher amounts of Fas, which may act as modulator of neuroinflammation.</p><p><strong>Conclusion: </strong>CDK2/9 inhibition shows promise as a therapeutic strategy for GBM. Fadraciclib exhibits multifaceted anti-tumor activity and spares nonmalignant cells of the central nervous system, supporting its further development in therapies that target transcriptional and immune pathways, as well as quiescent tumor cell populations.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"24 1","pages":""},"PeriodicalIF":11.6,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13633624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149118936","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":"Identification of a Ste20-like kinase-dependent signaling network orchestrating cytoskeletal and synaptic development of cortical neurons.","authors":"Anne Quatraccioni, Mark E Graham, Marc Sylvester, Robert Hardt, Ashley J van Waardenberg, Albert J Becker, Susanne Schoch","doi":"10.1186/s12964-026-03250-y","DOIUrl":"https://doi.org/10.1186/s12964-026-03250-y","url":null,"abstract":"<p><strong>Background: </strong>The Ste20-like kinase (SLK) is a serine/threonine kinase that regulates cytoskeletal organization, apoptosis, and cell polarity in non-neuronal cells. In neurons, SLK guides dendrite morphogenesis and the stability of inhibitory synapses, thereby controlling excitation-inhibition balance through parvalbumin interneuron function. Almost complete loss of SLK in dysmorphic neurons of epileptogenic cortical dysplasias implicates a function of this kinase in neurodevelopmental disorders. However, its neuronal signaling mechanisms remain poorly understood.</p><p><strong>Methods: </strong>To address this knowledge gap, we combined an affinity purification-mass spectrometry screen for candidate SLK-interacting proteins with quantitative phosphoproteomics after SLK knockdown to identify potential SLK interactors and the SLK-dependent phosphorylation landscape in cortical neurons.</p><p><strong>Results: </strong>Across the two datasets, we identified hundreds of candidate SLK-binding proteins and more than 1,000 regulated phosphosites after SLK knockdown. The datasets converged on cytoskeletal, synaptic, and signaling proteins involved in actin and microtubule regulation, cell adhesion, and synaptic stability. We identified two germinal center (GCK)-family kinases, MINK1 and TNIK, as direct SLK substrates at the activation-loop threonine (T181), suggesting that SLK may act upstream of a GCK kinase pathway implicated in dendritic development. Functionally, SLK knockdown also altered spontaneous network activity, changed the phosphorylation pattern of KCNQ2, and increased the sensitivity of neuronal networks to KCNQ2 blockade.</p><p><strong>Conclusions: </strong>These data position SLK within a broad neuronal signaling network that links cytoskeletal and synaptic regulation to kinase signaling and neuronal excitability. While the effects on KCNQ2 appear to be indirect, MINK1 and TNIK emerge as direct SLK substrates.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"24 1","pages":""},"PeriodicalIF":11.6,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13632193/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149118970","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":"Correction: The E3 ubiquitin ligase MARCH2 controls TNF-α mediated inflammation by autoubiquitination.","authors":"Kiramage Chathuranga, Pramodya Rathnapala, Asela Weerawardhana, Tae-Hwan Kim, Yebin Seong, W A Gayan Chathuranga, Ashan Subasinghe, D K Haluwana, Nuwan Gamage, Youn Jung Choi, Jae U Jung, Jong-Soo Lee","doi":"10.1186/s12964-026-03171-w","DOIUrl":"https://doi.org/10.1186/s12964-026-03171-w","url":null,"abstract":"","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"24 1","pages":""},"PeriodicalIF":11.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13629043/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149119005","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":"Daam-, FMNL-, and mDia-family formins jointly regulate cortical actin dynamics in melanoma cells.","authors":"Thomas Kaufmann, Jonas Scholz, Agnes Csiszár, Marius Karger, Moritz Walkenbach, Klemens Rottner, Rudolf Merkel, Ute Curth, Jan Faix","doi":"10.1186/s12964-026-03229-9","DOIUrl":"https://doi.org/10.1186/s12964-026-03229-9","url":null,"abstract":"<p><p>The actin-rich cell cortex is a viscoelastic structure essential for processes such as cell migration and division, yet the full spectrum of actin assembly factors that build and regulate the cortex in mammalian cells remains incompletely defined. While the Arp2/3 complex generates actin networks mostly comprising short, branched filaments, formins like mDia1 and mDia3 assemble long, linear filaments capable of withstanding the high mechanical load produced by myosin-driven contraction at the cell rear. To obtain a complete inventory of formins that regulate mechanics of the contractile cortex in B16-F1 melanoma cells, we systematically screened Diaphanous-related formins (DRFs) for interactions with Rho-family GTPases regulating contractility. This screen led to the identification of Daam1/2 and FMNL2/3 as cortical formins, since active variants of these formins as well as the endogenous proteins prominently localized to the rear cortex of polarized B16-F1 cells. Yeast two-hybrid (Y2H) and GST pull-down assays revealed prominent interactions of Daam1/2 with active RhoA, RhoB, RhoC, RhoD, and Cdc42, and weaker binding to Rac1 and Rif. Pyrene-actin polymerization and single-filament TIRF assays further demonstrated that these GTPases effectively relieve autoinhibition of Daam-family formins, with Daam1 and 2 emerging as a potent elongators. In line with this, CRISPR/Cas9-generated Daam1/2 double-knockout cells exhibited multiple defects, including formation of multiple leading edges, impaired random 2D migration, reduced focal adhesion (FA) turnover and inefficient rear retraction. However, contrary to earlier work, we found no evidence that Daam1/2 regulate the formation of finger-like protrusions. By comparison, FMNL2 appears to act as a dual-role formin at both the cell front and rear, interacting with and being activated by several GTPases linked to contractility and protrusion. Analytical ultracentrifugation further clarified previous inconsistencies by showing that the affinity of FMNL2 for GTPases, particularly for Rac1, depends on the length of its N-terminal fragment and the presence of the full FH3 domain. Finally, we show that cells lacking Daam1/2 and mDia1/3 display pronounced cortical defects, including reduced rigidity, excessive blebbing, and delayed cytokinesis, demonstrating that these formins cooperate to preserve cortical architecture and function.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"24 1","pages":""},"PeriodicalIF":11.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13632457/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149119001","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":"A Toxoplasma gondii-derived ROP38 protein engages Ser15/Thr18-linked p53 activation and DNA damage-associated apoptotic signaling in human cancer cells.","authors":"Seung-Hwan Seo, Ji-Eun Lee, Eun-Ji Cho, Eun-Hee Shin","doi":"10.1186/s12964-026-03257-5","DOIUrl":"10.1186/s12964-026-03257-5","url":null,"abstract":"<p><strong>Background: </strong>The tumor suppressor p53 integrates diverse cellular stresses to regulate DNA damage responses, cell-cycle progression, and apoptosis-associated signaling. Toxoplasma gondii secretes rhoptry effectors that remodel host signaling networks, but the host targets and signaling functions of the rhoptry kinase ROP38 remain poorly defined.</p><p><strong>Methods: </strong>GFP-tagged T. gondii ME49 ROP38 full-length protein (ROP38 Full) and its kinase-domain fragment (ROP38 KiD) were stably expressed in HCT116 and HepG2 human cancer cells. Kinase-associated activity was assessed in anti-GFP immunoprecipitates, and a candidate co-immunoprecipitation screen was used to identify ROP38-associated host proteins. ROP38-p53 association and phospho-p53 species were further examined by co-immunoprecipitation. Purified recombinant ROP38 and human p53 were used for direct interaction and in vitro phosphorylation assays. Whole-cell p53 signaling, DNA damage/apoptosis-associated markers, and cell-cycle distribution were also analyzed. Statistical analyses used one- or two-way ANOVA, as appropriate, followed by Tukey's multiple comparisons test.</p><p><strong>Results: </strong>ROP38 Full- and ROP38 KiD-containing immunoprecipitates showed increased kinase-associated activity. Among the candidate proteins examined, p53 was the only ROP38-associated host factor detected in both cell lines. ROP38 Full and ROP38 KiD co-immunoprecipitated with total p53 and preferentially enriched p53 phosphorylated at Ser15 and Thr18. Purified recombinant ROP38 directly associated with recombinant p53 and promoted Ser15/Thr18 phosphorylation in the presence of ATP. At the whole-cell level, ROP38 expression increased p53 abundance and multisite phosphorylation, with prominent Ser15/Thr18 induction, and was accompanied by increased γH2AX, PUMA, cleaved caspase-3, and p21 expression. ROP38-expressing cells also showed decreased G₁-phase populations with increased S- and G₂/M-phase populations.</p><p><strong>Conclusions: </strong>These data identify a candidate ROP38-associated p53 signaling module in human cancer cells and provide biochemical evidence that ROP38 can directly associate with p53 and promote Ser15/Thr18 phosphorylation in vitro. The requirement for intrinsic ROP38 catalytic activity and the physiological relevance of this relationship during T. gondii infection remain to be established.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"24 1","pages":""},"PeriodicalIF":11.6,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13670628/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149197963","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":"CDK7, CDK9, or CDK11 inhibition reduces neutrophil-driven inflammation and tissue damage in experimental autoimmune models.","authors":"Mareile Schlotfeldt, Leonie Voss, Adrian P Mansini, Daniel Mehlberg, Sophia Johannisson, Michael Radziewitz, Ann-Kathrin Schneider, Seyed Mohammad Vahabi, Yulu Wang, Haley Gainer, Jing Li, Colin Osterloh, Nancy Ernst, Remco Visser, Gestur Vidarsson, Frank Petersen, Xinhua Yu, Ralf J Ludwig, Artem Vorobyev, Kyle T Amber, Anja Lux, Katja Bieber","doi":"10.1186/s12964-026-03219-x","DOIUrl":"https://doi.org/10.1186/s12964-026-03219-x","url":null,"abstract":"<p><strong>Background: </strong>Cyclin-dependent kinases (CDKs) are involved in basic cellular processes like regulation of cell-cycle progression and transcription. However, recent data also indicate a specific role in terminally differentiated neutrophils by promoting reactive oxygen species (ROS) release, degranulation, neutrophil extracellular trap formation, or apoptosis. Since these mechanisms are implicated in multiple autoimmune diseases, we aimed to delineate the role of CDKs in immune complex (IC)-mediated autoimmune diseases both in vitro and in vivo.</p><p><strong>Methods: </strong>We analyzed CDK activity and gene expression in unstimulated and IC-stimulated neutrophils. Subsequently, we investigated the effect of pharmacological CDK inhibition on IC-activated neutrophil functions. To analyze the inhibitors in a more translational approach, we proceeded with the systemic and topical application of the effective inhibitors in a murine antibody transfer-induced local epidermolysis bullosa acquisita (EBA) model. The most effective inhibitor, MC180295, was validated in two other IC-mediated models of autoimmune disease: KBxN serum-transfer arthritis (KBxN STA), which also, but not exclusively, depends on neutrophils and immune thrombocytopenia (ITP), which is considered less neutrophil-dependent.</p><p><strong>Results: </strong>We found 14 CDKs expressed in unstimulated cells, while the IC-stimulation showed an upregulation of CDK2 and CDK4 expression. Inhibitors selectively targeting CDK1, CDK2, CDK4/6, CDK7, CDK9, CDK11, and CDK12 showed effects on different neutrophil functions (surface activation marker expression, ROS release, adhesion, apoptosis) in vitro. In the predominantly neutrophil-driven EBA model, we observed a reduction of disease severity upon treatment with CDK7, CDK9, or CDK11 inhibitors. Inhibiting these CDKs with topical THZ2, MC180295, or OTS964, respectively, also improved the clinical phenotype. In line with our hypothesis, MC180295 impaired the development of KBxN STA, but not ITP.</p><p><strong>Conclusions: </strong>CDK7, CDK11, and especially CDK9 inhibition show therapeutic potential in IC-driven neutrophil-mediated diseases such as inflammatory arthritis and EBA.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"24 1","pages":""},"PeriodicalIF":11.6,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13628873/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149118943","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}