bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2025–09–07
seventeen papers selected by
Ralitsa Radostinova Madsen, MRC-PPU
  1. Amino acid-dependent TSC2 dephosphorylation by lysosome-PP2A regulates mTORC1 signaling transduction.
  2. Iterative, multimodal, and scalable single-cell profiling for discovery and characterization of signaling regulators.
  3. PAX3-FOXO1 Drives Targetable Cell State-Dependent Metabolic Vulnerabilities in Rhabdomyosarcoma.
  4. A History of Cancer Research: Cancer Cell Growth and Metabolism.
  5. MAPK and mTORC1 signaling converge to drive cyclin D1 protein production to enable cell cycle reentry in melanoma persister cells.
  6. Shear Stress Induces Concentration Gradient Distributions of Membrane Proteins in Live Cells.
  7. spammR: an R package designed for analysis and integration of spatial multi-omic measurements.
  8. Tyrosine phosphoproteome profiling identifies cell-intrinsic signals limiting the efficacy of tyrosine kinase inhibitor therapies.
  9. Differential cell survival outcomes in response to diverse amino acid stress.
  10. Understanding Data Analysis Steps in Mass-Spectrometry-Based Proteomics Is Key to Transparent Reporting.
  11. Dual leucine zipper-bearing kinase DLK is necessary for cell autonomous regulation of insulin sensitivity.
  12. Human single-cell atlas analysis reveals heterogeneous endothelial signaling.
  13. Compression causes cancer cells to start spreading.
  14. Characterization of PROTAC specificity and endogenous protein interactomes using ProtacID.
  15. FBXO9 mediated the ubiquitination and degradation of YAP in a GSK-3β-dependent manner.
  16. Single-Cell Fluorescence Imaging Reveals Heterogeneity in Senescence Biomarkers and Identifies Rapamycin-Responsive Sub-Populations.
  17. Epidermal growth factor receptor is an essential component in E-cadherin force-transduction complexes.
  1. Life Sci Alliance. 2025 Nov;pii: e202503206. [Epub ahead of print]8(11):
    Amino acid-dependent TSC2 dephosphorylation by lysosome-PP2A regulates mTORC1 signaling transduction.
    Takanori Nakamura, Shigeyuki Nada, Masaki Matsumoto, Nuha Loling Othman, Hidetaka Kosako, Kazuki Ikeda, Naohiko Koshikawa, Junya Masumoto, Tatsuya Sawasaki, Mutsuhiro Takekawa, Takashi Suzuki, Masato Okada.
      The mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, composed of amino acid (AA)-sensing (Ragulator/LAMTOR-Rag) and growth factor (GF)-sensing (AKT-TSC1/2-Rheb) axes, pivotally regulates intracellular anabolism and catabolism. mTORC1 deregulation is associated with various metabolic diseases, including cancer and diabetes. As a key regulator of nutrient signaling, mTORC1 integrates a variety of nutrient signals. However, signal integration and crosstalk in the mTORC1 pathway remain incompletely understood. Therefore, in this study, we aimed to understand the complex mTORC1 signaling cascade by constructing an integrated mathematical model of temporal mTORC1 regulation using two AA-sensing and GF-sensing axes. Mathematical simulations and experimental data revealed robust AKT phosphorylation (P-T308/P-S473) after insulin stimulation, regardless of the intracellular AA levels. Conversely, AKT-mediated inhibitory TSC2 phosphorylation (P-T1462) substantially diminished during AA deprivation compared with AA treatment. Furthermore, we highlighted PP2A-mediated TSC2 dephosphorylation during AA removal, ensuring complete mTORC1 activation only upon concurrent AA and GF sensing. Thus, we elucidated mTORC1 signaling dynamics, revealing the complex interplay between AAs and GFs and offering insights into metabolic regulation.
    DOI:  https://doi.org/10.26508/lsa.202503206
  2. bioRxiv. 2025 Aug 30. pii: 2025.08.27.672635. [Epub ahead of print]
    Iterative, multimodal, and scalable single-cell profiling for discovery and characterization of signaling regulators.
    John D Blair, Alexandra Bradu, Carol Dalgarno, Isabella N Grabski, Rahul Satija.
      Cell signaling plays a critical role in regulating cellular state, yet uncovering regulators of signaling pathways and understanding their molecular consequences remains challenging. Here, we present an iterative experimental and computational framework to identify and characterize regulators of signaling proteins, using the mTOR marker phosphorylated RPS6 (pRPS6) as a case study. We present a customized workflow that uses the 10x Flex assay to jointly profile intracellular protein levels, transcriptomes, and CRISPR perturbations in single cells. We use this to generate a "glossary" dataset of paired protein-RNA measurements across targeted perturbations, which we leverage to train a predictive model of pRPS6 levels based solely on transcriptomic data. Applying this model to a genome-wide Perturb-seq dataset enables in silico screening for pRPS6 and nominates novel regulators of mTOR signaling. Experimental validation confirms these predictions and reveals mechanistic diversity among hits, including changes in signaling output driven by anabolic activity, cellular proliferation and multiple stress pathways. Our work demonstrates how integrated experimental and computational approaches provide a scalable framework for multimodal phenotyping and discovery.
    DOI:  https://doi.org/10.1101/2025.08.27.672635
  3. Cancer Res. 2025 Sep 05.
    PAX3-FOXO1 Drives Targetable Cell State-Dependent Metabolic Vulnerabilities in Rhabdomyosarcoma.
    Katrina I Paras, Julia S Brunner, Angela M Montero, Jacob A Boyer, Benjamin T Jackson, Sangita Chakraborty, Abigail Xie, Kristina Guillan, Armaan Siddiquee, Lourdes Pajuelo Torres, Joshua D Rabinowitz, Andrew L Kung, Daoqi You, Filemon S Dela Cruz, Lydia W S Finley.
      PAX3-FOXO1, an oncogenic transcription factor, drives a particularly aggressive subtype of rhabdomyosarcoma (RMS) by enforcing gene expression programs that support malignant cell states. Here, we showed that PAX3-FOXO1+ RMS cells exhibit altered pyrimidine metabolism and increased dependence on enzymes involved in de novo pyrimidine synthesis, including dihydrofolate reductase (DHFR). Consequently, PAX3-FOXO1+ cells displayed increased sensitivity to inhibition of DHFR by the chemotherapeutic drug methotrexate, and this dependence was rescued by provision of pyrimidine nucleotides. Methotrexate treatment mimicked the metabolic and transcriptional impact of PAX3-FOXO1 silencing, reducing expression of genes related to PAX3-FOXO1-driven malignant cell states. Accordingly, methotrexate treatment slowed the growth of multiple PAX3-FOXO1+ tumor xenograft models but not the fusion-negative counterparts. Taken together, these data demonstrate that PAX3-FOXO1 induces cell states characterized by altered pyrimidine dependence and nominate methotrexate as an addition to the current therapeutic arsenal for treatment of these malignant pediatric tumors.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-0315
  4. Cold Spring Harb Perspect Med. 2025 Sep 02. pii: a035782. [Epub ahead of print]15(9):
    A History of Cancer Research: Cancer Cell Growth and Metabolism.
    Joseph Lipsick.
      Dysregulation of cell growth and metabolic changes are a feature of tumorigenesis. Studies over the past 50 years have mapped the pathways that control cell growth and metabolism and revealed how these are altered in cancer. In this excerpt from his forthcoming book on the history of cancer research, Joe Lipsick looks at how we got here-from early work on insulin and growth factor receptor signaling to the discovery of phosphatidyl inositol 3-kinase (PI 3-kinase), the identification of mTOR as the target of rapamycin, and the unexpected finding that tumors can produce novel "oncometabolites."
    DOI:  https://doi.org/10.1101/cshperspect.a035782
  5. Sci Signal. 2025 Sep 02. 18(902): eadw3231
    MAPK and mTORC1 signaling converge to drive cyclin D1 protein production to enable cell cycle reentry in melanoma persister cells.
    Varuna Nangia, Humza Ashraf, Nasreen Marikar, Victor J Passanisi, Christopher R Ill, Sabrina L Spencer.
      In BRAF-mutant melanoma cells treated with inhibitors of the kinases BRAF and MEK, a subset of cells rapidly and nongenetically adapts to escape drug-induced quiescence and reenters the cell cycle. Here, we investigated the mechanisms enabling this drug escape by computationally reconstructing single-cell lineages from time-lapse imaging data, linking dynamic signaling pathways to distinct cell-cycle fate outcomes. We found that reactivation of the MEK substrate ERK was necessary but not sufficient to drive escape; rather, the activity of the protein complex mTORC1 was also required to promote cell growth and protein synthesis in drug-treated cells destined for cell-cycle reentry. ERK and mTORC1 signaling converged to increase the abundance of cyclin D1 protein, a critical bottleneck for cell-cycle commitment under drug pressure. In cells in which endogenous cyclin D1 was fluorescently tagged using CRISPR, the subset that escaped drug treatment exhibited marked accumulation of cyclin D1 at least 15 hours before cell-cycle reentry, enabling early prediction of future drug escape. Cyclin D1 thus represents both an early biomarker and potential therapeutic target for suppressing drug escape in melanoma. We observed a similar mTORC1-driven mechanism underlying escape in lung cancer cells, but not colon cancer cells, highlighting partial generalizability across cancer types.
    DOI:  https://doi.org/10.1126/scisignal.adw3231
  6. bioRxiv. 2025 Aug 29. pii: 2025.08.27.672548. [Epub ahead of print]
    Shear Stress Induces Concentration Gradient Distributions of Membrane Proteins in Live Cells.
    Sawako Yamashiro, Misato Nomura, Nils Chapin, Sreeja Sasidharan, Louis Elverston, Leah Knepper, Damien Thévenin, Naoki Watanabe, Aurelia Honerkamp-Smith.
      Cells sense and respond to fluid shear stress. Cell surfaces are exposed to flow, yet the influence of shear stress on the behavior of plasma membrane proteins remains unclear. Here we show that extracellular flow induces the gradient distribution of cell membrane proteins with increasing concentration toward the downstream direction of the flow. Shear stress at 10-30 dynes/cm2 caused formation of concentration gradients of both GPI-anchored proteins and transmembrane proteins, including integrinβ1, E-cadherin and the insulin receptor in Xenopus XTC cells. Using single-molecule live-cell imaging, we found that GPI-anchored T-cadherin molecules are dragged along the direction of flow under shear stress. In addition, shear stress induced concentration gradients of membrane proteins in COS-7 cells and human umbilical vein endothelial cells (HUVECs). Our findings suggest that external flow directly transports membrane proteins, establishing concentration gradients that may contribute to the cellular flow-sensing mechanism.
    DOI:  https://doi.org/10.1101/2025.08.27.672548
  7. bioRxiv. 2025 Aug 28. pii: 2025.08.26.672472. [Epub ahead of print]
    spammR: an R package designed for analysis and integration of spatial multi-omic measurements.
    Yannick Mahlich, Harkirat Sohi, Paul Piehowski, Jason E McDermott, Sara J Gosline.
       Summary: Spatial omics is a young and evolving field and as such shows rapid development of novel technologies and analysis methods to measure transcripts, proteins, metabolites, and post-translational modifications at high spatial resolution. These advances in technology have enabled the simultaneous generation of abundance profiles for multiple different omics types and associated microscopy imaging data, as well as their analysis in a spatial context. However, most analytical tools are designed for spatial transcriptomics platforms and are challenging to use in other contexts such as mass spectrometry-based measurements or metagenomics. To this end we present spammR ( sp atial a nalysis of m ulti-omics m easurements in R ), an R package that enables end-to-end analysis with a specific focus on mass-spectrometry derived spatial omics datasets with (1) smaller sample sizes and spatial sparsity of samples, (2) considerable missingness, and (3) no a-priori knowledge about proteins or genes of interest, relying on a fully data-driven approach.
    Availability and implementation: spammR is implemented in R. The package is currently installable from GitHub ( https://github.com/PNNL-CompBio/spammR ).
    DOI:  https://doi.org/10.1101/2025.08.26.672472
  8. bioRxiv. 2025 Aug 27. pii: 2025.08.22.670548. [Epub ahead of print]
    Tyrosine phosphoproteome profiling identifies cell-intrinsic signals limiting the efficacy of tyrosine kinase inhibitor therapies.
    Cameron T Flower, Forest M White.
      Tyrosine kinases (TKs) are frequently mutated or overexpressed in cancer, and TK inhibitors (TKIs) are an important therapeutic modality against TK-driven cancers, but many patients show an underwhelming response to TKIs prescribed on the basis of tumor genotype. To find cell-intrinsic TK signaling patterns which might be predictive of poor response to TKI exposure, we used high-sensitivity multiplexed mass spectrometry to quantify endogenous levels of 1,222 phosphotyrosine (pY) sites across the proteomes of TK-driven human cancer cell lines with variable response to genotype-matched TKIs. In direct comparisons between TKI-tolerant and TKI-sensitive lines with a common driver TK, we found that TKI treatment was equally effective at blocking driver TK signaling, and higher basal activity of the driver TK did not always predict higher sensitivity to TKI. All tolerant lines showed a dampened proteome-wide pY response to TKI exposure compared to sensitive lines, suggesting tumor cells with more robust TK signaling are less vulnerable to driver TK blockade. We found that each tolerant line depends on a unique set of compensatory TKs and signaling axes but are unified by hyperactivity of at least one of the SRC family kinases (SFKs) or the related ABL1/2 kinases, both at rest and under TKI treatment, despite absence of SFK/ABL genetic mutations. In time- and dose-resolved drug combination experiments, SFK/ABL inhibitors were potently synergistic with all TKIs tested, demonstrating that elevated SFK/ABL signaling is a conserved bottleneck for maximal TKI efficacy which could be exploited therapeutically.
    Significance: The last twenty-five years have seen a remarkable number of new anti-cancer therapies specifically targeting tyrosine kinases, which frequently drive tumorigenesis when hyperactive. While these therapies have brought undeniable improvements in survival time and quality of life for a large fraction of patients, many still do not respond to inhibitors aimed at their presumed driver kinase. By profiling tumor cell-intrinsic signaling networks using phosphotyrosine immunoaffinity pulldown and high-sensitivity mass spectrometry, we directly compare the signaling networks of drug-tolerant and drug-sensitive cancer cell lines across several oncogenic driver contexts and find both unique and shared signals promoting therapy tolerance.
    DOI:  https://doi.org/10.1101/2025.08.22.670548
  9. Life Sci Alliance. 2025 Nov;pii: e202503324. [Epub ahead of print]8(11):
    Differential cell survival outcomes in response to diverse amino acid stress.
    Marion Russier, Alessandra Fiore, Ana Bici, Annette Groß, Maria Tanzer, Assa Yeroslaviz, Matthias Mann, Peter J Murray.
      Amino acid (AA) detection is fundamental for cellular function, balancing translation demands, biochemical pathways, and signaling networks. Although the GCN2 and mTORC1 pathways are known to regulate AA sensing, the global cellular response to AA deprivation remains poorly understood, particularly in non-transformed cells, which may exhibit distinct adaptive strategies compared with cancer cells. Here, we employed murine pluripotent embryonic stem (ES) cells as a model system to dissect responses to AA stress. Using multi-omics analyses over an extended time course, we examined the effects of arginine (Arg) and leucine (Leu) deprivation. We uncovered a broad array of proteomic, phosphoproteomic, transcriptomic, and metabolomic adaptations, including an increase in lysosome production, all occurring without lethality. We found that Arg or Leu starvation induces reversible cell cycle exit, promoting a quiescent state that enhances resistance to cytotoxic stressors. In contrast, cysteine (Cys) and threonine (Thr) deprivation led to cell death via distinct pathways: ferroptosis for Cys starvation, whereas Thr deprivation triggered a previously uncharacterized form of cell death, which could be entirely suppressed by methionine (Met) co-starvation, and mTOR or translational inhibition. These findings suggest that ES cells implement specialized survival strategies in response to different AA limitations, highlighting their ability to reprogram cellular biochemistry under nutrient stress.
    DOI:  https://doi.org/10.26508/lsa.202503324
  10. J Proteome Res. 2025 Sep 03.
    Understanding Data Analysis Steps in Mass-Spectrometry-Based Proteomics Is Key to Transparent Reporting.
    Nadezhda T Doncheva, Veit Schwämmle, Marie Locard-Paulet.
      Mass spectrometry (MS)-based proteomics data analysis is composed of many stages from quality control, data cleaning, and normalization to statistical and functional analysis, without forgetting multiple visualization steps. All of these need to be reported next to published results to make them fully understandable and reusable for the community. Although this seems straightforward, exhaustively reporting all aspects of an analysis workflow can be tedious and error prone. This letter reports good practices when describing data analysis of MS-based proteomics data and discusses why and how the community should put efforts into more transparently reporting data analysis workflows.
    Keywords:  data analysis; mass-spectrometry; proteomics; reporting; reproducibility; statistics; transparency
    DOI:  https://doi.org/10.1021/acs.jproteome.5c00287
  11. Mol Metab. 2025 Sep 01. pii: S2212-8778(25)00151-6. [Epub ahead of print] 102244
    Dual leucine zipper-bearing kinase DLK is necessary for cell autonomous regulation of insulin sensitivity.
    Hetty N Wong, Nathan Qi, Edward B Arias, Kae Won Cho, Deepak Nihalani, Gregory D Cartee, Lawrence B Holzman.
      Metabolic syndrome and insulin resistance are driven in part by dysregulated signaling through the c-Jun N-terminal kinase (JNK) pathway. The scaffold protein JIP1 and its upstream kinase DLK (dual leucine zipper kinase) form a dynamic signaling complex that modulates JNK activity, yet the physiological role of DLK in glucose metabolism remains undefined. Here, we identify DLK as a critical regulator of insulin sensitivity using three genetically modified mouse models: a hypomorphic DLK allele, a tamoxifen-inducible whole-body DLK knockout, and a high-fat diet-induced obese model with DLK ablation. All models exhibited enhanced insulin sensitivity independent of adiposity, characterized by increased glucose uptake in muscle and adipose tissue, and improved suppression of hepatic glucose production during hyperinsulinemic-euglycemic clamp studies. Mechanistically, we demonstrate that DLK functions in a cell-autonomous manner, limiting insulin signaling through modulation of AKT and IRS1 phosphorylation downstream of insulin stimulation. In cultured myoblasts and fibroblasts, DLK was required for JNK activation and subsequent dampening of insulin signaling. These findings establish DLK as a regulator of whole-body insulin sensitivity, independent of obesity through a JIP-JNK signaling module. The results suggest that targeting DLK could represent a therapeutic strategy for improving insulin sensitivity in metabolic disease.
    Keywords:  DLK; JNK signaling; cell-autonomous signaling; glucose metabolism; insulin sensitivity
    DOI:  https://doi.org/10.1016/j.molmet.2025.102244
  12. bioRxiv. 2025 Aug 19. pii: 2025.08.15.670370. [Epub ahead of print]
    Human single-cell atlas analysis reveals heterogeneous endothelial signaling.
    Zimo Zhu, Rongbin Zheng, Yang Yu, Lili Zhang, Kaifu Chen.
      Endothelial cells (ECs) play complex roles across tissues and vessel types. Yet, systematic investigations of EC heterogeneity in the combined context of vessel type and tissue microenvironment are still largely lacking. We integrated over three million single cells of scRNA-seq datasets in 15 human tissues and found that ECs in some tissues (e.g., heart and kidney) exhibited greater tissue specificity, while others displayed more substantial vessel specificity. We developed a computational pipeline to analyze cell-cell communications (CCC) mediated by metabolites or proteins to explore microenvironmental regulation. Interestingly, our results showed that CCC events involving ECs varied vastly across tissues, highlighting tissue-specific EC interactions. Using topic modeling, we identified CCC patterns, termed CCC topics, representing metabolite- and protein-mediated interactions between ECs and other tissue-resident cells. Most CCC topics exhibited high tissue specificity, potentially explaining microenvironmental regulations for EC heterogeneity. The work systematically investigates EC heterogeneity and provides insights into how EC heterogeneity was regulated across diverse tissue microenvironments.
    DOI:  https://doi.org/10.1101/2025.08.15.670370
  13. Nature. 2025 Sep 03.
    Compression causes cancer cells to start spreading.
      
    Keywords:  Cancer; Cell biology
    DOI:  https://doi.org/10.1038/d41586-025-02768-4
  14. Nat Commun. 2025 Aug 29. 16(1): 8089
    Characterization of PROTAC specificity and endogenous protein interactomes using ProtacID.
    Suman Shrestha, Matthew E R Maitland, Laili Jing, Shili Duan, David Y Nie, Jonathan St-Germain, Michael Kanaris, Dalia Barsyte-Lovejoy, Cheryl H Arrowsmith, Brian Raught.
      Here we describe ProtacID, a flexible BioID (proximity-dependent biotinylation)-based approach to identify PROTAC-proximal proteins in living cells. ProtacID analysis of VHL- and CRBN-recruiting PROTACs targeting a number of different proteins (localized to chromatin or cellular membranes, and tested across six different human cell lines) demonstrates how this technique can be used to validate PROTAC degradation targets and identify non-productive (i.e. non-degraded) PROTAC-interacting proteins, addressing a critical need in the field of PROTAC development. We also demonstrate that ProtacID can be used to characterize native, endogenous multiprotein complexes without the use of antibodies, or modification of the protein of interest with epitope tags or biotin ligase tagging.
    DOI:  https://doi.org/10.1038/s41467-025-63357-7
  15. J Biol Chem. 2025 Sep 01. pii: S0021-9258(25)02504-9. [Epub ahead of print] 110652
    FBXO9 mediated the ubiquitination and degradation of YAP in a GSK-3β-dependent manner.
    Yili Jin, Xue Yun, Jiatao Yao, Chengyun Xu, Rui Yu.
      The Hippo signaling pathway effector YAP (Yes-associated protein) serves as a critical transcriptional regulator involved in a wide range of biological processes, including oncogenesis. Despite its potential as a therapeutic target, pharmacologically targeting the Hippo/YAP axis remains challenging, necessitating further exploration of the mechanisms governing YAP regulation. In this study, we identify the Cullin-RING E3 ligase complex SCF-FBXO9-CRL1 as a novel posttranslational regulator of YAP stability. Mechanistically, FBXO9 recognizes YAP through a conserved degron motif and facilitates its K48-linked polyubiquitination at lysine 76 (K76), thereby promoting proteasomal degradation. Notably, We demonstrate that phosphorylation of YAP at Ser338 and Thr342 by GSK-3β primes YAP for FBXO9 recognition, leading to subsequent ubiquitination. Furthermore, our analysis of the signaling cascade reveals that Akt kinase activity modulates this regulatory axis by influencing the phosphorylation status of GSK-3β. Pharmacological inhibition of Akt signaling leads to YAP degradation in a GSK-3β/FBXO9-dependent manner, significantly enhancing chemosensitivity in cancer models. These findings establish a previously unrecognized regulatory axis involving Akt, GSK-3β, FBXO9, and YAP that controls YAP protein turnover, providing a mechanistic basis for therapeutic strategies that combine Akt inhibitors with conventional chemotherapeutics. Our work advances the understanding of posttranslational YAP regulation and identifies several potential therapeutic targets for YAP-driven malignancies.
    Keywords:  FBXO9; GSK-3β; Hippo signaling pathway; YAP; ubiquitination
    DOI:  https://doi.org/10.1016/j.jbc.2025.110652
  16. Aging Cell. 2025 Sep 03. e70209
    Single-Cell Fluorescence Imaging Reveals Heterogeneity in Senescence Biomarkers and Identifies Rapamycin-Responsive Sub-Populations.
    Vijayraghavan Seshadri, Charmaine Chng, Joel Tyler, Cestarangga Adikerta, Kaveh Baghaei, Yan Wang, Nuri Gueven, Sharon Ricardo, Iman Azimi.
      Cellular senescence is a state of irreversible cell cycle arrest accompanied by a distinctive inflammatory secretory profile known as the senescence-associated secretory phenotype (SASP). While various biomarkers, such as senescence-associated beta-galactosidase (SA-βgal), EdU incorporation, p21 and p16, are used to identify senescent cells, no single biomarker universally defines cellular senescence and current methods often fail to address heterogeneity in biomarker expression levels. This study leverages single-cell fluorescence imaging to assess multiple senescence markers including SA-βgal enzymatic activity, p21 and IL-6 expression and nuclear and cell area in chemotherapy-induced (mitomycin C) and oxidative stress-induced (D-galactose) senescence models in human fibroblasts. Our findings reveal significant heterogeneity in SA-βgal activity and distinct sub-populations within senescent cells. Nuclear and cell area measurements emerged as robust indicators of cellular senescence, displaying similar variability across individual cells. Importantly, we identified specific nuclear area sub-populations that strongly correlate with IL-6 expression levels, demonstrating a relationship between the heterogeneous expression of senescence biomarkers and the SASP. To address this heterogeneity, we introduced an induction threshold method to more accurately quantify the percentage of cells expressing senescence biomarkers. Furthermore, in both senescence models, we observed that rapamycin, a well-known senomorphic agent, selectively targets specific biomarker-expressing sub-populations. This study underscores the value of assessing cellular heterogeneity in senescence research and provides an improved approach for analysing senescence markers in diverse cellular contexts.
    DOI:  https://doi.org/10.1111/acel.70209
  17. J Cell Sci. 2025 Sep 05. pii: jcs.264350. [Epub ahead of print]
    Epidermal growth factor receptor is an essential component in E-cadherin force-transduction complexes.
    Yubo Zou, Nicolas Allen, Emaan Rauf, Deborah Leckband.
      We present evidence that the association of Epithelial (E)-cadherin (CHD1) extracellular domain and epidermal growth factor receptor (EGFR, ErbB1) is obligatory for cadherin force transduction signaling. E-cadherin and EGFR associate at cell surfaces, independent of their cytoplasmic domains, and tension on E-cadherin activates EGFR signaling. Using engineered cadherin mutants that disrupt co-immunoprecipitation with EGFR, but not adhesion, we show that the hetero-receptor complex is required to mechanically activate signaling and downstream cytoskeletal remodeling at cadherin adhesions. The mutants localized the essential region on E-cadherin to the extracellular region and domain 4, EC4. The ectodomain is also required for hetero-receptor co-localization at intercellular junctions. Although the E-cadherin mutants disrupt EGFR signaling, integrin pre-activation together with tension rescues cytoskeletal reinforcement at cadherin adhesions, confirming the role of integrins in intercellular force transduction. Furthermore, although E-cadherin suppresses EGFR-mediated proliferation, in response to extracellular matrix stiffening, the force-sensitive hetero-receptor complex regulates growth factor-dependent epithelial proliferation. These findings support the hypothesis that E-cadherin complexes with EGFR are mechano-switches at cell-cell contacts that directly couple intercellular force fluctuations to mitogen-dependent signaling.
    Keywords:  Cadherin; Epidermal growth factor receptor; Mechano-transduction
    DOI:  https://doi.org/10.1242/jcs.264350
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