Science Signaling最新文献

{"title":"Adherens junctions co-opt EGFR-ERK signaling for epithelial mechanotransduction","authors":"Ellen K. Potoczky,&nbsp;Alpha S. Yap","doi":"10.1126/scisignal.adx0682","DOIUrl":"10.1126/scisignal.adx0682","url":null,"abstract":"<div >In this issue of <i>Science Signaling</i>, Houtekamer <i>et al</i>. report a mechanism by which adherens junctions enable epithelia to respond to mechanical stress. They demonstrate that E-cadherin–containing adhesions stimulate ERK signaling in response to tissue tension through a metalloproteinase pathway that releases EGF receptor ligands.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 886","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An atlas of bacterial serine-threonine kinases reveals functional diversity and key distinctions from eukaryotic kinases","authors":"Brady O’Boyle,&nbsp;Wayland Yeung,&nbsp;Jason D. Lu,&nbsp;Samiksha Katiyar,&nbsp;Tomer M. Yaron-Barir,&nbsp;Jared L. Johnson,&nbsp;Lewis C. Cantley,&nbsp;Natarajan Kannan","doi":"10.1126/scisignal.adt8686","DOIUrl":"10.1126/scisignal.adt8686","url":null,"abstract":"<div >Bacterial serine-threonine kinases (STKs) regulate diverse cellular processes associated with cell growth, virulence, and pathogenicity and are evolutionarily related to the druggable eukaryotic STKs. A deeper understanding of how bacterial STKs differ from their eukaryotic counterparts and how they have evolved to regulate diverse bacterial signaling functions is crucial for advancing the discovery and development of new antibiotic therapies. Here, we classified more than 300,000 bacterial STK sequences from the NCBI RefSeq nonredundant and UniProt protein databases into 35 canonical and seven pseudokinase families on the basis of the patterns of evolutionary constraints in the conserved catalytic domain and flanking regulatory domains. Through statistical comparisons, we identified features distinguishing bacterial STKs from eukaryotic STKs, including an arginine residue in a regulatory helix (C helix) that dynamically couples the ATP- and substrate-binding lobes of the kinase domain. Biochemical and peptide library screens demonstrated that evolutionarily constrained residues contributed to substrate specificity and kinase activation in the <i>Mycobacterium tuberculosis</i> kinase PknB. Together, these findings open previously unidentified avenues for investigating bacterial STK functions in cellular signaling and for developing selective bacterial STK inhibitors.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 885","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143914784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insights into the intramembrane protease SPPL2b and its substrates: Functions and disease implications","authors":"Jack Badman,&nbsp;Antonietta Parracino,&nbsp;Rajnish Kumar,&nbsp;Simone Tambaro","doi":"10.1126/scisignal.adt2272","DOIUrl":"10.1126/scisignal.adt2272","url":null,"abstract":"<div >Specialized intramembrane proteases, known as iCLiPs, regulate the processing of transmembrane proteins by releasing intracellular domains, which can function as transcriptional regulators. The signal peptide peptidase–like (SPPL) family of iCLiPs, particularly SPPL2b, has roles in immune regulation, neuronal function, and disease pathogenesis. In the brain, SPPL2b localizes mainly in the plasma membrane of neurons and microglia and is abundant in the cortex and hippocampus. Its known substrates regulate neuronal growth, inflammation, and synaptic function, and increased amounts of SPPL2b have been found in postmortem brain tissue from patients with Alzheimer’s disease. In this review, we discuss the currently known roles of SPPL2b, its substrates, and its disease implications. Understanding the downstream effects of SPPL2b-cleaved substrates will provide clearer insights into the impact of SPPL2b on cellular homeostasis and disease, potentially leading to new therapeutic strategies.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 885","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143914785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pericytes under pressure: TRPC3 channels as gatekeepers of capillary flow","authors":"Scott Earley","doi":"10.1126/scisignal.adw7185","DOIUrl":"10.1126/scisignal.adw7185","url":null,"abstract":"<div >Intrinsic control of cerebral blood flow in response to intravascular pressure is traditionally attributed to smooth muscle cells in arterioles. However, in this issue of <i>Science Signaling</i>, Ferris <i>et al.</i> demonstrate that capillary constriction is caused by pressure-induced depolarization of pericytes, mural cells that encircle capillaries, and is mediated by TRPC3 cation channels, identifying the channel as critical for fine-tuning brain perfusion.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 884","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143889205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A good side of STING","authors":"Leslie K. Ferrarelli","doi":"10.1126/scisignal.ady4818","DOIUrl":"10.1126/scisignal.ady4818","url":null,"abstract":"<div >The innate immunity mediator STING senses and repairs lysosomal dysfunction.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 884","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143889206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased luminal pressure in brain capillaries drives TRPC3-dependent depolarization and constriction of transitional pericytes","authors":"Hannah R. Ferris,&nbsp;Danielle A. Jeffrey,&nbsp;Mayra Bueno Guerrero,&nbsp;Lutz Birnbaumer,&nbsp;Fang Zheng,&nbsp;Fabrice Dabertrand","doi":"10.1126/scisignal.ads1903","DOIUrl":"10.1126/scisignal.ads1903","url":null,"abstract":"<div >Cerebral autoregulation ensures constant blood flow, an essential condition of brain health. A fundamental parameter of the brain circulation is the dynamic regulation of microvessel diameter to allow for adjustments in resistance to blood pressure changes. Pericytes are a family of mural cells that wrap around the capillary endothelium and contribute to the dynamic control of capillary diameter. We sought to determine whether and how brain pericytes constrict in response to blood pressure elevation with in vivo two-photon microscopy, electrophysiology, and ex vivo arteriolar-capillary myography of mice with conditional mural cell knockout or with expression of a genetically encoded Ca²⁺ indicator. In first- to fourth-order capillaries, pericytes displayed a rapid and measurable response to pressure by decreasing luminal diameter, depolarizing membrane potentials, and increasing cytoplasmic Ca²⁺ signaling. Pharmacological and imaging approaches revealed that transient receptor potential channel 3 (TRPC3) and voltage-gated Ca²⁺ channels were sequentially activated to promote fast constriction. Genetic ablation of <i>TRPC3</i> resulted in decreased currents, loss of membrane depolarization, and near-complete ablation of the generation of tone over a standard pressure curve in transitional pericytes but not in upstream arterioles. Together, our findings identify TRPC3 channel activation as critical for proximal pericyte depolarization and contraction in response to pressure, highlighting the signaling differences between arteriolar and capillary blood flow regulation.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 884","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.ads1903","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143889207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Making complexes less complicated","authors":"John F. Foley","doi":"10.1126/scisignal.ady2914","DOIUrl":"10.1126/scisignal.ady2914","url":null,"abstract":"<div >A blended proteomics platform provides new depth to the proteome of breast cancer.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 883","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural robustness and temporal vulnerability of the starvation-responsive metabolic network in healthy and obese mouse liver","authors":"Keigo Morita,&nbsp;Atsushi Hatano,&nbsp;Toshiya Kokaji,&nbsp;Hikaru Sugimoto,&nbsp;Takaho Tsuchiya,&nbsp;Haruka Ozaki,&nbsp;Riku Egami,&nbsp;Dongzi Li,&nbsp;Akira Terakawa,&nbsp;Satoshi Ohno,&nbsp;Hiroshi Inoue,&nbsp;Yuka Inaba,&nbsp;Yutaka Suzuki,&nbsp;Masaki Matsumoto,&nbsp;Masatomo Takahashi,&nbsp;Yoshihiro Izumi,&nbsp;Takeshi Bamba,&nbsp;Akiyoshi Hirayama,&nbsp;Tomoyoshi Soga,&nbsp;Shinya Kuroda","doi":"10.1126/scisignal.ads2547","DOIUrl":"10.1126/scisignal.ads2547","url":null,"abstract":"<div >Adaptation to starvation is a multimolecular and temporally ordered process. We sought to elucidate how the healthy liver regulates various molecules in a temporally ordered manner during starvation and how obesity disrupts this process. We used multiomic data collected from the plasma and livers of wild-type and leptin-deficient obese (<i>ob</i>/<i>ob</i>) mice at multiple time points during starvation to construct a starvation-responsive metabolic network that included responsive molecules and their regulatory relationships. Analysis of the network structure showed that in wild-type mice, the key molecules for energy homeostasis, ATP and AMP, acted as hub molecules to regulate various metabolic reactions in the network. Although neither ATP nor AMP was responsive to starvation in <i>ob</i>/<i>ob</i> mice, the structural properties of the network were maintained. In wild-type mice, the molecules in the network were temporally ordered through metabolic processes coordinated by hub molecules, including ATP and AMP, and were positively or negatively coregulated. By contrast, both temporal order and coregulation were disrupted in <i>ob</i>/<i>ob</i> mice. These results suggest that the metabolic network that responds to starvation was structurally robust but temporally disrupted by the obesity-associated loss of responsiveness of the hub molecules. In addition, we propose how obesity alters the response to intermittent fasting.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 883","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Re-epithelialization of cancer cells increases autophagy and DNA damage: Implications for breast cancer dormancy and relapse","authors":"Diana Drago-Garcia,&nbsp;Suvendu Giri,&nbsp;Rishita Chatterjee,&nbsp;Arturo Simoni-Nieves,&nbsp;Maha Abedrabbo,&nbsp;Alessandro Genna,&nbsp;Mary Luz Uribe Rios,&nbsp;Moshit Lindzen,&nbsp;Arunachalam Sekar,&nbsp;Nitin Gupta,&nbsp;Noa Aharoni,&nbsp;Tithi Bhandari,&nbsp;Agalyan Mayalagu,&nbsp;Luisa Schwarzmüller,&nbsp;Nooraldeen Tarade,&nbsp;Rong Zhu,&nbsp;Harsha-Raj Mohan-Raju,&nbsp;Feride Karatekin,&nbsp;Francesco Roncato,&nbsp;Yaniv Eyal-Lubling,&nbsp;Tal Keidar,&nbsp;Yam Nof,&nbsp;Nishanth Belugali Nataraj,&nbsp;Karin Shira Bernshtein,&nbsp;Bettina Wagner,&nbsp;Nishanth Ulhas Nair,&nbsp;Neel Sanghvi,&nbsp;Ronen Alon,&nbsp;Rony Seger,&nbsp;Eli Pikarsky,&nbsp;Sara Donzelli,&nbsp;Giovanni Blandino,&nbsp;Stefan Wiemann,&nbsp;Sima Lev,&nbsp;Ron Prywes,&nbsp;Dalit Barkan,&nbsp;Oscar M. Rueda,&nbsp;Carlos Caldas,&nbsp;Eytan Ruppin,&nbsp;Yosef Shiloh,&nbsp;Maik Dahlhoff,&nbsp;Yosef Yarden","doi":"10.1126/scisignal.ado3473","DOIUrl":"10.1126/scisignal.ado3473","url":null,"abstract":"<div >Cellular plasticity mediates tissue development as well as cancer growth and progression. In breast cancer, a shift to a more epithelial phenotype (epithelialization) underlies a state of reversible cell growth arrest called tumor dormancy, which enables drug resistance, tumor recurrence, and metastasis. Here, we explored the mechanisms driving epithelialization and dormancy in aggressive mesenchymal-like breast cancer cells in three-dimensional cultures. Overexpressing either of the epithelial lineage-associated transcription factors OVOL1 or OVOL2 suppressed cell proliferation and migration and promoted transition to an epithelial morphology. The expression of <i>OVOL1</i> (and of <i>OVOL2</i> to a lesser extent) was regulated by steroid hormones and growth factors and was more abundant in tumors than in normal mammary cells. An uncharacterized and indirect target of OVOL1/2, <i>C1ORF116</i>, exhibited genetic and epigenetic aberrations in breast tumors, and its expression correlated with poor prognosis in patients. We further found that C1ORF116 was an autophagy receptor that directed the degradation of antioxidant proteins, including thioredoxin. Through C1ORF116 and unidentified mediators, OVOL1 expression dysregulated both redox homeostasis (in association with increased ROS, decreased glutathione, and redistribution of the transcription factor NRF2) and DNA damage and repair (in association with increased DNA oxidation and double-strand breaks and an altered interplay among the kinases p38-MAPK, ATM, and others). Because these effects, as they accumulate in cells, can promote metastasis and dormancy escape, the findings suggest that OVOLs not only promote dormancy entry and maintenance in breast cancer but also may ultimately drive dormancy exit and tumor recurrence.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 883","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A drug that induces the microRNA miR-124 enables differentiation of retinoic acid–resistant neuroblastoma cells","authors":"Lien D. Nguyen,&nbsp;Satyaki Sengupta,&nbsp;Kevin I. Cho,&nbsp;Alexander Floru,&nbsp;Rani E. George,&nbsp;Anna M. Krichevsky","doi":"10.1126/scisignal.ads2641","DOIUrl":"10.1126/scisignal.ads2641","url":null,"abstract":"<div >Tumor cell heterogeneity in neuroblastoma, a pediatric cancer arising from neural crest–derived progenitor cells, presents clinical challenges. Unlike adrenergic (ADRN) neuroblastoma cells, neuroblastoma cells with a mesenchymal (MES) identity are resistant to chemotherapy and retinoid therapy, which contributes to relapses and treatment failures. We explored whether up-regulation of the neurogenic, tumor suppressor microRNA miR-124 could promote the differentiation of retinoic acid–resistant MES neuroblastoma cells. Leveraging our screen for miRNA-modulatory small molecules, we identified and validated the tyrosine and phosphoinositide kinase inhibitor PP121 as a robust inducer of miR-124. Combining PP121 and BDNF-activating bufalin synergistically arrested proliferation and promoted the sustained differentiation of MES/heterogeneous SK-N-AS cells over several weeks. This protocol also resulted in the differentiation of multiple MES neuroblastoma and glioblastoma cell lines. RNA-seq analysis of differentiated MES/heterogeneous SK-N-AS cells revealed the replacement of the ADRN core regulatory circuitry with circuitries associated with chromaffin cells and Schwann cell precursors. Furthermore, differentiation was associated with inhibition of the CDK4/CDK6 pathway and activation of a transcriptional program that correlated with improved outcomes for patients with neuroblastoma. Our findings suggest an approach with translational potential to induce the differentiation of therapy-resistant cancers of the nervous system. Moreover, these long-lived, differentiated cells could be used to study mechanisms underlying cancer biology and therapies.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 882","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.ads2641","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143840988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}