Science Signaling最新文献

{"title":"The E3 ligase TRIM21 promotes progression of pancreatic ductal adenocarcinoma by down-regulating TAp63α and derepressing IL20RB","authors":"Zejiao Li,&nbsp;Fengwei Gao,&nbsp;Xuesha Liu,&nbsp;Shijie Fan,&nbsp;Yucheng Qi,&nbsp;Mingzhu He,&nbsp;Xiushuang Luo,&nbsp;Xiaoyun Nie,&nbsp;Jia Wang,&nbsp;Yajun Wang,&nbsp;Zhi-Xiong Jim Xiao,&nbsp;Chenghua Li","doi":"10.1126/scisignal.adv4579","DOIUrl":"10.1126/scisignal.adv4579","url":null,"abstract":"<div >Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor and frequently has mutations in the transcription factor p53. TAp63α is a member of the p53 protein family that is generally tumor suppressive in various other p53-mutant or p53-deficient cancers. Here, we found that TAp63α inhibited cell proliferation, epithelial-mesenchymal transition (EMT), and migration in several p53-mutant PDAC cell lines. TAp63α transcriptionally repressed <i>IL20RB</i> (which encodes a subunit of the interleukin-20 receptor), potentially by inducing the methylation of its promoter. However, mutations in p53 or KRAS that are common in PDAC increased the abundance of the E3 ligase TRIM21, which promoted the ubiquitin-dependent degradation of TAp63α. Thus, the degradation of TAp63α enabled increases in <i>IL20RB</i> expression and formation of IL-20 receptors, resulting in the activation of downstream JAK1-STAT3 signaling that stimulated the proliferation, EMT, migration, and in vivo metastatic seeding of PDAC cells. Our findings identify a signaling axis involving TRIM21, TAp63α, and IL-20RB in PDAC progression.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 889","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207116","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":"Nociceptor-specific signaling of the receptor guanylyl cyclase Npr2 contributes to acute and persistent pain","authors":"Hannah Gerninghaus,&nbsp;Jörg Isensee,&nbsp;Lea Kennel,&nbsp;Fangyuan Zhou,&nbsp;Anja Kaiser,&nbsp;Tilman Gross,&nbsp;Cathrin Flauaus,&nbsp;Patrick Engel,&nbsp;Christoph Jacobs,&nbsp;Jonas Petersen,&nbsp;Wiebke Kallenborn-Gerhardt,&nbsp;Ruirui Lu,&nbsp;Katharina Metzner,&nbsp;Julia Adler,&nbsp;Peter Ruth,&nbsp;Robert Lukowski,&nbsp;Tim Hucho,&nbsp;Hannes Schmidt,&nbsp;Achim Schmidtko","doi":"10.1126/scisignal.adq4238","DOIUrl":"10.1126/scisignal.adq4238","url":null,"abstract":"<div >Natriuretic peptide receptor 2 (Npr2; also termed guanylyl cyclase B) is a transmembrane guanylyl cyclase that is highly abundant in nociceptors. Here, we investigated the role of production of cyclic GMP (cGMP) by Npr2 in pain processing. Adult mice with a deletion of Npr2 specifically in nociceptive sensory neurons exhibited deficits in noxious heat sensing, which can activate the nonselective cation channels TRPV1 and TRPA1. In parallel, Npr2-deficient mice showed a reduction in TRPV1-mediated nocifensive behavior and Ca²⁺ influx into sensory neurons. Furthermore, Npr2-deficient mice had considerably reduced hypersensitivity after hindpaw injection of TRPA1 and TRPV1 activators or after hindpaw injection of complete Freund adjuvant, a model of persistent inflammatory pain. These results indicate that Npr2 contributes to the pain sensitization that can lead to chronic pain. Patch-clamp recordings revealed that the endogenous Npr2 ligand, C-type natriuretic peptide (CNP), enhanced the excitability of nociceptive sensory neurons through Npr2. CNP/Npr2 signaling led to the phosphorylation of cysteine-rich LIM-only protein 4 (CRP4), a substrate of cGMP-dependent protein kinase I. Behavioral and electrophysiological analyses using CRP4-deficient mice revealed that CRP4 limited CNP/Npr2-mediated pain sensitization. Our findings reveal a role for CNP/Npr2 signaling in sensory neurons in acute nociceptive and chronic pain and suggest that CRP4 is a downstream target that attenuates pain sensitization.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 889","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207117","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":"SMAD2 S-palmitoylation promotes its linker region phosphorylation and TH17 cell differentiation in a mouse model of multiple sclerosis","authors":"Mingming Zhang,&nbsp;Tao Yu,&nbsp;Yinong Liu,&nbsp;Xuan Lu,&nbsp;Wenzhe Chen,&nbsp;Lixing Zhou,&nbsp;Yuejie Xu,&nbsp;Min Yang,&nbsp;Andrew D. Miller,&nbsp;Hening Lin","doi":"10.1126/scisignal.adr2008","DOIUrl":"10.1126/scisignal.adr2008","url":null,"abstract":"<div >The transcriptional regulators SMAD2 and SMAD3 share the same primary signaling pathway in response to the cytokine TGFβ. However, whereas SMAD2 stimulates the differentiation of naive CD4⁺ T cells into proinflammatory T helper 17 cells (T_H17 cells), SMAD3 stimulates the differentiation of anti-inflammatory regulatory T cells (T_reg cells). Here, we report a dynamic SMAD2-specific posttranslational modification important for T_H17 cell differentiation. SMAD2, but not SMAD3, was reversibly S-palmitoylated at cysteine-41 and cysteine-81 by the palmitoyltransferase DHHC7 and depalmitoylated by the acyl protein thioesterase APT2. As a result, SMAD2 was recruited to intracellular membranes where its linker region was phosphorylated, leading to its interaction with the transcriptional regulator STAT3. Nuclear translocation of the SMAD2-STAT3 complex induced the expression of their target genes that promoted T_H17 cell differentiation. Perturbation of SMAD2-STAT3 binding by inhibiting the palmitoylation-depalmitoylation cycle suppressed T_H17 cell differentiation and reduced disease severity in mice with experimental autoimmune encephalomyelitis, a model of multiple sclerosis (MS). Thus, the S-palmitoylation–depalmitoylation cycle mediated by DHHC7 and APT2 specifically regulates SMAD2, providing insights into the functional differences between SMAD2 and SMAD3 and the distinct role of SMAD2 in T_H17 cell differentiation. The findings further highlight DHHC7 and APT2 as potential therapeutic targets for the treatment of T_H17 cell–mediated inflammatory diseases, including MS.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 888","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144163519","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":"YAP controls cell migration and invasion through a Rho GTPase switch","authors":"Sagar R. Shah,&nbsp;Chunxiao Ren,&nbsp;Nathaniel D. Tippens,&nbsp;JinSeok Park,&nbsp;Ahmed Mohyeldin,&nbsp;Shuyan Wang,&nbsp;Guillermo Vela,&nbsp;Juan C. Martinez-Gutierrez,&nbsp;Seth S. Margolis,&nbsp;Susanne Schmidt,&nbsp;Alfredo Quiñones-Hinojosa,&nbsp;Andre Levchenko","doi":"","DOIUrl":"","url":null,"abstract":"<div >Delineating the mechanisms that control the movement of cells is central to understanding diverse physiological and pathophysiological processes. The transcriptional coactivator YAP is important during development and associated with cancer metastasis. Here, we found that YAP promoted cell migration by modulating a Rho family guanosine triphosphatase (GTPase) switch involving Rac1 and RhoA, which are key regulators of cytoskeletal dynamics. YAP transcriptionally transactivated the gene encoding the Rac1 guanine nucleotide exchange factor TRIO by directly binding to its intronic enhancer. This led to the activation of Rac1 and inhibition of RhoA, which increased cell migration and invasion in vitro and in vivo. This YAP-dependent program was observed across many cell types, including human breast epithelial cells and astrocytes, but it was particularly enhanced in a patient-specific manner in glioblastoma (GBM), the most common malignant brain tumor. Additionally, YAP-TRIO signaling activated STAT3, a transcription factor implicated in invasive growth in cancer, suggesting potential for cross-talk with this pathway to exacerbate invasive behavior. Clinically, hyperactivation of YAP, TRIO, and STAT3 gene signatures in GBM were associated with poor survival outcomes in patients. Our findings suggest that the YAP-TRIO-Rho-GTPase signaling network regulates invasive cell spread in both physiological and pathological contexts.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 888","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.adu3794","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144179458","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":"Lulled to sleep by ROS","authors":"Wei Wong","doi":"10.1126/scisignal.adz1684","DOIUrl":"10.1126/scisignal.adz1684","url":null,"abstract":"<div >ROS generated by sleep-promoting neurons tracks the need for sleep and initiates sleep.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 888","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144163516","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":"Morphological control of merlin-Rac antagonism in proliferation-promoting signaling","authors":"Byron G. Weiss,&nbsp;Justine M. Keth,&nbsp;Kushal Bhatt,&nbsp;Meghan Doyal,&nbsp;Klaus M. Hahn,&nbsp;Jungsik Noh,&nbsp;Tadamoto Isogai,&nbsp;Gaudenz Danuser","doi":"10.1126/scisignal.adk0922","DOIUrl":"10.1126/scisignal.adk0922","url":null,"abstract":"<div >The extension of lamellipodia, which are thin, fanlike projections at the cell periphery, requires the assembly of branched actin networks under the control of the small GTPase Rac1. In melanoma, a hyperactive P29S Rac1 mutant is associated with resistance to inhibitors that target the kinases BRAF and MAPK and with more aggressive disease because it sequesters and inactivates the tumor suppressor merlin (encoded by <i>NF2</i>) inside abnormally large lamellipodia. Here, we investigated how these merlin-inactivating lamellipodia are maintained using quantitative, live cell imaging of cell morphology and signaling dynamics. We showed that Rac1 and merlin activity were regulated in spatially confined regions or microdomains within the lamellipodium. The role of merlin as a proliferation-limiting tumor suppressor required its ability to inhibit lamellipodial extension and to locally inhibit Rac1 signaling. Conversely, local inactivation of merlin in lamellipodia released these restraints on morphology and signaling, leading to enhanced proliferation. Merlin and Rac1 are thus in a morphologically and dynamically regulated double-negative feedback loop, a signaling motif that can amplify and stabilize modest stimuli of lamellipodia extensions that enable melanoma to sustain mitogenic signaling under growth challenge. This represents an example of how acute oncogenicity is promoted by collaborations between cell morphological programs and biochemical signaling.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 887","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109006","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":"Loss-of-function Gαs rare disease variants exert mutation-specific effects on GPCR signaling","authors":"Theo Redfern-Nichols,&nbsp;Shannon L. O’Brien,&nbsp;Xianglin Huang,&nbsp;Brian Medel-Lacruz,&nbsp;Davide Calebiro,&nbsp;Jana Selent,&nbsp;Graham Ladds,&nbsp;Maria Marti-Solano","doi":"10.1126/scisignal.ado7543","DOIUrl":"10.1126/scisignal.ado7543","url":null,"abstract":"<div >G protein–coupled receptors (GPCRs) are transmembrane detectors of extracellular signals that activate heterotrimeric G proteins to regulate intracellular responses. Because there are only 16 Gα proteins that can couple to GPCRs, variation in a single Gα can affect the function of numerous receptors. Here, we investigated two mutant forms of Gα_s (L388R and E392K) that are associated with pseudohypoparathyroidism type Ic (PHPIc), a maternally inherited rare disease. Gα_s is encoded by an imprinted gene, resulting in the mutant form of Gα_s being the only version of the protein present in certain tissues, which leads to tissue-specific disease manifestations. By integrating data from three-dimensional structures, GPCR–G protein coupling specificity, transcriptomics, biophysics, and molecular dynamics with systems pharmacology modeling, we identified GPCRs whose signaling could be altered by Gα_s mutations in the kidney, a tissue involved in the pathophysiology of PHPIc. Analysis of G protein activation by the parathyroid hormone receptor 1 (PTH1R) revealed that L388R impaired Gα_s interaction with the receptor, whereas E392K reduced the receptor-induced activation of heterotrimeric G_s. This indicates that different signal transduction steps can be altered by specific Gα_s mutants associated with the same disease. These findings highlight the importance of investigating mutation-specific perturbations in GPCR signaling to suggest patient-specific treatment strategies. Furthermore, our methods provide a blueprint for interrogating GPCR signaling diversity in different physiological and pathophysiological contexts.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 887","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109013","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":"Technical recommendations for analyzing oxylipins by liquid chromatography–mass spectrometry","authors":"Nils Helge Schebb,&nbsp;Nadja Kampschulte,&nbsp;Gerhard Hagn,&nbsp;Kathrin Plitzko,&nbsp;Sven W. Meckelmann,&nbsp;Soumita Ghosh,&nbsp;Robin Joshi,&nbsp;Julia Kuligowski,&nbsp;Dajana Vuckovic,&nbsp;Marina T. Botana,&nbsp;Ángel Sánchez-Illana,&nbsp;Fereshteh Zandkarimi,&nbsp;Aditi Das,&nbsp;Jun Yang,&nbsp;Louis Schmidt,&nbsp;Antonio Checa,&nbsp;Helen M. Roche,&nbsp;Aaron M. Armando,&nbsp;Matthew L. Edin,&nbsp;Fred B. Lih,&nbsp;Juan J. Aristizabal-Henao,&nbsp;Sayuri Miyamoto,&nbsp;Francesca Giuffrida,&nbsp;Arieh Moussaieff,&nbsp;Rosário Domingues,&nbsp;Michael Rothe,&nbsp;Christine Hinz,&nbsp;Ujjalkumar Subhash Das,&nbsp;Katharina M. Rund,&nbsp;Ameer Y. Taha,&nbsp;Robert K. Hofstetter,&nbsp;Markus Werner,&nbsp;Oliver Werz,&nbsp;Astrid S. Kahnt,&nbsp;Justine Bertrand-Michel,&nbsp;Pauline Le Faouder,&nbsp;Robert Gurke,&nbsp;Dominique Thomas,&nbsp;Federico Torta,&nbsp;Ivana Milic,&nbsp;Irundika H. K. Dias,&nbsp;Corinne M. Spickett,&nbsp;Denise Biagini,&nbsp;Tommaso Lomonaco,&nbsp;Helena Idborg,&nbsp;Jun-Yan Liu,&nbsp;Maria Fedorova,&nbsp;David A. Ford,&nbsp;Anne Barden,&nbsp;Trevor A. Mori,&nbsp;Paul D. Kennedy,&nbsp;Kirk Maxey,&nbsp;Julijana Ivanisevic,&nbsp;Hector Gallart-Ayala,&nbsp;Cécile Gladine,&nbsp;Markus Wenk,&nbsp;Jean-Marie Galano,&nbsp;Thierry Durand,&nbsp;Ken D. Stark,&nbsp;Coral Barbas,&nbsp;Ulrike Garscha,&nbsp;Stacy L. Gelhaus,&nbsp;Uta Ceglarek,&nbsp;Nicolas Flamand,&nbsp;Julian L. Griffin,&nbsp;Robert Ahrends,&nbsp;Makoto Arita,&nbsp;Darryl C. Zeldin,&nbsp;Francisco J. Schopfer,&nbsp;Oswald Quehenberger,&nbsp;Randall Julian,&nbsp;Anna Nicolaou,&nbsp;Ian A. Blair,&nbsp;Michael P. Murphy,&nbsp;Bruce D. Hammock,&nbsp;Bruce Freeman,&nbsp;Gerhard Liebisch,&nbsp;Charles N. Serhan,&nbsp;Harald C. Köfeler,&nbsp;Per-Johan Jakobsson,&nbsp;Dieter Steinhilber,&nbsp;Michael H. Gelb,&nbsp;Michal Holčapek,&nbsp;Ruth Andrew,&nbsp;Martin Giera,&nbsp;Garret A. FitzGerald,&nbsp;Robert C. Murphy,&nbsp;John W. Newman,&nbsp;Edward A. Dennis,&nbsp;Kim Ekroos,&nbsp;Ginger L. Milne,&nbsp;Miguel A. Gijón,&nbsp;Hubert W. Vesper,&nbsp;Craig E. Wheelock,&nbsp;Valerie B. O’Donnell","doi":"10.1126/scisignal.adw1245","DOIUrl":"10.1126/scisignal.adw1245","url":null,"abstract":"<div >Several oxylipins are potent lipid mediators that regulate diverse aspects of health and disease and whose quantitative analysis by liquid chromatography–mass spectrometry (LC-MS) presents substantial technical challenges. As members of the lipidomics community, we developed technical recommendations to ensure best practices when quantifying oxylipins by LC-MS.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 887","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109015","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":"Gut stem cells get stressed out","authors":"Annalisa M. VanHook","doi":"10.1126/scisignal.ady6765","DOIUrl":"10.1126/scisignal.ady6765","url":null,"abstract":"<div >Chronic stress impairs intestinal stem cell function through the parasympathetic nervous system.</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":"143945062","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":"E-cadherin mechanotransduction activates EGFR-ERK signaling in epithelial monolayers by inducing ADAM-mediated ligand shedding","authors":"Ronja M. Houtekamer,&nbsp;Mirjam C. van der Net,&nbsp;Marjolein J. Vliem,&nbsp;Tomas E. J. C. Noordzij,&nbsp;Lisa van Uden,&nbsp;Robert M. van Es,&nbsp;Joo Yong Sim,&nbsp;Eriko Deguchi,&nbsp;Kenta Terai,&nbsp;Matthew A. Hopcroft,&nbsp;Harmjan R. Vos,&nbsp;Beth L. Pruitt,&nbsp;Michiyuki Matsuda,&nbsp;Willem-Jan Pannekoek,&nbsp;Martijn Gloerich","doi":"10.1126/scisignal.adr7926","DOIUrl":"10.1126/scisignal.adr7926","url":null,"abstract":"<div >The behavior of cells is governed by signals originating from their local environment, including mechanical forces exerted on the cells. Forces are transduced by mechanosensitive proteins, which can impinge on signaling cascades that are also activated by growth factors. We investigated the cross-talk between mechanical and biochemical signals in the regulation of intracellular signaling networks in epithelial monolayers. Phosphoproteomic and transcriptomic analyses on epithelial monolayers subjected to mechanical strain revealed the activation of extracellular signal–regulated kinase (ERK) downstream of the epidermal growth factor receptor (EGFR) as a predominant strain-induced signaling event. Strain-induced EGFR-ERK signaling depended on mechanosensitive E-cadherin adhesions. Proximity labeling showed that the metalloproteinase ADAM17, an enzyme that mediates shedding of soluble EGFR ligands, was closely associated with E-cadherin. A probe that we developed to monitor ADAM-mediated shedding demonstrated that mechanical strain induced ADAM activation. Mechanically induced ADAM activation was essential for mechanosensitive, E-cadherin–dependent EGFR-ERK signaling. Together, our data demonstrate that mechanical strain transduced by E-cadherin adhesion triggers the shedding of EGFR ligands that stimulate downstream ERK activity. Our findings illustrate how mechanical signals and biochemical ligands can operate within a linear signaling cascade.</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":"https://www.science.org/doi/reader/10.1126/scisignal.adr7926","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945063","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}