Pub Date : 2026-02-10DOI: 10.1126/scisignal.aeg1336
John F. Foley
Inhibiting the deacetylase SIRT2 increases the activity of the kinase Lck to enhance T cell receptor signaling.
{"title":"SIRT2 versus Lck","authors":"John F. Foley","doi":"10.1126/scisignal.aeg1336","DOIUrl":"10.1126/scisignal.aeg1336","url":null,"abstract":"<div >Inhibiting the deacetylase SIRT2 increases the activity of the kinase Lck to enhance T cell receptor signaling.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"19 924","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146148391","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}
Pub Date : 2026-02-10DOI: 10.1126/scisignal.adr4063
Zhenbo Tu, Leah Moses, Yi Hu, Sworaj Sapkota, Liza M. Quintana, Leismi Guerrero, George W. Bell, Antoine E. Karnoub
Triple-negative breast cancers (TNBCs) lack targeted therapeutics that can inhibit their growth and progression. The long intergenic noncoding RNA LINC01133 promotes TNBC pathogenesis by increasing the abundance of proline-rich protein 5 (PRR5), an mTORC2 component that activates the kinase AKT in a PI3K-independent, mTORC2-dependent manner. Here, however, we found that TNBC cell proliferation was incompletely sensitive to AKT inhibitors alone because PRR5 also stimulated the mitogen-activated protein kinase (MAPK) cascade in an mTORC2-dependent manner. PRR5 associated with and prevented the ubiquitin-dependent proteasomal degradation of IQGAP1, an adaptor protein that promotes activation of the MAP kinase ERK. ERK signaling was essential for LINC01133-mediated TNBC proliferation in two- and three-dimensional cultures, and ERK inhibitors synergized with AKT blockade to suppress LINC01133-induced TNBC cell growth. Furthermore, PRR5 abundance was particularly enriched and correlated with that of phosphorylated ERK in samples from patients with TNBC. Our results highlight cross-talk between mTORC2 and ERK signaling downstream of LINC01133 and PRR5 that may be therapeutically targeted to treat TNBC.
{"title":"Stabilization of IQGAP1 by the mTORC2 component PRR5 mediates mitogenic LINC01133-to-ERK signaling in triple-negative breast cancer","authors":"Zhenbo Tu, Leah Moses, Yi Hu, Sworaj Sapkota, Liza M. Quintana, Leismi Guerrero, George W. Bell, Antoine E. Karnoub","doi":"10.1126/scisignal.adr4063","DOIUrl":"10.1126/scisignal.adr4063","url":null,"abstract":"<div >Triple-negative breast cancers (TNBCs) lack targeted therapeutics that can inhibit their growth and progression. The long intergenic noncoding RNA LINC01133 promotes TNBC pathogenesis by increasing the abundance of proline-rich protein 5 (PRR5), an mTORC2 component that activates the kinase AKT in a PI3K-independent, mTORC2-dependent manner. Here, however, we found that TNBC cell proliferation was incompletely sensitive to AKT inhibitors alone because PRR5 also stimulated the mitogen-activated protein kinase (MAPK) cascade in an mTORC2-dependent manner. PRR5 associated with and prevented the ubiquitin-dependent proteasomal degradation of IQGAP1, an adaptor protein that promotes activation of the MAP kinase ERK. ERK signaling was essential for LINC01133-mediated TNBC proliferation in two- and three-dimensional cultures, and ERK inhibitors synergized with AKT blockade to suppress LINC01133-induced TNBC cell growth. Furthermore, PRR5 abundance was particularly enriched and correlated with that of phosphorylated ERK in samples from patients with TNBC. Our results highlight cross-talk between mTORC2 and ERK signaling downstream of LINC01133 and PRR5 that may be therapeutically targeted to treat TNBC.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"19 924","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146148393","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}
Pub Date : 2026-02-10DOI: 10.1126/scisignal.adw5054
Jaewoong Lee, Ruifeng Sun, Kohei Kume, Mark E. Robinson, Zhangliang Cheng, Kadriye Nehir Cosgun, Ning Ma, Christian Hurtz, Huimin Geng, Selina M. Luger, Mark R. Litzow, Elisabeth Paietta, Jianjun Chen, Nagarajan Vaidehi, Markus Müschen
CD25 is a subunit of the interleukin-2 (IL-2) receptor on T cells and natural killer (NK) cells. Acute leukemias with oncogenic tyrosine kinases often include CD25+ leukemia subpopulations, which portend poor clinical outcomes for patients; however, acute leukemia cells do not respond to IL-2. Here, we identified CD25 and its phosphorylation by protein kinase Cδ (PKCδ) as central elements of a feedback loop that stabilized fluctuations in oncogenic tyrosine kinase signaling in acute lymphoblastic and myeloid leukemia. Genetic ablation of CD25 in murine and patient-derived xenograft (PDX) models of acute leukemias reduced clonal fitness, colony formation, and leukemia-initiation capacity in serial transplant recipients. Oncogenic tyrosine kinase signaling in leukemia cells stimulated NF-κB–mediated CD25 expression, whereas PKCδ-mediated phosphorylation of CD25 suppressed oncogenic tyrosine kinase signaling through inhibitory phosphatases, such as PTPN6. Interactome analyses and mass spectrometry–based global phosphoproteomic analyses showed that CD25 deletion abolished the phosphatase activity of PTPN6, resulting in enhanced activation of tyrosine kinases and NF-κB. Four injections of a CD25 antibody-drug conjugate induced complete remission in mice transplanted with PDX refractory leukemia. These findings highlight the dependency of tyrosine kinase–driven leukemias on robust feedback control and the role of PKCδ and CD25 in assembling its components.
{"title":"Dynamic feedback control of oncogenic tyrosine kinase signaling in acute leukemia","authors":"Jaewoong Lee, Ruifeng Sun, Kohei Kume, Mark E. Robinson, Zhangliang Cheng, Kadriye Nehir Cosgun, Ning Ma, Christian Hurtz, Huimin Geng, Selina M. Luger, Mark R. Litzow, Elisabeth Paietta, Jianjun Chen, Nagarajan Vaidehi, Markus Müschen","doi":"10.1126/scisignal.adw5054","DOIUrl":"10.1126/scisignal.adw5054","url":null,"abstract":"<div >CD25 is a subunit of the interleukin-2 (IL-2) receptor on T cells and natural killer (NK) cells. Acute leukemias with oncogenic tyrosine kinases often include CD25<sup>+</sup> leukemia subpopulations, which portend poor clinical outcomes for patients; however, acute leukemia cells do not respond to IL-2. Here, we identified CD25 and its phosphorylation by protein kinase Cδ (PKCδ) as central elements of a feedback loop that stabilized fluctuations in oncogenic tyrosine kinase signaling in acute lymphoblastic and myeloid leukemia. Genetic ablation of <i>CD25</i> in murine and patient-derived xenograft (PDX) models of acute leukemias reduced clonal fitness, colony formation, and leukemia-initiation capacity in serial transplant recipients. Oncogenic tyrosine kinase signaling in leukemia cells stimulated NF-κB–mediated <i>CD25</i> expression, whereas PKCδ-mediated phosphorylation of CD25 suppressed oncogenic tyrosine kinase signaling through inhibitory phosphatases, such as PTPN6. Interactome analyses and mass spectrometry–based global phosphoproteomic analyses showed that <i>CD25</i> deletion abolished the phosphatase activity of PTPN6, resulting in enhanced activation of tyrosine kinases and NF-κB. Four injections of a CD25 antibody-drug conjugate induced complete remission in mice transplanted with PDX refractory leukemia. These findings highlight the dependency of tyrosine kinase–driven leukemias on robust feedback control and the role of PKCδ and CD25 in assembling its components.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"19 924","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146148392","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}
Pub Date : 2026-02-03DOI: 10.1126/scisignal.adt0986
Marton Olbei, Isabelle Hautefort, John P. Thomas, Luca Csabai, Balazs Bohar, Sandra S. Koigi, Hajir Ibraheim, Aamir Saifuddin, Diana Coman, Emma Højmose Kromann, Joana F. Neves, Diana Papp, Nick Powell, Dezso Modos, Tamas Korcsmaros
Ulcerative colitis (UC) is a chronic inflammatory disorder of the gastrointestinal tract that is characterized by dysregulated cytokine signaling. Treatment outcomes for patients with UC remain suboptimal despite the advent of cytokine-targeting therapies, necessitating a better understanding of the interconnected cytokine signaling networks that are perturbed in patients with UC. To address this, we undertook systems immunology modeling of single-cell transcriptomics data from colonic biopsies of treatment-naive and treatment-exposed patients with UC to build complex cytokine signaling networks underpinned by putative cytokine-cytokine interactions. The generated cytokine networks effectively captured known, physiologically relevant cytokine-cytokine interactions, which we validated in vitro in colonic epithelial organoids derived from patients with UC and with organoids cocultured with innate lymphoid cells. These networks revealed several previously unrecognized aspects of UC pathogenesis. These included the identification of a cytokine subnetwork that is unique to treatment-naive patients with UC, of cytokines with altered interaction patterns across UC disease states (including IL-22, TL1A, IL-23A, and OSM), and of cytokine-cytokine interactions that were mediated by specific members of the Janus-associated kinase (JAK) family. In particular, our network analysis positioned TL1A as an important upstream regulator of TNF and IL-23A (both of which are targeted by approved UC drugs) and suggested it as a potential therapeutic target. Together, these findings open several avenues for guiding future cytokine-targeting therapeutic approaches in UC, and the presented methodology can be readily applied to gain similar insights into other immune-mediated inflammatory diseases.
{"title":"Decoding cytokine networks in ulcerative colitis to identify pathogenic mechanisms and therapeutic targets","authors":"Marton Olbei, Isabelle Hautefort, John P. Thomas, Luca Csabai, Balazs Bohar, Sandra S. Koigi, Hajir Ibraheim, Aamir Saifuddin, Diana Coman, Emma Højmose Kromann, Joana F. Neves, Diana Papp, Nick Powell, Dezso Modos, Tamas Korcsmaros","doi":"10.1126/scisignal.adt0986","DOIUrl":"10.1126/scisignal.adt0986","url":null,"abstract":"<div >Ulcerative colitis (UC) is a chronic inflammatory disorder of the gastrointestinal tract that is characterized by dysregulated cytokine signaling. Treatment outcomes for patients with UC remain suboptimal despite the advent of cytokine-targeting therapies, necessitating a better understanding of the interconnected cytokine signaling networks that are perturbed in patients with UC. To address this, we undertook systems immunology modeling of single-cell transcriptomics data from colonic biopsies of treatment-naive and treatment-exposed patients with UC to build complex cytokine signaling networks underpinned by putative cytokine-cytokine interactions. The generated cytokine networks effectively captured known, physiologically relevant cytokine-cytokine interactions, which we validated in vitro in colonic epithelial organoids derived from patients with UC and with organoids cocultured with innate lymphoid cells. These networks revealed several previously unrecognized aspects of UC pathogenesis. These included the identification of a cytokine subnetwork that is unique to treatment-naive patients with UC, of cytokines with altered interaction patterns across UC disease states (including IL-22, TL1A, IL-23A, and OSM), and of cytokine-cytokine interactions that were mediated by specific members of the Janus-associated kinase (JAK) family. In particular, our network analysis positioned TL1A as an important upstream regulator of TNF and IL-23A (both of which are targeted by approved UC drugs) and suggested it as a potential therapeutic target. Together, these findings open several avenues for guiding future cytokine-targeting therapeutic approaches in UC, and the presented methodology can be readily applied to gain similar insights into other immune-mediated inflammatory diseases.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"19 923","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146111417","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}
Pub Date : 2026-02-03DOI: 10.1126/scisignal.adv2400
Sumati Rajagopalan, Saurav Majumder, Christiana Wang, Winston Hibler, Amirhossein Shamsaddini, Paul Gardina, Eric O. Long
Most of the lymphocytes in the human pregnant uterus are natural killer (NK) cells. Here, we showed that soluble HLA-G expressed by fetal trophoblast cells at the maternal-fetal interface in early pregnancy stimulated transcription of mostly the same genes in primary NK cells as an agonistic antibody to the receptor KIR2DL4. An exception was the transcription of type I interferon (IFN-I)–stimulated genes (ISGs), which were selectively induced by HLA-G through a noncanonical pathway. This ISG response required the transcription factor IRF7 and the kinase JAK1. The carboxyl-terminal portion of the KIR2DL4 cytoplasmic tail includes a sequence analogous to conserved JAK1 binding sites in IFN receptors and was required for JAK1 binding to KIR2DL4. Phosphorylation of IRF7 and the JAK substrate STAT2, which link IFN-I stimulation to ISG transcription, was detected in the nuclei of HLA-G–stimulated NK cells. Single-cell RNA sequencing (scRNA-seq) showed that HLA-G induced a broader transcriptional response in CD56bright NK cells than in CD56dim NK cells and that ISG expression was similar in both NK cell subsets. Comparison of our data with scRNA-seq data from the early maternal-fetal interface revealed that HLA-G induced the transcription of genes that distinguish decidual NK cells from maternal blood NK cells. Thus, ISG transcription, which is inducible by HLA-G, is detected in early pregnancy and may underlie intrinsic antipathogen resistance of NK cells in the maternal decidua.
{"title":"The fetal trophoblast cell marker HLA-G activates a type I interferon response in primary NK cells through the receptor KIR2DL4","authors":"Sumati Rajagopalan, Saurav Majumder, Christiana Wang, Winston Hibler, Amirhossein Shamsaddini, Paul Gardina, Eric O. Long","doi":"10.1126/scisignal.adv2400","DOIUrl":"10.1126/scisignal.adv2400","url":null,"abstract":"<div >Most of the lymphocytes in the human pregnant uterus are natural killer (NK) cells. Here, we showed that soluble HLA-G expressed by fetal trophoblast cells at the maternal-fetal interface in early pregnancy stimulated transcription of mostly the same genes in primary NK cells as an agonistic antibody to the receptor KIR2DL4. An exception was the transcription of type I interferon (IFN-I)–stimulated genes (ISGs), which were selectively induced by HLA-G through a noncanonical pathway. This ISG response required the transcription factor IRF7 and the kinase JAK1. The carboxyl-terminal portion of the KIR2DL4 cytoplasmic tail includes a sequence analogous to conserved JAK1 binding sites in IFN receptors and was required for JAK1 binding to KIR2DL4. Phosphorylation of IRF7 and the JAK substrate STAT2, which link IFN-I stimulation to ISG transcription, was detected in the nuclei of HLA-G–stimulated NK cells. Single-cell RNA sequencing (scRNA-seq) showed that HLA-G induced a broader transcriptional response in CD56<sup>bright</sup> NK cells than in CD56<sup>dim</sup> NK cells and that ISG expression was similar in both NK cell subsets. Comparison of our data with scRNA-seq data from the early maternal-fetal interface revealed that HLA-G induced the transcription of genes that distinguish decidual NK cells from maternal blood NK cells. Thus, ISG transcription, which is inducible by HLA-G, is detected in early pregnancy and may underlie intrinsic antipathogen resistance of NK cells in the maternal decidua.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"19 923","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146111416","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}
Pub Date : 2026-01-27DOI: 10.1126/scisignal.adt9566
Renping Zhao, Jingnan Zhang, Sijia Zhang, Eva C. Schwarz, Aránzazu del Campo, Markus Hoth, Bin Qu
T cell activation requires cell polarization and changes in gene expression. Target cell stiffness contributes to the activation of immune cells, and tumor cell softening is linked to cancer progression. We investigated how substrate stiffness influences T cell activation using functionalized, T cell–activating substrates of varying stiffness and softened target cells. Reorientation of the microtubule-organizing center (MTOC) toward the immunological synapse and nuclear translocation of the transcription factor NFAT1 were impaired on softer hydrogels or upon contact with softer target cells. The increase in intracellular Ca2+ induced by target engagement also depended on stiffness and was reduced on soft substrates. Stiffness-dependent Ca2+ signaling was crucial for both rapid (MTOC reorientation) and long-term (NFAT translocation) responses. Whereas MTOC reorientation depended on the mechanosensitive Ca2+-permeable channel PIEZO1, NFAT1 translocation depended on the Ca2+ channel ORAI1. Our results demonstrate that target stiffness directly influences MTOC reorientation and NFAT1 translocation in T cells, and these two processes are governed by different plasma membrane Ca2+ channels, indicating that these stiffness-regulated rapid and long-term responses can be decoupled. Our findings imply that tumor cell stiffness regulates T cell functionality and suggest that pathways regulated by PIEZO1 and ORAI1 might differentially control rapid and long-term responses to stiffness in other cell types.
{"title":"T cell polarization and NFAT activation are stiffness dependent and differentially regulated by the channels PIEZO1 and ORAI1","authors":"Renping Zhao, Jingnan Zhang, Sijia Zhang, Eva C. Schwarz, Aránzazu del Campo, Markus Hoth, Bin Qu","doi":"10.1126/scisignal.adt9566","DOIUrl":"10.1126/scisignal.adt9566","url":null,"abstract":"<div >T cell activation requires cell polarization and changes in gene expression. Target cell stiffness contributes to the activation of immune cells, and tumor cell softening is linked to cancer progression. We investigated how substrate stiffness influences T cell activation using functionalized, T cell–activating substrates of varying stiffness and softened target cells. Reorientation of the microtubule-organizing center (MTOC) toward the immunological synapse and nuclear translocation of the transcription factor NFAT1 were impaired on softer hydrogels or upon contact with softer target cells. The increase in intracellular Ca<sup>2+</sup> induced by target engagement also depended on stiffness and was reduced on soft substrates. Stiffness-dependent Ca<sup>2+</sup> signaling was crucial for both rapid (MTOC reorientation) and long-term (NFAT translocation) responses. Whereas MTOC reorientation depended on the mechanosensitive Ca<sup>2+</sup>-permeable channel PIEZO1, NFAT1 translocation depended on the Ca<sup>2+</sup> channel ORAI1. Our results demonstrate that target stiffness directly influences MTOC reorientation and NFAT1 translocation in T cells, and these two processes are governed by different plasma membrane Ca<sup>2+</sup> channels, indicating that these stiffness-regulated rapid and long-term responses can be decoupled. Our findings imply that tumor cell stiffness regulates T cell functionality and suggest that pathways regulated by PIEZO1 and ORAI1 might differentially control rapid and long-term responses to stiffness in other cell types.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"19 922","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146049469","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}
Pub Date : 2026-01-27DOI: 10.1126/scisignal.adt3026
Naijiang Liu, Xiaojie Shi, Shao-Rui Chen, Hong Chen, Maria Daniela Santi, Dong Minh Phuong, Maria Fernanda Pessano Fialho, Tongxin Xie, Frederico Gleber-Netto, Rocco Latorre, Nigel W. Bunnett, Chi Viet, Moran Amit, Hui-Lin Pan, Yi Ye
Pain associated with oral cancer is debilitating. Opioids are the gold standard for cancer pain management, but tolerance and side effects limit their use. Epidermal growth factor receptor (EGFR) signaling is commonly amplified in oral tumors. Here, we found that EGFR activation contributed to both oral cancer pain and opioid tolerance by sensitizing trigeminal ganglion (TG) cells, the main sensory neurons innervating the face and mouth. EGFR ligands were secreted by oral squamous cell carcinoma (OSCC) cells and by peripheral glial cells cocultured with OSCC cells. In human OSCC and an orthotopic mouse model, EGFR was abundant in tumor-innervating TG nerves. Oral cancer pain and opioid tolerance in the mice were increased by EGFR ligands and reduced by EGFR inhibitors. In mice, the abundance of glutamate-type NMDA receptors (NMDARs) was also increased in both the TG and the brainstem. Upon activation by ligands or OSCC cell supernatant, EGFR phosphorylated the NMDAR subunit GluN2B, which increased electrical currents and sensitized pre- and postsynaptic NMDARs in the brainstem. This sensitization was also seen in the brainstems of mice receiving chronic morphine treatment and was mitigated by EGFR blockade. These findings suggest that EGFR-targeted cancer therapeutics may be repurposed to manage cancer pain and reduce opioid tolerance in patients with OSCC.
{"title":"EGFR activation sensitizes trigeminal NMDA receptors to promote pain and morphine analgesic tolerance in oral cancer","authors":"Naijiang Liu, Xiaojie Shi, Shao-Rui Chen, Hong Chen, Maria Daniela Santi, Dong Minh Phuong, Maria Fernanda Pessano Fialho, Tongxin Xie, Frederico Gleber-Netto, Rocco Latorre, Nigel W. Bunnett, Chi Viet, Moran Amit, Hui-Lin Pan, Yi Ye","doi":"10.1126/scisignal.adt3026","DOIUrl":"10.1126/scisignal.adt3026","url":null,"abstract":"<div >Pain associated with oral cancer is debilitating. Opioids are the gold standard for cancer pain management, but tolerance and side effects limit their use. Epidermal growth factor receptor (EGFR) signaling is commonly amplified in oral tumors. Here, we found that EGFR activation contributed to both oral cancer pain and opioid tolerance by sensitizing trigeminal ganglion (TG) cells, the main sensory neurons innervating the face and mouth. EGFR ligands were secreted by oral squamous cell carcinoma (OSCC) cells and by peripheral glial cells cocultured with OSCC cells. In human OSCC and an orthotopic mouse model, EGFR was abundant in tumor-innervating TG nerves. Oral cancer pain and opioid tolerance in the mice were increased by EGFR ligands and reduced by EGFR inhibitors. In mice, the abundance of glutamate-type NMDA receptors (NMDARs) was also increased in both the TG and the brainstem. Upon activation by ligands or OSCC cell supernatant, EGFR phosphorylated the NMDAR subunit GluN2B, which increased electrical currents and sensitized pre- and postsynaptic NMDARs in the brainstem. This sensitization was also seen in the brainstems of mice receiving chronic morphine treatment and was mitigated by EGFR blockade. These findings suggest that EGFR-targeted cancer therapeutics may be repurposed to manage cancer pain and reduce opioid tolerance in patients with OSCC.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"19 922","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146049468","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}
Pub Date : 2026-01-27DOI: 10.1126/scisignal.aef7044
Wei Wong
A high-fat diet impairs the growth of a commensal that produces lipids with anti-obesogenic effects in mice.
高脂肪饮食会损害共生体的生长，共生体产生具有抗肥胖作用的脂质。
{"title":"A hostile environment for a commensal","authors":"Wei Wong","doi":"10.1126/scisignal.aef7044","DOIUrl":"10.1126/scisignal.aef7044","url":null,"abstract":"<div >A high-fat diet impairs the growth of a commensal that produces lipids with anti-obesogenic effects in mice.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"19 922","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146049470","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}
Pub Date : 2026-01-20DOI: 10.1126/scisignal.aed6832
Neel H. Shah
The chemical reagent pervanadate is widely used to study phosphotyrosine signaling because it is a potent, irreversible inhibitor of protein tyrosine phosphatases that globally increases tyrosine phosphorylation across the proteome. In this issue of Science Signaling, Mulholland et al. show that pervanadate also modulates phosphotyrosine signaling by oxidizing specific cysteine residues on the tyrosine kinase SRC, thereby leading to hyperactivation of this ubiquitous signaling enzyme.
{"title":"Pervanadate: So much more than a protein tyrosine phosphatase inhibitor","authors":"Neel H. Shah","doi":"10.1126/scisignal.aed6832","DOIUrl":"10.1126/scisignal.aed6832","url":null,"abstract":"<div >The chemical reagent pervanadate is widely used to study phosphotyrosine signaling because it is a potent, irreversible inhibitor of protein tyrosine phosphatases that globally increases tyrosine phosphorylation across the proteome. In this issue of <i>Science Signaling</i>, Mulholland <i>et al.</i> show that pervanadate also modulates phosphotyrosine signaling by oxidizing specific cysteine residues on the tyrosine kinase SRC, thereby leading to hyperactivation of this ubiquitous signaling enzyme.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"19 921","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146002612","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}
Pub Date : 2026-01-20DOI: 10.1126/scisignal.ady9437
Katie E. Mulholland, Maxime Bourguet, Nuo Cheng, Oisharja Rahman, Daria Ezeriņa, Leonard A. Daly, Tiffany Lai, Silvia Aldaz Casanova, Therese Featherston, Pau Creixell, Claire E. Eyers, Joris Messens, Patrick A. Eyers, Dominic P. Byrne, Hayley J. Sharpe
Dynamic regulation of protein tyrosine phosphorylation (pTyr) by kinases and phosphatases enables cells to sense and respond to environmental changes. The widely used chemical pervanadate induces the accumulation of pTyr in mammalian cell lines. This effect is primarily attributed to its inhibition of protein tyrosine phosphatases (PTPs), leading to the assertion that PTPs are master gatekeepers of intracellular pTyr homeostasis. Here, we used several approaches to reveal that pervanadate disrupted cellular redox homeostasis and directly activated tyrosine kinases of the SRC family through the oxidation of specific cysteine residues. Mass spectrometry and biophysical approaches showed that pervanadate-induced oxidation of cysteine-188 and cysteine-280 activated SRC by disrupting autoinhibitory intramolecular interactions between the catalytic domain and the SH2/SH3 domains and by impairing SH2 domain binding to phosphopeptides, including the regulatory carboxyl-terminal tail phosphotyrosine-530. Redox-sensitive cysteine residues were essential for SRC to promote the overgrowth of mouse fibroblasts. Our findings call for a reevaluation of pervanadate-based experiments and demonstrate that SRC cysteines control its oncogenic properties.
{"title":"Pervanadate-induced oxidation relieves autoinhibition of the protein tyrosine kinase SRC","authors":"Katie E. Mulholland, Maxime Bourguet, Nuo Cheng, Oisharja Rahman, Daria Ezeriņa, Leonard A. Daly, Tiffany Lai, Silvia Aldaz Casanova, Therese Featherston, Pau Creixell, Claire E. Eyers, Joris Messens, Patrick A. Eyers, Dominic P. Byrne, Hayley J. Sharpe","doi":"10.1126/scisignal.ady9437","DOIUrl":"10.1126/scisignal.ady9437","url":null,"abstract":"<div >Dynamic regulation of protein tyrosine phosphorylation (pTyr) by kinases and phosphatases enables cells to sense and respond to environmental changes. The widely used chemical pervanadate induces the accumulation of pTyr in mammalian cell lines. This effect is primarily attributed to its inhibition of protein tyrosine phosphatases (PTPs), leading to the assertion that PTPs are master gatekeepers of intracellular pTyr homeostasis. Here, we used several approaches to reveal that pervanadate disrupted cellular redox homeostasis and directly activated tyrosine kinases of the SRC family through the oxidation of specific cysteine residues. Mass spectrometry and biophysical approaches showed that pervanadate-induced oxidation of cysteine-188 and cysteine-280 activated SRC by disrupting autoinhibitory intramolecular interactions between the catalytic domain and the SH2/SH3 domains and by impairing SH2 domain binding to phosphopeptides, including the regulatory carboxyl-terminal tail phosphotyrosine-530. Redox-sensitive cysteine residues were essential for SRC to promote the overgrowth of mouse fibroblasts. Our findings call for a reevaluation of pervanadate-based experiments and demonstrate that SRC cysteines control its oncogenic properties.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"19 921","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146002611","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：