Science Signaling最新文献

The E3 ubiquitin ligase ZNRF3 restricts WNT receptor complex activity by stimulating the selective degradation of WNT-engaged FZD E3泛素连接酶ZNRF3通过刺激WNT参与的FZD的选择性降解来限制WNT受体复合物的活性

IF 6.6 1区生物学

Science Signaling Pub Date : 2025-10-14 DOI: 10.1126/scisignal.adv1529

Bo Lu, Feng Cong

{"title":"The E3 ubiquitin ligase ZNRF3 restricts WNT receptor complex activity by stimulating the selective degradation of WNT-engaged FZD","authors":"Bo Lu, Feng Cong","doi":"10.1126/scisignal.adv1529","DOIUrl":"10.1126/scisignal.adv1529","url":null,"abstract":"<div >Ligands of the WNT family induce formation of the WNT receptor signalosome and promote stabilization of the transcriptional coactivator β-catenin. The homologous transmembrane E3 ubiquitin ligases ZNRF3 and RNF43 inhibit WNT-dependent stabilization of β-catenin by stimulating the degradation of the WNT receptor FZD, whereas the secreted R-spondin proteins promote the stabilization of FZD by inducing the degradation of ZNRF3 and RNF43. Here, we report that the R-spondin–induced stabilization of β-catenin in HEK293 cells was not mimicked by FZD overexpression, highlighting a gap in our understanding of this important regulatory mechanism. Contrary to the conventional view that ZNRF3 constitutively mediates the ubiquitylation and degradation of FZD, we found that ZNRF3-induced FZD degradation depended on endogenous WNT and that ZNRF3 selectively degraded WNT-engaged FZD. WNT enhanced the association between FZD and the intracellular adaptor protein DVL, and DVL subsequently recruited ZNRF3 to FZD to promote FZD degradation. Our data suggest that WNT signaling actively restricts itself through ZNRF3-dependent degradation of WNT-engaged FZD and that R-spondin enhances WNT signaling by prolonging the action of the WNT-engaged FZD complex, rather than by simply increasing the abundance of FZD on the cell surface.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 908","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145285015","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}

引用次数: 0

STING’s cysteine modifications STING的半胱氨酸修饰

IF 6.6 1区生物学

Science Signaling Pub Date : 2025-10-14 DOI: 10.1126/scisignal.aec8984

John F. Foley

引用次数: 0

Senataxin promotes recombination fidelity during antigen receptor gene diversification Senataxin促进抗原受体基因多样化过程中的重组保真度

IF 6.6 1区生物学

Science Signaling Pub Date : 2025-10-14 DOI: 10.1126/scisignal.adv8801

Alice Billie Libri, Jinglong Wang, Timea Marton, Wei Yu, François Dossin, Gabriel Balmus, Bernardo Reina-San-Martin, Richard Frock, Chloé Lescale, Ludovic Deriano

{"title":"Senataxin promotes recombination fidelity during antigen receptor gene diversification","authors":"Alice Billie Libri, Jinglong Wang, Timea Marton, Wei Yu, François Dossin, Gabriel Balmus, Bernardo Reina-San-Martin, Richard Frock, Chloé Lescale, Ludovic Deriano","doi":"10.1126/scisignal.adv8801","DOIUrl":"10.1126/scisignal.adv8801","url":null,"abstract":"<div >Antigen receptor diversity depends on the assembly of variable (V), diverse (D), and joining (J) exons in genes encoding immunoglobulins (Igs) and T cell receptors (TCRs). During V(D)J recombination, DNA double-strand breaks (DSBs) introduced by the RAG1/2 nuclease complex are repaired by the process of nonhomologous end-joining (NHEJ). We hypothesized that functional redundancies between NHEJ and the chromatin DSB response, which depends on the kinase ATM, potentially masked the activity of additional factors that regulate V(D)J recombination. We performed targeted CRISPR-Cas9 knockout screens for genes implicated in V(D)J recombination in pro-B cells that were either untreated or treated with an ATM inhibitor. We found that loss of the RNA/DNA helicase senataxin (SETX) impaired V(D)J recombination and led to the formation of aberrant hybrid joints between coding ends and signal ends, both in vitro and in mice. The loss of SETX in a background deficient in the NHEJ factor XLF or in which ATM was inhibited led to substantial impairment of V(D)J recombination and to the presence of unsealed coding ends. SETX limited aberrant activation-induced cytidine deaminase (AID)–induced DNA end-joining between <i>Igh</i>-containing alleles during the process of class-switch recombination. Together, our findings reveal a previously uncharacterized role for SETX in promoting recombination fidelity during antigen receptor gene diversification.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 908","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.adv8801","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145285014","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}

引用次数: 0

An ectopic Hedgehog signaling axis drives directional tumor outgrowth in a mouse model of hereditary multiple osteochondromas 异位的刺猬信号轴驱动遗传性多发性骨软骨瘤小鼠模型的定向肿瘤生长

IF 6.6 1区生物学

Science Signaling Pub Date : 2025-10-07 DOI: 10.1126/scisignal.adu6357

Sarah E. Catheline, Christina Mundy, Cheri Saunders, Sadhana Ramesh, Kelly A. Shaughnessy, Juliet Chung, Eiki Koyama, Maurizio Pacifici

{"title":"An ectopic Hedgehog signaling axis drives directional tumor outgrowth in a mouse model of hereditary multiple osteochondromas","authors":"Sarah E. Catheline, Christina Mundy, Cheri Saunders, Sadhana Ramesh, Kelly A. Shaughnessy, Juliet Chung, Eiki Koyama, Maurizio Pacifici","doi":"10.1126/scisignal.adu6357","DOIUrl":"10.1126/scisignal.adu6357","url":null,"abstract":"<div >Osteochondromas characterize the rare pediatric disorder hereditary multiple osteochondromas (HMO). The tumors originate from the growth plate perichondrium along skeletal elements, appear first as ectopic cartilage, and then grow unidirectionally, colliding with and damaging surrounding structures. HMO is caused by mutations that affect the heparan sulfate (HS) synthases EXT1 or EXT2, leading to HS deficiency and aberrant activity of HS-binding growth factors. We investigated the signaling pathways and mechanisms underlying tumor growth in HMO using mice with conditional <i>Ext1</i> deficiency in the growth plate and perichondrium. Developing tumors displayed active Hedgehog (Hh) signaling within their cartilaginous moiety and the presence of parathyroid hormone–related protein (PTHrP) at their distal edge, generating an ectopic Hh-PTHrP axis orthogonal to the one directing normal bone lengthening at the adjacent growth plate. In <i>Ext1</i> mutants, loss of the Hh signaling effector Smoothened (Smo) reduced tumor growth, whereas heterozygous loss of the Smo inhibitor Patched1 (Ptch1) increased tumor growth. Two HS-binding growth factors that promote normal cartilage growth in the growth plate, BMP2 and activin A, did not exert their normal prochondrogenic activity when Hh signaling was blocked, demonstrating that Hh signaling is essential for chondrogenesis. Together, our findings show that osteochondromas usurp a physiological signaling mechanism to guide and propel their directional outgrowth, enabling them to damage surrounding tissues, and suggest potential targets for therapeutic intervention.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 907","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145237421","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}

引用次数: 0

Phosphorylation of RYR1 at Ser2902 decreases Ca2+ leak in skeletal muscle and susceptibility to malignant hyperthermia and heat stroke RYR1 Ser2902位点的磷酸化减少骨骼肌Ca2+泄漏和对恶性高热和中暑的易感性

IF 6.6 1区生物学

Science Signaling Pub Date : 2025-10-07 DOI: 10.1126/scisignal.adx3087

Rachel Sue Zhen Yee, Chang Seok Lee, Ting Chang, Sung Yun Jung, Omar Yousif, Courtney Cavazos, John Colyer, Filip Van Petegem, George G. Rodney, Susan L. Hamilton

{"title":"Phosphorylation of RYR1 at Ser2902 decreases Ca2+ leak in skeletal muscle and susceptibility to malignant hyperthermia and heat stroke","authors":"Rachel Sue Zhen Yee, Chang Seok Lee, Ting Chang, Sung Yun Jung, Omar Yousif, Courtney Cavazos, John Colyer, Filip Van Petegem, George G. Rodney, Susan L. Hamilton","doi":"10.1126/scisignal.adx3087","DOIUrl":"10.1126/scisignal.adx3087","url":null,"abstract":"<div >Ryanodine receptor 1 (RYR1) is the sarcoplasmic reticulum (SR) Ca<sup>2+</sup> release channel required for both skeletal muscle contraction and Ca<sup>2+</sup> leak. Mutations in <i>RYR1</i> cause malignant hyperthermia susceptibility (MHS) and enhanced sensitivity to heat stroke (ESHS), which can result in death due to excessive skeletal muscle thermogenesis upon exposure to volatile anesthetics or heat. Here, we investigated the molecular and physiological functions of phosphorylation of RYR1 at Ser<sup>2902</sup> by the kinase striated muscle preferentially expressed protein (SPEG). Muscle from SPEG-deficient mice expressing RYR1 with a Ser<sup>2902</sup>→Asp<sup>2902</sup> (S2902D) point mutation to mimic phosphorylation by SPEG showed decreased SR Ca<sup>2+</sup> sparks. Muscle from mice homozygous for the S2902D point mutation had reduced SR Ca<sup>2+</sup> transients and small changes in force generation but overall mild phenotypic changes. YS mice, which are heterozygous for a Tyr<sup>524</sup>→Ser<sup>524</sup> point mutation in RYR1, show increased Ca<sup>2+</sup> leak and are a model of MHS and ESHS. Crossing YS mice with S2902D mice led to decreased SR Ca<sup>2+</sup> leak and desensitized the mice to both volatile anesthetics and heat. Thus, SPEG inhibits SR Ca<sup>2+</sup> leak in skeletal muscle by phosphorylating Ser<sup>2902</sup> on RYR1, and mutation of Ser<sup>2902</sup> to Asp<sup>2902</sup> to mimic this phosphorylation event rescues YS mice from heat-induced death.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 907","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145237422","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}

引用次数: 0

Molecular determinants for the endocytosis of the voltage-gated K+ channel Kv1.3 电压门控K+通道Kv1.3内吞作用的分子决定因素

IF 6.6 1区生物学

Science Signaling Pub Date : 2025-09-30 DOI: 10.1126/scisignal.ado8924

Irene Estadella, María Navarro-Pérez, Magalí Colomer-Molera, Michael L. Dustin, Alexander Sorkin, Jesusa Capera, Antonio Felipe

{"title":"Molecular determinants for the endocytosis of the voltage-gated K+ channel Kv1.3","authors":"Irene Estadella, María Navarro-Pérez, Magalí Colomer-Molera, Michael L. Dustin, Alexander Sorkin, Jesusa Capera, Antonio Felipe","doi":"10.1126/scisignal.ado8924","DOIUrl":"10.1126/scisignal.ado8924","url":null,"abstract":"<div >The voltage-gated potassium channel Kv1.3 contributes to action potential conduction in sensory neurons and to sustained increases in cytoplasmic Ca<sup>2+</sup> that activate immune cells. Here, we found that two distinct endocytosis-inducing stimuli acted through the same residues in Kv1.3 to control surface abundance and activity of the channel. Upon stimulation of the growth factor receptor EGFR, which stimulates Tyr-directed kinases and is important in neuronal differentiation, or of the Ser/Thr kinase PKC, which participates in the down-regulation of inflammatory responses, Kv1.3 underwent ubiquitination-dependent endocytosis that routed channel proteins to lysosomes for degradation. We mapped two lysine clusters in the N and C termini of Kv1.3, both of which became ubiquitinated upon activation of either Tyr or Ser/Thr kinases and whose combined mutation had an additive effect in reducing ubiquitination and endocytosis. Manipulations that prevented the ubiquitination or decreased the endocytosis of Kv1.3 resulted in increased Kv1.3 abundance at the immunological synapse and activity in primary human T cells. Prolonged channel accumulation at this location would be expected to increase Kv1.3-dependent leukocyte activation and lead to chronic inflammatory pathologies. Thus, ubiquitination fine-tunes cell biology by inducing the endocytosis and turnover of Kv1.3 in response to biological stimuli and insults.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 906","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197363","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}

引用次数: 0

Defining the MYC-regulated transcriptome and kinome that support KRAS- and ERK-dependent growth of pancreatic cancer 定义支持KRAS和erk依赖性胰腺癌生长的myc调控转录组和kinome

IF 6.6 1区生物学

Science Signaling Pub Date : 2025-09-30 DOI: 10.1126/scisignal.adu7145

Priya S. Hibshman, Clint A. Stalnecker, Jeffrey A. Klomp, Kristina Drizyte-Miller, Jennifer E. Klomp, A. Cole Edwards, Lily M. Pita, Richard G. Hodge, J. Nathaniel Diehl, Ryan D. Mouery, Brandon L. Mouery, Kayla R. Snare, Andrew M. Waters, Sen Peng, Natalie K. Barker, Mariaelena Pierobon, Naim U. Rashid, Nhan L. Tran, Laura A. Herring, Lee M. Graves, Emanuel F. Petricoin III, Kirsten L. Bryant, Adrienne D. Cox, Channing J. Der

{"title":"Defining the MYC-regulated transcriptome and kinome that support KRAS- and ERK-dependent growth of pancreatic cancer","authors":"Priya S. Hibshman, Clint A. Stalnecker, Jeffrey A. Klomp, Kristina Drizyte-Miller, Jennifer E. Klomp, A. Cole Edwards, Lily M. Pita, Richard G. Hodge, J. Nathaniel Diehl, Ryan D. Mouery, Brandon L. Mouery, Kayla R. Snare, Andrew M. Waters, Sen Peng, Natalie K. Barker, Mariaelena Pierobon, Naim U. Rashid, Nhan L. Tran, Laura A. Herring, Lee M. Graves, Emanuel F. Petricoin III, Kirsten L. Bryant, Adrienne D. Cox, Channing J. Der","doi":"10.1126/scisignal.adu7145","DOIUrl":"10.1126/scisignal.adu7145","url":null,"abstract":"<div >Of the thousands of genes and substrates identified in KRAS-mutant signaling networks in pancreatic ductal adenocarcinoma (PDAC), more than 200 are transcription factors, implying extensive and complex transcriptional regulation. However, we observed that genetic suppression of the transcription factor MYC alone was sufficient to phenocopy the effect of KRAS suppression in signaling, growth, and metabolic processes in PDAC cells. We determined the gene transcription changes caused by acute suppression of MYC function in <i>KRAS</i>-mutant PDAC cell lines and performed dependency map and pathway analyses on the affected gene sets. The expression of 1685 genes was increased upon suppression of MYC, and this gene set may comprise the bulk of the MYC-regulated genes essential for PDAC growth. In contrast, the 1325 genes whose expression was inhibited may comprise a compensatory response to oncogenic stress, mediated in part by the GTPase RHO. MYC-dependent transcriptional activity was largely ERK dependent, and almost one-third of ERK-regulated genes were also regulated by MYC in PDAC cells. Furthermore, chemical proteomic profiling revealed MYC-regulated protein kinases that can be targeted therapeutically. Together, these data provide a molecular portrait of MYC-dependent signaling that encompasses potentially exploitable mechanisms for treating PDAC.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 906","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.adu7145","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197362","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}

引用次数: 0

Adenosine 2A receptor–dependent activation of AMPK represses TH17 cell pathogenicity through epigenetic and metabolic reprogramming 腺苷2A受体依赖性激活AMPK通过表观遗传和代谢重编程抑制TH17细胞致病性

IF 6.6 1区生物学

Science Signaling Pub Date : 2025-09-23 DOI: 10.1126/scisignal.adr3177

Gina Papadopoulou, Dimitrios Valakos, Ioanna Polydouri, Afroditi Moulara, Giannis Vatsellas, Stefano Angiari, Marah C. Runtsch, Marc Foretz, Benoit Viollet, Antonino Cassotta, Luke A. J. O’Neill, Georgina Xanthou

{"title":"Adenosine 2A receptor–dependent activation of AMPK represses TH17 cell pathogenicity through epigenetic and metabolic reprogramming","authors":"Gina Papadopoulou, Dimitrios Valakos, Ioanna Polydouri, Afroditi Moulara, Giannis Vatsellas, Stefano Angiari, Marah C. Runtsch, Marc Foretz, Benoit Viollet, Antonino Cassotta, Luke A. J. O’Neill, Georgina Xanthou","doi":"10.1126/scisignal.adr3177","DOIUrl":"10.1126/scisignal.adr3177","url":null,"abstract":"<div >Metabolic reprogramming controls protective and pathogenic T helper 17 (T<sub>H</sub>17) cell responses. When naïve T cells are differentiated into T<sub>H</sub>17 cells in vitro, the presence of the cytokine activin A promotes their maturation into a nonpathogenic state. Here, we found that nonpathogenic T<sub>H</sub>17 cells induced by activin A displayed reduced aerobic glycolysis and increased oxidative phosphorylation (OXPHOS). In response to activin A, signaling through the adenosine A<sub>2A</sub> receptor (A<sub>2A</sub>R) and AMP-activated protein kinase (AMPK) enhanced OXPHOS and reprogrammed pathogenic T<sub>H</sub>17 cells toward nonpathogenic states that did not induce central nervous system autoimmunity in a mouse model of multiple sclerosis. In pathogenic T<sub>H</sub>17 cells, the transcriptional coactivator p300/CBP-associated factor (PCAF) increased acetylation at histone 3 Lys<sup>9</sup> (H3K9ac) of genes involved in aerobic glycolysis and T<sub>H</sub>17 pathogenic programs. In contrast, in nonpathogenic activin A–treated T<sub>H</sub>17 cells, AMPK signaling suppressed PCAF-mediated H3K9ac modification of genes involved in aerobic metabolism and enhanced H3K9ac modification of genes involved in OXPHOS and nonpathogenic T<sub>H</sub>17 programs. Together, our findings uncover A<sub>2A</sub>R-AMPK signaling as a central metabolic checkpoint that suppresses T<sub>H</sub>17 cell pathogenicity.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 905","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145123759","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}

引用次数: 0

Softer nuclei for whiter brown fat 软核为白色棕色脂肪

IF 6.6 1区生物学

Science Signaling Pub Date : 2025-09-23 DOI: 10.1126/scisignal.aec3820

Wei Wong

引用次数: 0

TIM3 is a context-dependent coregulator of cytotoxic T cell function TIM3是细胞毒性T细胞功能的上下文依赖的共调节因子

IF 6.6 1区生物学

Science Signaling Pub Date : 2025-09-23 DOI: 10.1126/scisignal.adk4594

Hanin Alamir, Carissa C. W. Wong, Amal Alsubaiti, Grace L. Edmunds, Maryam Alismail, Lan Huynh, Yiwei Shi, Philip A. Lewis, Tressan Grant, Safaa Alsulaimani, James Boyd, Christopher J. Holland, David J. Morgan, Awen M. Gallimore, Christoph Wülfing

{"title":"TIM3 is a context-dependent coregulator of cytotoxic T cell function","authors":"Hanin Alamir, Carissa C. W. Wong, Amal Alsubaiti, Grace L. Edmunds, Maryam Alismail, Lan Huynh, Yiwei Shi, Philip A. Lewis, Tressan Grant, Safaa Alsulaimani, James Boyd, Christopher J. Holland, David J. Morgan, Awen M. Gallimore, Christoph Wülfing","doi":"10.1126/scisignal.adk4594","DOIUrl":"10.1126/scisignal.adk4594","url":null,"abstract":"<div >TIM3 is a coregulatory receptor that is highly abundant on multiple immune cell types, including T cells in response to prolonged exposure to antigen, and it marks functionally suppressed cytotoxic T lymphocytes (CTLs) in the tumor microenvironment. TIM3 exhibits inhibitory function in vivo but paradoxically has costimulatory T cell signaling capability in vitro. Here, we found that TIM3 directly inhibited the function of murine and human CTLs in direct interaction with target tumor cell spheroids. TIM3 regulated the ability of suppressed CTLs to polarize their actin cytoskeleton as a required step in cytolysis. Whereas the expression of the proposed TIM3 ligands CEACAM1 and galectin 9 in trans on target tumor cells enhanced TIM3 function, expression of CEACAM1 in cis on CTLs had the opposite effect. TIM3 functioned as an inhibitory receptor on spheroid-suppressed CTLs but not on active CTLs in a two-dimensional tissue culture model. Together, these data suggest that TIM3 enhances T cell function, serving as either a coinhibitory or costimulatory receptor depending on the functional context of the T cell on which it is expressed.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 905","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145123755","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}

引用次数: 0