Science Signaling最新文献

Hour-scale single-molecule imaging reveals dynamic assembly of the Wnt co-receptors LRP6 and ROR2 into common signalosomes. 小时尺度的单分子成像揭示了Wnt共受体LRP6和ROR2在共同信号小体中的动态组装。

IF 6.6 1区生物学

Science Signaling Pub Date : 2026-03-03 DOI: 10.1126/scisignal.adr8141

Michael Philippi, Julia Dohle, Isabelle Watrinet, Michael Holtmannspötter, Yi Miao, Jinye Li, Oliver Birkholz, Ulrich Rothbauer, K Christopher Garcia, Rainer Kurre, Jacob Piehler, Changjiang You

{"title":"Hour-scale single-molecule imaging reveals dynamic assembly of the Wnt co-receptors LRP6 and ROR2 into common signalosomes.","authors":"Michael Philippi, Julia Dohle, Isabelle Watrinet, Michael Holtmannspötter, Yi Miao, Jinye Li, Oliver Birkholz, Ulrich Rothbauer, K Christopher Garcia, Rainer Kurre, Jacob Piehler, Changjiang You","doi":"10.1126/scisignal.adr8141","DOIUrl":"10.1126/scisignal.adr8141","url":null,"abstract":"Wnt ligands stimulate β-catenin-dependent (canonical) or β-catenin-independent (noncanonical) signaling, depending on which co-receptors are recruited to the Wnt receptor FZD. Both pathways are initiated by receptor oligomerization into signalosomes and involve a largely overlapping set of downstream effectors. To resolve the assembly of Wnt signalosomes with high spatiotemporal resolution for extended times, we developed single-molecule tracking and localization microscopy based on labeling with reversibly binding nanobodies (rbTALM). We engineered nanobody-tag pairs with finely tuned binding affinities to ensure single-molecule tracking with high fidelity while also permitting continuous exchange of photobleached labels. Multicolor rbTALM imaging enabled simultaneous tracking and super-resolution imaging of three different tagged Wnt co-receptors in the same cell for more than 1 hour at video rate. Time-lapse correlation analyses uncovered cooperative association of canonical (LRP6) and noncanonical (ROR2) Wnt co-receptors with FZD8 into a common, hybrid Wnt signalosome. These findings demonstrate the potential for rbTALM imaging for exploring nanoscale dynamics across millisecond to hour timescales and for deciphering the molecular dynamics that underlie signaling complex formation.","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":"19 927","pages":"eadr8141"},"PeriodicalIF":6.6,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147349630","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

Glucose metabolism sustains aberrant STAT3 signaling in colorectal cancer through glycosylated local signaling factors. 葡萄糖代谢通过糖基化的局部信号因子维持结直肠癌中异常的STAT3信号。

IF 6.6 1区生物学

Science Signaling Pub Date : 2026-03-03 DOI: 10.1126/scisignal.adz6443

Kathryn Buscher, Kelsey Temprine, Christopher Mays, Noora Aabed, Samuel A Kerk, Hannah N Bell, Joseph A Nieto Carrion, Harrison S Greenbaum, Zheng Hong Lee, Varun Ponnusamy, Sadeesh K Ramakrishnan, Costas A Lyssiotis, Xiang Xue, Yatrik M Shah

{"title":"Glucose metabolism sustains aberrant STAT3 signaling in colorectal cancer through glycosylated local signaling factors.","authors":"Kathryn Buscher, Kelsey Temprine, Christopher Mays, Noora Aabed, Samuel A Kerk, Hannah N Bell, Joseph A Nieto Carrion, Harrison S Greenbaum, Zheng Hong Lee, Varun Ponnusamy, Sadeesh K Ramakrishnan, Costas A Lyssiotis, Xiang Xue, Yatrik M Shah","doi":"10.1126/scisignal.adz6443","DOIUrl":"10.1126/scisignal.adz6443","url":null,"abstract":"The JAK-STAT3 signaling pathway is a key driver of colorectal cancer (CRC) progression. STAT3 is a transcription factor that is canonically activated by cytokines, such as IL-6, in a transient manner because of negative feedback mechanisms. However, STAT3 is aberrantly and persistently activated in CRC, promoting tumor cell proliferation and survival. Here, we demonstrated that glucose sustained STAT3 activation independently of cytokine availability. We manipulated glucose metabolism, which showed that both glucose and its downstream metabolite GlcNAc were essential to maintain STAT3 activation. Moreover, cells with high basal STAT3 activity produced proteins that were glycosylated in a glucose-dependent manner and that activated STAT3 in neighboring cells through paracrine signaling. Proteomic analysis identified multiple candidate proteins involved in this process; however, no single protein was sufficient to fully activate STAT3, suggesting that this activation process requires several glycosylated proteins. In a syngeneic mouse model of CRC, inhibition of glycolysis reduced STAT3 activation in tumors, and genetic deletion of STAT3 substantially decreased tumor growth. Together, these findings show how glucose metabolism supports sustained STAT3 activation in CRC, highlighting a potential metabolic vulnerability for therapeutic targeting.","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":"19 927","pages":"eadz6443"},"PeriodicalIF":6.6,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147349590","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

Temporal proteomic and phosphoproteomic dynamics during neuronal differentiation in the reference iPSC line KOLF2.1J. 参考iPSC细胞系KOLF2.1J神经元分化过程中的时间蛋白质组学和磷酸化蛋白质组学动态。

IF 6.6 1区生物学

Science Signaling Pub Date : 2026-02-24 DOI: 10.1126/scisignal.adx8680

Ying Hao, Ziyi Li, Erika Lara, Daniel M Ramos, Marianita Santiana, Benjamin Jin, Jacob Epstein, Isabelle Kowal, Jasmin Camacho, Nicole Carmiol, Jae-Hyeon Park, Aleksandra Beylina, Linda G Yang, Jessica T Root, Dylan C Sacks, Paige Jarreau, Cory A Weller, Sydney Klaisner, Laurel A Screven, Caroline B Pantazis, Mike A Nalls, Priyanka Narayan, Luigi Ferrucci, Andrew B Singleton, Michael E Ward, Mark R Cookson, Yue Andy Qi

{"title":"Temporal proteomic and phosphoproteomic dynamics during neuronal differentiation in the reference iPSC line KOLF2.1J.","authors":"Ying Hao, Ziyi Li, Erika Lara, Daniel M Ramos, Marianita Santiana, Benjamin Jin, Jacob Epstein, Isabelle Kowal, Jasmin Camacho, Nicole Carmiol, Jae-Hyeon Park, Aleksandra Beylina, Linda G Yang, Jessica T Root, Dylan C Sacks, Paige Jarreau, Cory A Weller, Sydney Klaisner, Laurel A Screven, Caroline B Pantazis, Mike A Nalls, Priyanka Narayan, Luigi Ferrucci, Andrew B Singleton, Michael E Ward, Mark R Cookson, Yue Andy Qi","doi":"10.1126/scisignal.adx8680","DOIUrl":"10.1126/scisignal.adx8680","url":null,"abstract":"Induced pluripotent stem cell (iPSC)-derived neurons are a powerful tool with which to investigate both neuronal development and neurodegenerative diseases. Here, we applied quantitative proteomic and phosphoproteomic analyses to profile the neuronal differentiation of the KOLF2.1J iPSC line, the first reference line of the iPSC Neurodegenerative Disease Initiative (iNDI) project. We developed an automated workflow enabling high-coverage enrichment of proteins and phosphorylated peptides, which revealed molecular signatures during the differentiation of iPSC-derived neurons. Proteomic data highlighted distinct changes in mitochondrial pathways throughout the course of differentiation, whereas phosphoproteomic data revealed specific regulatory dynamics in GTPase-mediated signaling pathways and microtubule proteins. Additionally, phosphosite dynamics were not correlated to changes in protein abundance, particularly in processes related to axon functions and RNA transport. We measured the dynamic changes in kinases that are critical for neuronal development and maturation and developed an interactive web app to visualize the temporal landscape dynamics of protein and phosphosite abundance. By establishing baselines of proteomic and phosphoproteomic profiles for neuronal differentiation, this dataset is a valuable resource for future research into neuronal development and neurodegenerative diseases using this reference iPSC line.","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":"19 926","pages":"eadx8680"},"PeriodicalIF":6.6,"publicationDate":"2026-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147286003","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

Acetate enhances long-term memory in female mice by sex-, context-, and brain region-specific epigenetic and transcriptional remodeling. 醋酸酯通过性别、环境和脑区域特异性表观遗传和转录重塑增强雌性小鼠的长期记忆。

IF 6.6 1区生物学

Science Signaling Pub Date : 2026-02-24 DOI: 10.1126/scisignal.aec0496

Erica M Periandri, Kala M Dodson, Francisca N de Luna Vitorino, Benjamin A Garcia, Karl M Glastad, Gabor Egervari

引用次数: 0

Fungi facilitate gut healing. 真菌促进肠道愈合。

IF 6.6 1区生物学

Science Signaling Pub Date : 2026-02-24 DOI: 10.1126/scisignal.aeg5547

Annalisa M VanHook

引用次数: 0

Metabolic alterations after traumatic neural injury: Mechanistic insights and potential translational targets for axon regeneration. 创伤性神经损伤后的代谢改变：轴突再生的机制见解和潜在的翻译靶点。

IF 6.6 1区生物学

Science Signaling Pub Date : 2026-02-24 DOI: 10.1126/scisignal.adx9003

Qianqian Cao, Wenwen Zhao, Junjie Yan, Stephane Belin, Bin Yu, Homaira Nawabi, Susu Mao

{"title":"Metabolic alterations after traumatic neural injury: Mechanistic insights and potential translational targets for axon regeneration.","authors":"Qianqian Cao, Wenwen Zhao, Junjie Yan, Stephane Belin, Bin Yu, Homaira Nawabi, Susu Mao","doi":"10.1126/scisignal.adx9003","DOIUrl":"https://doi.org/10.1126/scisignal.adx9003","url":null,"abstract":"Metabolism not only provides essential substances and energy for cells through catabolism and anabolism but also exerts broader regulatory roles through metabolic enzymes and products that influence gene expression, thereby maintaining homeostasis. Upon neuronal injury, metabolic changes in both neurons and supporting cells influence neuronal survival and regeneration by regulating energy supply, substrate availability, regeneration-related gene expression, and cell-cell metabolic interactions. Axon regeneration is a key process in neural repair after injury. Beyond the nervous system itself, systemic factors such as diet, exercise, circadian rhythms, and psychological stress also play crucial roles in axon regeneration through interorgan metabolic communication and microbiota-host metabolic cross-talk. In this Review, we summarize advances in understanding metabolic alterations during axon regeneration, with a focus on glycometabolism, lipid metabolism, protein degradation, mitochondrial activity, and systemic factor-driven metabolic cross-talk between nervous and non-nervous systems. We also highlight the therapeutic potential of metabolites themselves, analyze distinct metabolic responses after injury in the peripheral and central nervous systems, and discuss their spatiotemporal dynamics and cell type specificity. Last, we propose that successful neural repair requires the establishment of a systemic pro-regenerative state throughout the entire body.","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":"19 926","pages":"eadx9003"},"PeriodicalIF":6.6,"publicationDate":"2026-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147285962","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

The elephant in the adhesion GPCR room. 粘附GPCR室的大象。

IF 6.6 1区生物学

Science Signaling Pub Date : 2026-02-17 DOI: 10.1126/scisignal.aed6070

Tobias Langenhan

引用次数: 0

Erratum for the Research Article "Wild-type RAS signaling is an essential therapeutic target in RAS-mutated cancers". 研究文章“野生型RAS信号是RAS突变癌症的重要治疗靶点”的勘误。

IF 6.6 1区生物学

Science Signaling Pub Date : 2026-02-17 DOI: 10.1126/scisignal.aef9601

引用次数: 0

Activation of GPR97/ADGRG3 by its tethered agonist, but not by beclomethasone, induces neutrophil polarization and migration. GPR97/ADGRG3被其栓系激动剂激活，而不是被倍氯米松激活，诱导中性粒细胞极化和迁移。

IF 6.6 1区生物学

Science Signaling Pub Date : 2026-02-17 DOI: 10.1126/scisignal.abo5234

Tyler Bernadyn, Frank Kwarcinski, Naincy Chandan, Riya Gandhi, Yuling Feng, Michael Holinstat, Carole A Parent, Alan V Smrcka, Gregory G Tall

{"title":"Activation of GPR97/ADGRG3 by its tethered agonist, but not by beclomethasone, induces neutrophil polarization and migration.","authors":"Tyler Bernadyn, Frank Kwarcinski, Naincy Chandan, Riya Gandhi, Yuling Feng, Michael Holinstat, Carole A Parent, Alan V Smrcka, Gregory G Tall","doi":"10.1126/scisignal.abo5234","DOIUrl":"10.1126/scisignal.abo5234","url":null,"abstract":"Most adhesion G protein-coupled receptors (AGPCRs) are activated by the intramolecular binding of a tethered agonist, which is exposed by shear force-induced dissociation of the N- and C-terminal fragments of AGPCRs. The decrypted tethered agonist binds to its orthosteric site in the C-terminal fragment to stabilize the active state of the AGPCR. Corticosteroids have been proposed to be orthosteric agonists for GPR97/ADGRG3. Here, we showed that GPR97/ADGRG3 is activated by the canonical tethered agonist mechanism. In cell-based luciferase reporter assays and receptor/G protein reconstitution assays, GPR97/ADGRG3 was stimulated by agonist peptidomimetics and by 3-acetoxydihydrodeoxygeduin (3-α-DOG), a partial agonist of the ADGRG subfamily, but not by corticosteroids. We showed that GPR97 was a promiscuous AGPCR that coupled to G13, Gs, and Gi but not to Gq. GPR97 is abundant in neutrophils, which undergo cell shape changes and polarization and migrate upon activation. GPR97 activation by tethered agonist peptidomimetics or 3-α-DOG robustly stimulated cAMP production, polarization, and chemotaxis in human and mouse neutrophils. These effects in mouse neutrophils required GPR97 and were not mimicked by the corticosteroid beclomethasone in either cell type. Together, our results demonstrate that GPR97/ADGRG3 uses a tethered agonist mechanism to activate G protein signaling and induce neutrophil polarization and migration.","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":"19 925","pages":"eabo5234"},"PeriodicalIF":6.6,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146214818","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

Microglial reactivity and neuroinflammation-driven changes in motivational behaviors are regulated by Orai1 calcium channels. 小胶质细胞反应性和神经炎症驱动的动机行为变化由Orai1钙通道调节。

IF 6.6 1区生物学

Science Signaling Pub Date : 2026-02-17 DOI: 10.1126/scisignal.ady8398

Kaitlyn E DeMeulenaere, Rogan A Grant, Megan E Martin, Hiam A Valencia, Jelena Radulovic, Michael W Salter, Murali Prakriya

{"title":"Microglial reactivity and neuroinflammation-driven changes in motivational behaviors are regulated by Orai1 calcium channels.","authors":"Kaitlyn E DeMeulenaere, Rogan A Grant, Megan E Martin, Hiam A Valencia, Jelena Radulovic, Michael W Salter, Murali Prakriya","doi":"10.1126/scisignal.ady8398","DOIUrl":"https://doi.org/10.1126/scisignal.ady8398","url":null,"abstract":"Microglia are the brain's resident immune cells that respond to injury and disease by transitioning between homeostatic and reactive states. These cell state transitions determine whether microglia promote or resolve inflammation in the central nervous system (CNS). In this study, we explored the role of Ca2+ signaling in regulating broader microglial cell state transitions and identified Orai1 Ca2+ channels as critical regulators of microglial plasticity and neuroinflammatory signaling. Conditional deletion of Orai1 in microglia impaired their ability to adopt reactive, proinflammatory states. Transcriptomic and metabolomic profiling revealed that Orai1 deletion suppressed the expression of proinflammatory genes linked to immunity, inflammation, and cell metabolism. Conversely, Orai1-deficient microglia generated greater amounts of neuroprotective and anti-inflammatory mediators, including BDNF, ARG1, and the mitochondrial metabolite itaconate. In a model of CNS inflammation induced by peripheral lipopolysaccharide (LPS) challenge, microglial Orai1 deletion attenuated microglial and astrocyte reactivity and reduced hippocampal amounts of the proinflammatory cytokines IL-1β and IL-6. Consistent with these cellular changes, microglial Orai1 knockout mice were protected against LPS-induced decreases in motivational behaviors, including impaired reward-seeking and escape behaviors. These findings establish Orai1 channels as key regulators of microglial cell state transitions, linking Ca2+ signaling to neuroinflammation and inflammation-driven behavioral dysfunction.","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":"19 925","pages":"eady8398"},"PeriodicalIF":6.6,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146214826","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