Science Signaling最新文献_第2页

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":"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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13401804/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Autophosphorylation of oncoprotein TEL-ABL in myeloid and lymphoid cells confers resistance to the allosteric ABL inhibitor asciminib. 髓细胞和淋巴细胞中癌蛋白TEL-ABL的自磷酸化赋予对变构ABL抑制剂阿西米尼的抗性。

IF 6.6 1区生物学

Science Signaling Pub Date : 2025-07-15 DOI: 10.1126/scisignal.adt5931

Serena Muratcioglu, Christopher A Eide, Chien-Lun Hung, Kent Gorday, Emily Sumpena, Wenqi Zuo, Jay T Groves, Brian J Druker, John Kuriyan

{"title":"Autophosphorylation of oncoprotein TEL-ABL in myeloid and lymphoid cells confers resistance to the allosteric ABL inhibitor asciminib.","authors":"Serena Muratcioglu, Christopher A Eide, Chien-Lun Hung, Kent Gorday, Emily Sumpena, Wenqi Zuo, Jay T Groves, Brian J Druker, John Kuriyan","doi":"10.1126/scisignal.adt5931","DOIUrl":"10.1126/scisignal.adt5931","url":null,"abstract":"Chromosomal translocations that fuse ABL1 to BCR or TEL cause human leukemias. In BCR-ABL and TEL-ABL fusion proteins, oligomerization and loss of an autoinhibitory myristoylation site in the SH3 domain of ABL lead to increased ABL tyrosine kinase activity. We assessed the ability of asciminib, an allosteric inhibitor of BCR-ABL that binds to the myristoyl-binding site in the ABL kinase domain, to inhibit these fusion proteins. Although the ABL components of the two fusion proteins have identical sequences, asciminib was much less effective against TEL-ABL than it was against BCR-ABL in cell-growth assays. In contrast, ATP-competitive tyrosine kinase inhibitors, such as imatinib and ponatinib, were equally effective against both fusion proteins. A helix in the ABL kinase domain that closes over bound asciminib was required for the sensitivity of BCR-ABL to the drug but had no effect on that of TEL-ABL, suggesting that the native autoinhibitory mechanism that asciminib engages in BCR-ABL is disrupted in TEL-ABL. Single-molecule microscopy demonstrated that BCR-ABL was mainly dimeric in cells, whereas TEL-ABL formed higher-order oligomers, which promoted trans-autophosphorylation, including of a regulatory phosphorylation site (Tyr89) in the SH3 domain of ABL. Nonphosphorylated TEL-ABL was intrinsically susceptible to inhibition by asciminib, but phosphorylation at Tyr89 disassembled the autoinhibited conformation of ABL, thereby preventing asciminib from binding. Our results demonstrate that phosphorylation determines whether an ABL fusion protein is sensitive to allosteric inhibition.","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":"18 895","pages":"eadt5931"},"PeriodicalIF":6.6,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12313245/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144643999","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

Astrocytic RIPK3 exerts protective anti-inflammatory activity in mice with viral encephalitis by transcriptional induction of serpins. 星形细胞RIPK3通过转录诱导蛇形蛋白在病毒性脑炎小鼠中发挥保护性抗炎活性。

IF 6.6 1区生物学

Science Signaling Pub Date : 2025-07-15 DOI: 10.1126/scisignal.adq6422

Marissa Lindman, Irving Estevez, Eduard Marmut, Evan M DaPrano, Tsui-Wen Chou, Kimberly Newman, Colm Atkins, Natasha M O'Brown, Brian P Daniels

{"title":"Astrocytic RIPK3 exerts protective anti-inflammatory activity in mice with viral encephalitis by transcriptional induction of serpins.","authors":"Marissa Lindman, Irving Estevez, Eduard Marmut, Evan M DaPrano, Tsui-Wen Chou, Kimberly Newman, Colm Atkins, Natasha M O'Brown, Brian P Daniels","doi":"10.1126/scisignal.adq6422","DOIUrl":"10.1126/scisignal.adq6422","url":null,"abstract":"Flaviviruses pose a substantial threat to public health because of their ability to infect the central nervous system (CNS). Receptor-interacting protein kinase 3 (RIPK3) is a central coordinator that promotes neuroinflammation during viral infection of the CNS, a role that occurs independently of its canonical function in inducing necroptosis. Here, we used mouse genetic tools to induce astrocyte-specific deletion, overexpression, and chemogenetic activation of RIPK3 to demonstrate an anti-inflammatory function for astrocytic RIPK3. RIPK3 activation in astrocytes promoted host survival during flavivirus encephalitis by limiting immune cell recruitment to the CNS. Despite inducing a proinflammatory transcriptional program, astrocytic RIPK3 restrained neuroinflammation by increasing the abundance of the protease inhibitor SerpinA3N, which preserved blood-brain barrier integrity, reduced leukocyte infiltration, and improved survival outcomes during flavivirus encephalitis. These findings highlight a previously unappreciated role for astrocytic RIPK3 in suppressing pathologic neuroinflammation.","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":"18 895","pages":"eadq6422"},"PeriodicalIF":6.6,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12407229/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144643998","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

YAP controls cell migration and invasion through a Rho GTPase switch. YAP通过Rho GTPase开关控制细胞迁移和侵袭。

IF 7.3 1区生物学

Science Signaling Pub Date : 2025-05-27 DOI: 10.1126/scisignal.adu3794

Sagar R Shah, Chunxiao Ren, Nathaniel D Tippens, JinSeok Park, Ahmed Mohyeldin, Shuyan Wang, Guillermo Vela, Juan C Martinez-Gutierrez, Seth S Margolis, Susanne Schmidt, Alfredo Quiñones-Hinojosa, Andre Levchenko

{"title":"YAP controls cell migration and invasion through a Rho GTPase switch.","authors":"Sagar R Shah, Chunxiao Ren, Nathaniel D Tippens, JinSeok Park, Ahmed Mohyeldin, Shuyan Wang, Guillermo Vela, Juan C Martinez-Gutierrez, Seth S Margolis, Susanne Schmidt, Alfredo Quiñones-Hinojosa, Andre Levchenko","doi":"10.1126/scisignal.adu3794","DOIUrl":"10.1126/scisignal.adu3794","url":null,"abstract":"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.","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":"18 888","pages":"eadu3794"},"PeriodicalIF":7.3,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12268267/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144163544","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

Myeloid sirtuin 6 deficiency causes obesity in mice by inducing norepinephrine degradation to limit thermogenic tissue function. 髓系sirtuin 6缺乏通过诱导去甲肾上腺素降解限制产热组织功能导致小鼠肥胖。

IF 6.6 1区生物学

Science Signaling Pub Date : 2025-03-11 DOI: 10.1126/scisignal.adl6441

Wei Wang, Jichao Liang, Yinliang Zhang, Junjun Wang, Xiaolei Miao, Yongsheng Chang, Yong Chen

{"title":"Myeloid sirtuin 6 deficiency causes obesity in mice by inducing norepinephrine degradation to limit thermogenic tissue function.","authors":"Wei Wang, Jichao Liang, Yinliang Zhang, Junjun Wang, Xiaolei Miao, Yongsheng Chang, Yong Chen","doi":"10.1126/scisignal.adl6441","DOIUrl":"10.1126/scisignal.adl6441","url":null,"abstract":"Brown and beige adipocytes dissipate energy to generate heat through uncoupled respiration, and the hormone norepinephrine plays an important role in stimulating brown fat thermogenesis and beige adipocyte development in white adipose depots. Increasing energy expenditure by promoting the function and development of brown and beige fat is a potential approach to treat obesity and diabetes. Here, we investigated the effects of macrophage sirtuin 6 (SIRT6) on the regulation of the norepinephrine content of brown adipose tissue (BAT) and on obesity in mice. Myeloid SIRT6 deficiency impaired the thermogenic function of BAT, thereby decreasing core body temperatures because of reduced norepinephrine concentrations in BAT and subsequently leading to cold sensitivity. In addition, the oxygen consumption rate was reduced, resulting in severe insulin resistance and obesity. Furthermore, macrophage SIRT6 deficiency inhibited BAT thermogenesis after cold exposure or norepinephrine treatment and cold exposure-induced increases in markers of lipid metabolism and thermogenesis in white adipose tissue. Myeloid-specific SIRT6 deficiency promoted H3K9 acetylation in the promoter regions and the expression of genes encoding the norepinephrine-degrading enzyme MAOA and the norepinephrine transporter SLC6A2 in macrophages in BAT, leading to norepinephrine degradation and obesity. Our findings indicate that SIRT6 in macrophages is essential for maintaining norepinephrine concentrations in BAT in mice.","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":"18 877","pages":"eadl6441"},"PeriodicalIF":6.6,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143606971","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

Metabolic pressure from sensory neurons. 来自感觉神经元的代谢压力。

IF 7.3 1区生物学

Science Signaling Pub Date : 2025-03-11 DOI: 10.1126/scisignal.adx2289

Wei Wong

引用次数: 0

The NEMO/ATM/IKKα complex: A key player in colorectal cancer progression and treatment. NEMO/ATM/IKKα复合物：结直肠癌进展和治疗的关键参与者

IF 7.3 1区生物学

Science Signaling Pub Date : 2025-03-11 DOI: 10.1126/scisignal.adv1265

Neil D Perkins

引用次数: 0