Science Signaling最新文献_第2页

Cholinergic signals and antibodies 胆碱能信号和抗体

IF 6.6 1区生物学

Science Signaling Pub Date : 2026-04-14 DOI: 10.1126/scisignal.aeh8929

John F. Foley

引用次数: 0

Wnt-dependent Frizzled clustering is required for Dishevelled phosphorylation but insufficient for β-catenin stabilization wnt依赖的卷曲聚类是无序磷酸化所必需的，但对β-连环蛋白稳定却不够

IF 6.6 1区生物学

Science Signaling Pub Date : 2026-04-07 DOI: 10.1126/scisignal.aec0204

Sarah Moldaver, Pierre E. Thibeault, Mélanie Robitaille, Aaron Au, Sichun Lin, Graham MacLeod, Harald J. Junge, Melissa V. Gammons, Christopher M. Yip, Stephane Angers

{"title":"Wnt-dependent Frizzled clustering is required for Dishevelled phosphorylation but insufficient for β-catenin stabilization","authors":"Sarah Moldaver, Pierre E. Thibeault, Mélanie Robitaille, Aaron Au, Sichun Lin, Graham MacLeod, Harald J. Junge, Melissa V. Gammons, Christopher M. Yip, Stephane Angers","doi":"10.1126/scisignal.aec0204","DOIUrl":"10.1126/scisignal.aec0204","url":null,"abstract":"<div >Wnt–β-catenin signaling begins when Wnt ligands engage the receptors Frizzled (Fzd) and LRP5 or LRP6 (LRP5/6), leading to the recruitment and phosphorylation of the intracellular protein Dishevelled (Dvl), which is necessary for stabilization of the transcriptional coactivator β-catenin. Understanding the mechanisms by which ligand binding to Fzd activates Wnt–β-catenin signaling is crucial for rational ligand design to selectively modulate Wnt responses in the context of diseases and tissue regeneration. Here, we determined that ligand-induced Fzd clustering was the initiating event for the recruitment and phosphorylation of the downstream signaling mediator Dvl. Using synthetic, bivalent antibodies and single-molecule microscopy, we found that Wnts and bivalent Fzd-binding antibodies, but not monovalent antibodies, clustered Fzd at the plasma membrane in cells, activating Dvl independently of LRP5/6. However, β-catenin–mediated signaling required LRP5/6 recruitment as an additional step to enable inhibition of the kinase GSK3α or GSK3β and stabilization of β-catenin. This two-step mechanism may separate Fzd activation from β-catenin pathway output, underlying a mechanism by which Wnts encode signaling specificity and may inform the design of selective Wnt pathway modulators.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"19 932","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147626392","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

Emerging paradigms in the study of brain metastases 脑转移研究的新范式

IF 6.6 1区生物学

Science Signaling Pub Date : 2026-04-07 DOI: 10.1126/scisignal.adj9726

Shawn C. Chafe, Daniel Mobilio, Kui Zhai, Agata M. Kieliszek, Chitra Venugopal, Sheila K. Singh

引用次数: 0

Antimuscarinic drugs exert β-arrestin–biased agonism at the muscarinic acetylcholine type 1 receptor to promote DRG neuritogenesis 抗毒蕈碱药物对毒蕈碱乙酰胆碱1型受体发挥β-抑制蛋白偏激激动作用，促进DRG神经生成

IF 6.6 1区生物学

Science Signaling Pub Date : 2026-03-31 DOI: 10.1126/scisignal.ady7187

Shayan Amiri, Mohamad-Reza Aghanoori, Darrell R. Smith, T. M. Zaved Waise, Ying Lao, Asuka Inoue, René P. Zahedi, Henry A. Dunn, Paul Fernyhough

{"title":"Antimuscarinic drugs exert β-arrestin–biased agonism at the muscarinic acetylcholine type 1 receptor to promote DRG neuritogenesis","authors":"Shayan Amiri, Mohamad-Reza Aghanoori, Darrell R. Smith, T. M. Zaved Waise, Ying Lao, Asuka Inoue, René P. Zahedi, Henry A. Dunn, Paul Fernyhough","doi":"10.1126/scisignal.ady7187","DOIUrl":"10.1126/scisignal.ady7187","url":null,"abstract":"<div >Pirenzepine (PZ) and muscarinic toxin 7 (MT7) are muscarinic acetylcholine type 1 receptor (M<sub>1</sub>R) antagonists that promote neuritogenesis in primary adult rodent dorsal root ganglion (DRG) sensory neurons, in part through β-arrestin–dependent activation of ERK1/2. Here, we found that PZ and MT7 exhibited β-arrestin–biased agonism at M<sub>1</sub>R. PZ and MT7 recruited β-arrestin 2 to M<sub>1</sub>R and increased ERK phosphorylation in both HEK293 cells and DRG neurons in a concentration-dependent manner. Moreover, ERK activation by MT7 occurred only in M<sub>1</sub>R-positive DRG neurons and did not require G protein signaling or receptor internalization. PZ stimulated M<sub>1</sub>R phosphorylation at multiple serine and threonine residues. Mutation of Ser<sup>251</sup> and Thr<sup>254</sup> in M<sub>1</sub>R suppressed PZ- and MT7-dependent activation of β-arrestins and PZ-dependent β-arrestin binding and ERK activation. The β-arrestin–biased activities of PZ and MT7 required the activity of casein kinase 2 (CK2) but not that of Gα<sub>q</sub> or GPCR kinases (GRKs). Pharmacological or siRNA-based inhibition of CK2 blocked PZ-dependent β-arrestin recruitment, ERK activation, and neurite outgrowth in DRG neurons. These results implicate a GRK- and G protein–independent mechanism for the β-arrestin–biased agonism and antimuscarinic effects of PZ and MT7.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"19 931","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147588692","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 protein RAB5IF promotes BDNF signaling by stimulating the SUMOylation of Gαi1/3 to reduce depressive-like behaviors in mice RAB5IF蛋白通过刺激g - α 1/3的sumo化来促进BDNF信号传导，从而减少小鼠的抑郁样行为

IF 6.6 1区生物学

Science Signaling Pub Date : 2026-03-31 DOI: 10.1126/scisignal.aec8898

Xin Shi, Han-qi Liu, Shi-zhong Cai, Yi-hang Shen, Jin-long Chai, Mei-qing Zhang, Chen-yang Xu, Zhi-qing Zhang, John Marshall, Cong Cao

{"title":"The protein RAB5IF promotes BDNF signaling by stimulating the SUMOylation of Gαi1/3 to reduce depressive-like behaviors in mice","authors":"Xin Shi, Han-qi Liu, Shi-zhong Cai, Yi-hang Shen, Jin-long Chai, Mei-qing Zhang, Chen-yang Xu, Zhi-qing Zhang, John Marshall, Cong Cao","doi":"10.1126/scisignal.aec8898","DOIUrl":"10.1126/scisignal.aec8898","url":null,"abstract":"<div >Chronic stress and impaired signaling by the neurotrophic factor BDNF are associated with depression. The heterotrimeric G protein subunits Gα<sub>i1</sub> and Gα<sub>i3</sub> (Gα<sub>i1/3</sub>) are critical mediators of BDNF signaling in a mouse model of chronic mild stress–induced depression. Here, we found that chronic mild stress impairs the SUMOylation of Gα<sub>i1/3</sub> and, consequently, their formation of signaling complexes with the BDNF receptor TrkB. Impaired SUMOylation of the G protein subunits was the result of a decrease in RAB5-interacting factor (RAB5IF) and a consequent decrease in the translational efficiency of <i>Sumo2</i> mRNA. RAB5IF silencing or knockout in cultured murine hippocampal neurons impaired BDNF-induced signaling and mitochondrial function that compromised dendritic branching and synaptic density. Neuronal knockdown or conditional knockout of RAB5IF in the mouse hippocampus recapitulated these cellular deficits and induced depressive-like behaviors. Conversely, neuronal overexpression of RAB5IF in the hippocampus mitigated the depressive phenotype. SUMOylation of Gα<sub>i1/3</sub> at Lys<sup>277</sup> was required for BDNF-induced formation of TrkB-SUMO2-Gα<sub>i1/3</sub> complexes and activation of downstream Akt-mTOR signaling. Neuronal knockdown of SUMO2 or hippocampal overexpression of a Gα<sub>i1/3</sub> mutant that could not be SUMOylated impaired BDNF signaling and induced depressive-like behaviors in mice. The findings reveal that the RAB5IF-SUMO2-Gα<sub>i1/3</sub> signaling axis is crucial for TrkB signaling and preventing depressive behaviors.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"19 931","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147588693","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

Location-biased β-arrestin conformations direct GPCR signaling 位置偏倚的β-阻滞蛋白构象直接GPCR信号传导。

IF 6.6 1区生物学

Science Signaling Pub Date : 2026-03-24 DOI: 10.1126/scisignal.ady4950

Uyen Pham, Anand Chundi, Tomasz M. Stępniewski, Srikrishna Darbha, Dylan S. Eiger, Sonia Gazula, Julia Gardner, Chloe Hicks, Jana Selent, Sudarshan Rajagopal

{"title":"Location-biased β-arrestin conformations direct GPCR signaling","authors":"Uyen Pham, Anand Chundi, Tomasz M. Stępniewski, Srikrishna Darbha, Dylan S. Eiger, Sonia Gazula, Julia Gardner, Chloe Hicks, Jana Selent, Sudarshan Rajagopal","doi":"10.1126/scisignal.ady4950","DOIUrl":"10.1126/scisignal.ady4950","url":null,"abstract":"<div >β-Arrestins are multifunctional, intracellular proteins that regulate the desensitization, internalization, and signaling of more than 800 G protein–coupled receptors (GPCRs) and interact with a diverse array of intracellular partners. Beyond the plasma membrane, GPCRs can initiate distinct signaling cascades from various subcellular locations, a phenomenon known as “location bias.” Here, we investigated how β-arrestins directed location-biased signaling of the angiotensin II type 1 receptor (AT1R) using bioluminescence resonance energy transfer (BRET) conformational biosensors and extracellular signal–regulated kinase (ERK) activity reporters. We found that, in response to the endogenous agonist angiotensin II and the β-arrestin–biased agonist TRV023, β-arrestin 1 and β-arrestin 2 adopted distinct conformations across different subcellular locations, which were associated with different ERK activation profiles. We also uncovered a population of receptor-free, activated β-arrestins in the plasma membrane that exhibited insensitivity to different agonists and promoted ERK activation at the plasma membrane independently of G proteins. These findings deepen our understanding of GPCR signaling complexity and highlight the nuanced roles of β-arrestins beyond traditional G protein pathways.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"19 930","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147515866","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

RXRα marks the spot for Crohn’s disease RXRα标志着克罗恩病的位置。

IF 6.6 1区生物学

Science Signaling Pub Date : 2026-03-24 DOI: 10.1126/scisignal.aeh3241

Wei Wong

引用次数: 0

DDX3X is a Cl−-sensitive RNA helicase DDX3X是一种Cl敏感的RNA解旋酶。

IF 6.6 1区生物学

Science Signaling Pub Date : 2026-03-24 DOI: 10.1126/scisignal.adv4376

Ivan Rosa e Silva, Paula F. V. do Prado, Felipe Z. Benevenutti, Renata R. de Oliveira, Aline R. Passos, Camila Canateli, Isabelly G. Messias, Daniel M. Trindade, Leandro O. Bortot, João V. S. Guerra, Thaís Hancio, Mauricio L. Sforça, Andrey F. Z. Nascimento, Gustavo F. Mercaldi, José G. C. Pereira, Matheus C. Fonseca, Paulo S. L. de Oliveira, Murilo de Carvalho, Juliana H. C. Smetana, Ana C. V. Krepischi, Kleber G. Franchini, Juliana F. de Oliveira

{"title":"DDX3X is a Cl−-sensitive RNA helicase","authors":"Ivan Rosa e Silva, Paula F. V. do Prado, Felipe Z. Benevenutti, Renata R. de Oliveira, Aline R. Passos, Camila Canateli, Isabelly G. Messias, Daniel M. Trindade, Leandro O. Bortot, João V. S. Guerra, Thaís Hancio, Mauricio L. Sforça, Andrey F. Z. Nascimento, Gustavo F. Mercaldi, José G. C. Pereira, Matheus C. Fonseca, Paulo S. L. de Oliveira, Murilo de Carvalho, Juliana H. C. Smetana, Ana C. V. Krepischi, Kleber G. Franchini, Juliana F. de Oliveira","doi":"10.1126/scisignal.adv4376","DOIUrl":"10.1126/scisignal.adv4376","url":null,"abstract":"<div >Cl<sup>−</sup> homeostasis is pivotal during neurodevelopment and in multiple processes in mature neurons, and its disruption is implicated in several neurodevelopmental disorders. Here, we investigated the role of Cl<sup>−</sup> in regulating DDX3X, an ATP-dependent RNA helicase that is associated with a neurodevelopmental disorder and is involved in stress granule assembly through biomolecular condensation. Cl<sup>−</sup> directly interacted with the DDX3X helicase core in the RNA binding region. This interaction impaired both ATPase and RNA helicase activities at physiologically relevant concentrations in a manner similar to inorganic phosphate and disrupted its condensation propensity in vitro. In neuroblastoma cells, Cl<sup>−</sup> efflux induced the formation of large, persistent DDX3X-containing stress granules. Furthermore, the R326H mutation, which is linked to a severe neurodevelopmental disorder, altered the chemical environment of the Cl<sup>−</sup>-binding site and impaired Cl<sup>−</sup>-sensitive functions. Together, our findings demonstrate that Cl<sup>−</sup> binding regulates DDX3X functions and provide insights into the molecular pathophysiology of a neurodevelopmental disorder–linked mutation in DDX3X.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"19 930","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147515725","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

Erratum for the Research Article “Caveolin-1–mediated internalization of the vitamin C transporter SVCT2 in microglia triggers an inflammatory phenotype” 研究文章“小胶质细胞中caveolin -1介导的维生素C转运体SVCT2内化引发炎症表型”的勘误。

IF 6.6 1区生物学

Science Signaling Pub Date : 2026-03-17 DOI: 10.1126/scisignal.aeg7521

引用次数: 0

The unphosphorylated, closed form of ezrin binds to RNA to maintain a metastatic phenotype in osteosarcoma cells 未磷酸化的，封闭形式的ezrin与RNA结合以维持骨肉瘤细胞的转移表型。

IF 6.6 1区生物学

Science Signaling Pub Date : 2026-03-17 DOI: 10.1126/scisignal.ady8367

Emre Deniz, Prakriti Tiwari, Purushottam B. Tiwari, Eric Glasgow, Brent T. Harris, Anup Tiwari, Chunyan Hou, Junfeng Ma, Jeffrey A. Toretsky, Aykut Üren

{"title":"The unphosphorylated, closed form of ezrin binds to RNA to maintain a metastatic phenotype in osteosarcoma cells","authors":"Emre Deniz, Prakriti Tiwari, Purushottam B. Tiwari, Eric Glasgow, Brent T. Harris, Anup Tiwari, Chunyan Hou, Junfeng Ma, Jeffrey A. Toretsky, Aykut Üren","doi":"10.1126/scisignal.ady8367","DOIUrl":"10.1126/scisignal.ady8367","url":null,"abstract":"<div >Ezrin is a cytoplasmic protein that can exist in multiple conformations that are regulated by phosphorylation at Thr<sup>567</sup>. The phosphorylated, open form of ezrin generally has been considered the active form because it translocates to the plasma membrane. In contrast, the unphosphorylated, closed form of ezrin is sequestered in the cytoplasm and is considered inactive, although it directly interacts with cytoplasmic RNA binding proteins. Here, we found that the closed form of ezrin is itself an RNA binding protein with biological activity. The abundance of ezrin correlated with that of RBPs in human osteosarcoma samples. Purified recombinant ezrin protein engineered to maintain a closed conformation (rEZRIN-T567A) directly bound RNA, with greatest affinity for guanine-rich sequences and RNA G-quadruplexes (G4 RNAs). Expressing closed ezrin in ezrin-null osteosarcoma cells restored the transcriptomic and proteomic profiles. Closed ezrin bound to endogenous mRNAs associated with pathways related to RNA processing and splicing, DNA maintenance, and cellular metabolism. In zebrafish, expression of closed ezrin rescued the metastatic capability of ezrin-null osteosarcoma xenografts. Our findings demonstrate that the closed conformation of ezrin—previously thought to be inactive—can directly bind RNA, regulate transcription and translation, and contribute to a metastatic phenotype in osteosarcoma cells.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"19 929","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147476271","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