Science Signaling最新文献_第7页

G protein–coupled receptor endocytosis generates spatiotemporal bias in β-arrestin signaling G蛋白偶联受体的内吞作用在β-arrestin信号传导中产生时空偏差。

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-06-25 DOI: 10.1126/scisignal.adi0934

András D. Tóth, Bence Szalai, Orsolya T. Kovács, Dániel Garger, Susanne Prokop, Eszter Soltész-Katona, András Balla, Asuka Inoue, Péter Várnai, Gábor Turu, László Hunyady

{"title":"G protein–coupled receptor endocytosis generates spatiotemporal bias in β-arrestin signaling","authors":"András D. Tóth, Bence Szalai, Orsolya T. Kovács, Dániel Garger, Susanne Prokop, Eszter Soltész-Katona, András Balla, Asuka Inoue, Péter Várnai, Gábor Turu, László Hunyady","doi":"10.1126/scisignal.adi0934","DOIUrl":"10.1126/scisignal.adi0934","url":null,"abstract":"<div >The stabilization of different active conformations of G protein–coupled receptors is thought to underlie the varying efficacies of biased and balanced agonists. Here, profiling the activation of signal transducers by angiotensin II type 1 receptor (AT<sub>1</sub>R) agonists revealed that the extent and kinetics of β-arrestin binding exhibited substantial ligand-dependent differences, which were lost when receptor internalization was inhibited. When AT<sub>1</sub>R endocytosis was prevented, even weak partial agonists of the β-arrestin pathway acted as full or near-full agonists, suggesting that receptor conformation did not exclusively determine β-arrestin recruitment. The ligand-dependent variance in β-arrestin translocation was much larger at endosomes than at the plasma membrane, showing that ligand efficacy in the β-arrestin pathway was spatiotemporally determined. Experimental investigations and mathematical modeling demonstrated how multiple factors concurrently shaped the effects of agonists on endosomal receptor–β-arrestin binding and thus determined the extent of functional selectivity. Ligand dissociation rate and G protein activity had particularly strong, internalization-dependent effects on the receptor–β-arrestin interaction. We also showed that endocytosis regulated the agonist efficacies of two other receptors with sustained β-arrestin binding: the V<sub>2</sub> vasopressin receptor and a mutant β<sub>2</sub>-adrenergic receptor. In the absence of endocytosis, the agonist-dependent variance in β-arrestin2 binding was markedly diminished. Our results suggest that endocytosis determines the spatiotemporal bias in GPCR signaling and can aid in the development of more efficacious, functionally selective compounds.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 842","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141452041","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

Palmitoylation promotes pores 棕榈酰化可促进毛孔形成。

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-06-25 DOI: 10.1126/scisignal.adr1306

John F. Foley

引用次数: 0

A gut punch for PCOS 多囊卵巢综合症的一记重拳

IF 7.3 1区生物学

Science Signaling Pub Date : 2024-06-18 DOI: 10.1126/scisignal.adr0297

Wei Wong

引用次数: 0

Conformation- and activation-based BRET sensors differentially report on GPCR–G protein coupling 基于构象和激活的 BRET 传感器对 GPCR-G 蛋白耦合有不同的报告。

IF 7.3 1区生物学

Science Signaling Pub Date : 2024-06-18 DOI: 10.1126/scisignal.adi4747

Shane C. Wright, Charlotte Avet, Supriya A. Gaitonde, Itziar Muneta-Arrate, Christian Le Gouill, Mireille Hogue, Billy Breton, Stefania Koutsilieri, Rebeca Diez Alarcia, Madeleine Héroux, Volker M. Lauschke, Michel Bouvier

{"title":"Conformation- and activation-based BRET sensors differentially report on GPCR–G protein coupling","authors":"Shane C. Wright, Charlotte Avet, Supriya A. Gaitonde, Itziar Muneta-Arrate, Christian Le Gouill, Mireille Hogue, Billy Breton, Stefania Koutsilieri, Rebeca Diez Alarcia, Madeleine Héroux, Volker M. Lauschke, Michel Bouvier","doi":"10.1126/scisignal.adi4747","DOIUrl":"10.1126/scisignal.adi4747","url":null,"abstract":"<div >G protein–coupled receptors (GPCRs) regulate cellular signaling processes by coupling to diverse combinations of heterotrimeric G proteins composed of Gα, Gβ, and Gγ subunits. Biosensors based on bioluminescence resonance energy transfer (BRET) have advanced our understanding of GPCR functional selectivity. Some BRET biosensors monitor ligand-induced conformational changes in the receptor or G proteins, whereas others monitor the recruitment of downstream effectors to sites of G protein activation. Here, we compared the ability of conformation-and activation-based BRET biosensors to assess the coupling of various class A and B GPCRs to specific Gα proteins in cultured cells. These GPCRs included serotonin 5-HT<sub>2A</sub> and 5-HT<sub>7</sub> receptors, the GLP-1 receptor (GLP-1R), and the M<sub>3</sub> muscarinic receptor. We observed different signaling profiles between the two types of sensors, highlighting how data interpretation could be affected by the nature of the biosensor. We also found that the identity of the Gβγ subunits used in the assay could differentially influence the selectivity of a receptor toward Gα subtypes, emphasizing the importance of the receptor-Gβγ pairing in determining Gα coupling specificity. Last, the addition of epitope tags to the receptor could affect stoichiometry and coupling selectivity and yield artifactual findings. These results highlight the need for careful sensor selection and experimental design when probing GPCR–G protein coupling.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 841","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.adi4747","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141421619","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

Pin1-catalyzed conformational regulation after phosphorylation: A distinct checkpoint in cell signaling and drug discovery 磷酸化后 Pin1 催化的构象调控：细胞信号传导和药物发现中的一个独特检查点

IF 7.3 1区生物学

Science Signaling Pub Date : 2024-06-18 DOI: 10.1126/scisignal.adi8743

Kun Ping Lu, Xiao Zhen Zhou

引用次数: 0

Slow proliferation of BAP1-deficient uveal melanoma cells is associated with reduced S6 signaling and resistance to nutrient stress BAP1缺陷的葡萄膜黑色素瘤细胞增殖缓慢与S6信号的减少和对营养压力的抵抗有关。

IF 7.3 1区生物学

Science Signaling Pub Date : 2024-06-11 DOI: 10.1126/scisignal.adn8376

Vivian Chua, Melisa Lopez-Anton, Mizue Terai, Ryota Tanaka, Usman Baqai, Timothy J. Purwin, Jelan I. Haj, Francis J. Waltrich Jr., Isabella Trachtenberg, Kristine Luo, Rohith Tudi, Angela Jeon, Anna Han, Inna Chervoneva, Michael A. Davies, Julio A. Aguirre-Ghiso, Takami Sato, Andrew E. Aplin

{"title":"Slow proliferation of BAP1-deficient uveal melanoma cells is associated with reduced S6 signaling and resistance to nutrient stress","authors":"Vivian Chua, Melisa Lopez-Anton, Mizue Terai, Ryota Tanaka, Usman Baqai, Timothy J. Purwin, Jelan I. Haj, Francis J. Waltrich Jr., Isabella Trachtenberg, Kristine Luo, Rohith Tudi, Angela Jeon, Anna Han, Inna Chervoneva, Michael A. Davies, Julio A. Aguirre-Ghiso, Takami Sato, Andrew E. Aplin","doi":"10.1126/scisignal.adn8376","DOIUrl":"10.1126/scisignal.adn8376","url":null,"abstract":"<div >Uveal melanoma (UM) is the deadliest form of eye cancer in adults. Inactivating mutations and/or loss of expression of the gene encoding BRCA1-associated protein 1 (BAP1) in UM tumors are associated with an increased risk of metastasis. To investigate the mechanisms underlying this risk, we explored the functional consequences of BAP1 deficiency. UM cell lines expressing mutant <i>BAP1</i> grew more slowly than those expressing wild-type <i>BAP1</i> in culture and in vivo. The ability of BAP1 reconstitution to restore cell proliferation in BAP1-deficient cells required its deubiquitylase activity. Proteomic analysis showed that BAP1-deficient cells had decreased phosphorylation of ribosomal S6 and its upstream regulator, p70S6K1, compared with both wild-type and BAP1 reconstituted cells. In turn, expression of p70S6K1 increased S6 phosphorylation and proliferation of BAP1-deficient UM cells. Consistent with these findings, <i>BAP1</i> mutant primary UM tumors expressed lower amounts of p70S6K1 target genes, and S6 phosphorylation was decreased in <i>BAP1</i> mutant patient-derived xenografts (PDXs), which grew more slowly than wild-type PDXs in the liver (the main metastatic site of UM) in mice. BAP1-deficient UM cells were also more resistant to amino acid starvation, which was associated with diminished phosphorylation of S6. These studies demonstrate that BAP1 deficiency slows the proliferation of UM cells through regulation of S6 phosphorylation. These characteristics may be associated with metastasis by ensuring survival during amino acid starvation.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 840","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141307192","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

MCTP1 increases the malignancy of androgen-deprived prostate cancer cells by inducing neuroendocrine differentiation and EMT MCTP1 通过诱导神经内分泌分化和 EMT 增加雄激素缺乏的前列腺癌细胞的恶性程度。

IF 7.3 1区生物学

Science Signaling Pub Date : 2024-06-11 DOI: 10.1126/scisignal.adc9142

Yen-Nien Liu, Wei-Yu Chen, Hsiu-Lien Yeh, Wei-Hao Chen, Kuo-Ching Jiang, Han-Ru Li, Phan Vu Thuy Dung, Zi-Qing Chen, Wei-Jiunn Lee, Michael Hsiao, Jiaoti Huang, Yu-Ching Wen

{"title":"MCTP1 increases the malignancy of androgen-deprived prostate cancer cells by inducing neuroendocrine differentiation and EMT","authors":"Yen-Nien Liu, Wei-Yu Chen, Hsiu-Lien Yeh, Wei-Hao Chen, Kuo-Ching Jiang, Han-Ru Li, Phan Vu Thuy Dung, Zi-Qing Chen, Wei-Jiunn Lee, Michael Hsiao, Jiaoti Huang, Yu-Ching Wen","doi":"10.1126/scisignal.adc9142","DOIUrl":"10.1126/scisignal.adc9142","url":null,"abstract":"<div >Neuroendocrine prostate cancer (PCa) (NEPC), an aggressive subtype that is associated with poor prognosis, may arise after androgen deprivation therapy (ADT). We investigated the molecular mechanisms by which ADT induces neuroendocrine differentiation in advanced PCa. We found that transmembrane protein 1 (MCTP1), which has putative Ca<sup>2+</sup> sensing function and multiple Ca<sup>2+</sup>-binding C2 domains, was abundant in samples from patients with advanced PCa. MCTP1 was associated with the expression of the EMT-associated transcription factors ZBTB46, FOXA2, and HIF1A. The increased abundance of MCTP1 promoted PC3 prostate cancer cell migration and neuroendocrine differentiation and was associated with SNAI1-dependent EMT in C4-2 PCa cells after ADT. ZBTB46 interacted with FOXA2 and HIF1A and increased the abundance of MCTP1 in a hypoxia-dependent manner. MCTP1 stimulated Ca<sup>2+</sup> signaling and AKT activation to promote EMT and neuroendocrine differentiation by increasing the SNAI1-dependent expression of EMT and neuroendocrine markers, effects that were blocked by knockdown of MCTP1. These data suggest an oncogenic role for MCTP1 in the maintenance of a rare and aggressive prostate cancer subtype through its response to Ca<sup>2+</sup> and suggest its potential as a therapeutic target.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 840","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141307191","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

To B or not to B To B or not to B.

IF 7.3 1区生物学

Science Signaling Pub Date : 2024-06-11 DOI: 10.1126/scisignal.adq9088

Amy E. Baek

引用次数: 0

Growth factor–dependent phosphorylation of Gαi shapes canonical signaling by G protein–coupled receptors 依赖于生长因子的 Gαi 磷酸化决定了 G 蛋白偶联受体的典型信号转导。

IF 7.3 1区生物学

Science Signaling Pub Date : 2024-06-04 DOI: 10.1126/scisignal.ade8041

Suchismita Roy, Saptarshi Sinha, Ananta James Silas, Majid Ghassemian, Irina Kufareva, Pradipta Ghosh

{"title":"Growth factor–dependent phosphorylation of Gαi shapes canonical signaling by G protein–coupled receptors","authors":"Suchismita Roy, Saptarshi Sinha, Ananta James Silas, Majid Ghassemian, Irina Kufareva, Pradipta Ghosh","doi":"10.1126/scisignal.ade8041","DOIUrl":"10.1126/scisignal.ade8041","url":null,"abstract":"<div >A long-standing question in the field of signal transduction is how distinct signaling pathways interact with each other to control cell behavior. Growth factor receptors and G protein–coupled receptors (GPCRs) are the two major signaling hubs in eukaryotes. Given that the mechanisms by which they signal independently have been extensively characterized, we investigated how they may cross-talk with each other. Using linear ion trap mass spectrometry and cell-based biophysical, biochemical, and phenotypic assays, we found at least three distinct ways in which epidermal growth factor affected canonical G protein signaling by the G<sub>i</sub>-coupled GPCR CXCR4 through the phosphorylation of Gα<sub>i</sub>. Phosphomimicking mutations in two residues in the α<sub>E</sub> helix of Gα<sub>i</sub> (tyrosine-154/tyrosine-155) suppressed agonist-induced Gα<sub>i</sub> activation while promoting constitutive Gβγ signaling. Phosphomimicking mutations in the P loop (serine-44, serine-47, and threonine-48) suppressed G<sub>i</sub> activation entirely, thus completely segregating growth factor and GPCR pathways. As expected, most of the phosphorylation events appeared to affect intrinsic properties of Gα<sub>i</sub> proteins, including conformational stability, nucleotide binding, and the ability to associate with and to release Gβγ. However, one phosphomimicking mutation, targeting the carboxyl-terminal residue tyrosine-320, promoted mislocalization of Gα<sub>i</sub> from the plasma membrane, a previously uncharacterized mechanism of suppressing GPCR signaling through G protein subcellular compartmentalization. Together, these findings elucidate not only how growth factor and chemokine signals cross-talk through the phosphorylation-dependent modulation of Gα<sub>i</sub> but also how such cross-talk may generate signal diversity.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 839","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141249013","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

Bacteria-induced BBB breakdown 细菌诱导的 BBB 崩溃

IF 7.3 1区生物学

Science Signaling Pub Date : 2024-06-04 DOI: 10.1126/scisignal.adq7330

Annalisa M. VanHook

引用次数: 0