Science Signaling最新文献

{"title":"Sustained chromosomal passenger complex activity preserves the pluripotency of human embryonic carcinoma cells.","authors":"Takaaki Tsunematsu, Yasuhiro Mouri, Wenhua Shao, Rieko Arakaki, Jan G Ruppert, Kensaku Murano, Naozumi Ishimaru, Daniele Guardavaccaro, Michele Pagano, Yasusei Kudo","doi":"10.1126/scisignal.adg4626","DOIUrl":"10.1126/scisignal.adg4626","url":null,"abstract":"<p><p>Human embryonic carcinoma (hEC) cells are derived from teratocarcinomas, exhibit robust proliferation, have a high differentiation potential, are the malignant counterparts of human embryonic stem cells (hESCs), and are considered hESC-like. The chromosomal passenger complex (CPC), made up of the microtuble binding protein Borealin, the kinase Aurora-B, the CPC-stabilizing inner centromere protein (INCENP), and the inhibitor of apoptosis family member Survivin, regulates cell division and is active exclusively during mitosis in somatic cells. The anaphase-promoting complex/cyclosome and its cofactor Cdh1 (APC/C^Cdh1) is a ubiquitylating complex that catalyzes the degradation of Aurora-B and Borealin in somatic cells but has low activity during interphase in hESCs. Here, we found that Borealin and Aurora-B exhibited sustained stability throughout the cell cycle of hEC cells due to low APC/C^Cdh1 activity. In contrast with somatic cells, CPC activity persisted across the cell cycle of hEC cells because of diminished APC/C^Cdh1 activity. Disrupting the CPC complex by depleting its constituents triggered spontaneous differentiation in hEC cells. As hEC cells differentiated, APC/C^Cdh1 activation curtailed CPC activity. Inactivating the CPC by pharmacologically inhibiting Aurora-B induced hEC cell differentiation by activating the epithelial-to-mesenchymal transition (EMT) program. Hence, APC/C^Cdh1-mediated termination of CPC activity triggered hEC cell differentiation. Collectively, these findings demonstrate a role for the CPC in governing hESC cell fate.</p>","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":"18 874","pages":"eadg4626"},"PeriodicalIF":7.3,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143711915","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}

{"title":"Stem cell health from mom's gut.","authors":"Leslie K Ferrarelli","doi":"10.1126/scisignal.adw6790","DOIUrl":"10.1126/scisignal.adw6790","url":null,"abstract":"<p><p>A bacterium in the maternal gut promotes stem cell activity and long-term gut and brain health in offspring.</p>","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":"18 874","pages":"eadw6790"},"PeriodicalIF":7.3,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143711913","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}

{"title":"Sustained Gα_s signaling mediated by vasopressin type 2 receptors is ligand dependent but endocytosis and β-arrestin independent.","authors":"Larissa B Teixeira, Marie-José Blouin, Christian Le Gouill, Louis-Philippe Picard, Claudio M Costa-Neto, Michel Bouvier, Lucas T Parreiras-E-Silva","doi":"10.1126/scisignal.adf6206","DOIUrl":"10.1126/scisignal.adf6206","url":null,"abstract":"<p><p>The canonical model of G protein-coupled receptor (GPCR) signaling comprises G protein activation at the plasma membrane, followed by receptor phosphorylation and β-arrestin recruitment, which leads to receptor desensitization and endocytosis. However, the activation of some GPCRs results in sustained G protein signaling from intracellular compartments in a manner reportedly dependent on β-arrestin and receptor endocytosis. The vasopressin type 2 receptor (V₂R) can be activated by two structurally similar hormones, arginine vasopressin and oxytocin, both of which stimulate the production of the second messenger cyclic adenosine monophosphate (cAMP). In this study, we showed that sustained V₂R signaling and endosomal Gα_s (stimulatory G protein alpha subunit) translocation could occur without β-arrestin-mediated receptor endocytosis and was primarily controlled by the residence time of the ligand on the receptor. β-Arrestin had opposing effects on sustained signaling: It facilitated receptor internalization into endosomes, where it activated Gα_s, and promoted cAMP production from this compartment. However, β-arrestin-mediated receptor endocytosis also induced ligand dissociation due to the acidic endosomal environment, thereby limiting the signal. Overall, our data suggest that signals originating at the plasma membrane play a dominant role in sustained V₂R signaling stimulated by arginine vasopressin.</p>","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":"18 874","pages":"eadf6206"},"PeriodicalIF":7.3,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143711917","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}

{"title":"Targeting c-MYC and gain-of-function p53 through inhibition or degradation of the kinase LZK suppresses the growth of HNSCC tumors.","authors":"Amy L Funk, Meghri Katerji, Marwa Afifi, Katherine Nyswaner, Carolyn C Woodroofe, Zoe C Edwards, Eric Lindberg, Knickole L Bergman, Nancy R Gough, Maxine R Rubin, Kamila Karpińska, Eleanor W Trotter, Sweta Dash, Amy L Ries, Amy James, Christina M Robinson, Simone Difilippantonio, Baktiar O Karim, Ting-Chia Chang, Li Chen, Xin Xu, James H Doroshow, Ivan Ahel, Anna A Marusiak, Rolf E Swenson, Steven D Cappell, John Brognard","doi":"10.1126/scisignal.ado2857","DOIUrl":"10.1126/scisignal.ado2857","url":null,"abstract":"<p><p>The worldwide annual frequency and lethality of head and neck squamous cell carcinoma (HNSCC) is not improving, and thus, new therapeutic approaches are needed. Approximately 70% of HNSCC cases have either amplification or overexpression of <i>MAP3K13</i>, which encodes the kinase LZK. Here, we found that LZK is a therapeutic target in HNSCC and that small-molecule inhibition of its catalytic function decreased the viability of HNSCC cells with amplified <i>MAP3K13</i>. Inhibition of LZK suppressed tumor growth in <i>MAP3K13</i>-amplified xenografts derived from HNSCC patients. LZK stabilized the transcription factor c-MYC through its kinase activity and gain-of-function mutants of p53 in a kinase-independent manner. We designed a proteolysis-targeting chimera (PROTAC) that induced LZK degradation, leading to decreased abundance of both c-MYC and gain-of-function p53, and reduced the viability of HNSCC cells. Our findings demonstrate that LZK-targeted therapeutics, particularly PROTACs, may be effective in treating HNSCCs with <i>MAP3K13</i> amplification.</p>","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":"18 873","pages":"eado2857"},"PeriodicalIF":7.3,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11912006/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143400493","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}

{"title":"Seeing new partners for GPCRs.","authors":"John F Foley","doi":"10.1126/scisignal.adw5249","DOIUrl":"10.1126/scisignal.adw5249","url":null,"abstract":"<p><p>A proximity assay identifies putative interactors and regulators of endogenous GPCRs in cell membranes.</p>","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":"18 873","pages":"eadw5249"},"PeriodicalIF":7.3,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143400490","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}

{"title":"G protein peptidomimetics reveal allosteric effects and stepwise interactions in ghrelin receptor-G protein coupling.","authors":"Morgane Mannes, Charlotte Martin, Marjorie Damian, Sonia Cantel, Hélène Orcel, Jean-Alain Fehrentz, Bernard Mouillac, Julie Kniazeff, Jean-Louis Banères, Steven Ballet","doi":"10.1126/scisignal.ado7692","DOIUrl":"10.1126/scisignal.ado7692","url":null,"abstract":"<p><p>G protein-coupled receptor (GPCR) signaling is a dynamic process involving various conformational intermediates in addition to those captured in static three-dimensional structures. Here, we used newly developed G protein peptidomimetics to characterize the interactions of the ghrelin receptor (GHSR) with G proteins. Coupling to the G protein peptidomimetic not only affected the conformational features of the cytoplasmic regions of the receptor where the G protein binds but also allosterically affected the extracellular ligand-binding pocket. These conformational and allosteric changes increased the affinity of G protein-coupled GHSR for the endogenous agonist ghrelin. In addition, our data identified different complexes along the G protein activation pathway that differed in the engagement of the Gα_q C-terminal helix. Given that this helix is the main link between the activated receptor and the Gα nucleotide-binding pocket, these findings suggested a stepwise process involving distinct states in GPCR-catalyzed G protein activation. Collectively, our results provide evidence for the dynamic behavior of GPCR-G protein signaling complexes, with such dynamics most likely contributing to signaling selectivity and/or efficacy.</p>","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":"18 872","pages":"eado7692"},"PeriodicalIF":7.3,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143190882","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}

{"title":"Rebuilding duct work from the gallbladder.","authors":"Wei Wong","doi":"10.1126/scisignal.adw3651","DOIUrl":"10.1126/scisignal.adw3651","url":null,"abstract":"<p><p>Smooth muscle cells from the gallbladder induce retinoic acid signaling to promote repair of intrahepatic biliary ducts.</p>","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":"18 872","pages":"eadw3651"},"PeriodicalIF":7.3,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143191051","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}

{"title":"The biology of addiction.","authors":"Eric J Nestler","doi":"10.1126/scisignal.adq0031","DOIUrl":"10.1126/scisignal.adq0031","url":null,"abstract":"<p><p>The tools of modern genetics and neurobiology have propelled a renaissance of research that has advanced our understanding of the pathophysiology of drug addiction. We know that an individual's risk for addiction is determined by interactions between genetics and environment and that only a minute fraction of chemical agents share the ability to act on this vulnerability to induce a state of addiction. Repeated exposure to these drugs causes addiction through repeated activation of dopaminergic transmission (and many other actions) in the brain, inducing changes at the molecular, cellular, and synaptic levels that, over time, rewire the circuitry throughout the limbic system. In this Review, I discuss how we are gaining a clearer picture of this drug-induced plasticity-some of which is shared by all addictive drugs, whereas other aspects are specific to certain drug classes-and of the ways in which these adaptations mediate the range of behavioral abnormalities that define the addicted state. Despite the challenges, there is reason for optimism in translating this rich biological understanding of addiction into improved treatments for the many individuals burdened by this illness around the world.</p>","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":"18 872","pages":"eadq0031"},"PeriodicalIF":7.3,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143191053","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}

{"title":"Inhibition of the lysine demethylase LSD1 modulates the balance between inflammatory and antiviral responses against coronaviruses.","authors":"Luca Mazzarella, Fabio Santoro, Roberto Ravasio, Valeria Fumagalli, Paul E Massa, Simona Rodighiero, Elena Gavilán, Mauro Romanenghi, Bruno A Duso, Emanuele Bonetti, Lara Manganaro, Rani Pallavi, Deborah Trastulli, Isabella Pallavicini, Claudia Gentile, Silvia Monzani, Tommaso Leonardi, Sebastiano Pasqualato, Gabriele Buttinelli, Angela Di Martino, Giorgio Fedele, Ilaria Schiavoni, Paola Stefanelli, Giuseppe Meroni, Raffaele de Francesco, Christian Steinkuhler, Gianluca Fossati, Matteo Iannacone, Saverio Minucci, Pier Giuseppe Pelicci","doi":"10.1126/scisignal.ade0326","DOIUrl":"10.1126/scisignal.ade0326","url":null,"abstract":"<p><p>Innate immune responses to coronavirus infections are highly cell specific. Tissue-resident macrophages, which are infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients but are inconsistently infected in vitro, exert critical but conflicting effects by secreting both antiviral type I interferons (IFNs) and tissue-damaging inflammatory cytokines. Steroids, the only class of host-targeting drugs approved for the treatment of coronavirus disease 2019 (COVID-19), indiscriminately suppress both responses, possibly impairing viral clearance. Here, we established in vitro cell culture systems that enabled us to separately investigate the cell-intrinsic and cell-extrinsic proinflammatory and antiviral activities of mouse macrophages infected with the prototypical murine coronavirus MHV-A59. We showed that the nuclear factor κB-dependent inflammatory response to viral infection was selectively inhibited by loss of the lysine demethylase LSD1, which was previously implicated in innate immune responses to cancer, with negligible effects on the antiviral IFN response. LSD1 ablation also enhanced an IFN-independent antiviral response, blocking viral egress through the lysosomal pathway. The macrophage-intrinsic antiviral and anti-inflammatory activity of Lsd1 inhibition was confirmed in vitro and in a humanized mouse model of SARS-CoV-2 infection. These results suggest that LSD1 controls innate immune responses against coronaviruses at multiple levels and provide a mechanistic rationale for potentially repurposing LSD1 inhibitors for COVID-19 treatment.</p>","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":"16 816","pages":"eade0326"},"PeriodicalIF":7.3,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138812462","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}

{"title":"RHOA^L57V drives the development of diffuse gastric cancer through IGF1R-PAK1-YAP1 signaling.","authors":"Antje Schaefer, Richard G Hodge, Haisheng Zhang, G Aaron Hobbs, Julien Dilly, Minh V Huynh, Craig M Goodwin, Feifei Zhang, J Nathaniel Diehl, Mariaelena Pierobon, Elisa Baldelli, Sehrish Javaid, Karson Guthrie, Naim U Rashid, Emanuel F Petricoin, Adrienne D Cox, William C Hahn, Andrew J Aguirre, Adam J Bass, Channing J Der","doi":"10.1126/scisignal.adg5289","DOIUrl":"10.1126/scisignal.adg5289","url":null,"abstract":"<p><p>Cancer-associated mutations in the guanosine triphosphatase (GTPase) RHOA are found at different locations from the mutational hotspots in the structurally and biochemically related RAS. Tyr⁴²-to-Cys (Y42C) and Leu⁵⁷-to-Val (L57V) substitutions are the two most prevalent RHOA mutations in diffuse gastric cancer (DGC). RHOA^Y42C exhibits a gain-of-function phenotype and is an oncogenic driver in DGC. Here, we determined how RHOA^L57V promotes DGC growth. In mouse gastric organoids with deletion of <i>Cdh1</i>, which encodes the cell adhesion protein E-cadherin, the expression of RHOA^L57V, but not of wild-type RHOA, induced an abnormal morphology similar to that of patient-derived DGC organoids. RHOA^L57V also exhibited a gain-of-function phenotype and promoted F-actin stress fiber formation and cell migration. RHOA^L57V retained interaction with effectors but exhibited impaired RHOA-intrinsic and GAP-catalyzed GTP hydrolysis, which favored formation of the active GTP-bound state. Introduction of missense mutations at KRAS residues analogous to Tyr⁴² and Leu⁵⁷ in RHOA did not activate KRAS oncogenic potential, indicating distinct functional effects in otherwise highly related GTPases. Both RHOA mutants stimulated the transcriptional co-activator YAP1 through actin dynamics to promote DGC progression; however, RHOA^L57V additionally did so by activating the kinases IGF1R and PAK1, distinct from the FAK-mediated mechanism induced by RHOA^Y42C. Our results reveal that RHOA^L57V and RHOA^Y42C drive the development of DGC through distinct biochemical and signaling mechanisms.</p>","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":"16 816","pages":"eadg5289"},"PeriodicalIF":7.3,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10791543/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138812482","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}