Pub Date : 2024-05-28DOI: 10.1126/scisignal.adp3504
Emilio Hirsch, Emanuele Fantastico, Lorenzo Prever, Federico Gulluni
The Hippo pathway blocks epithelial-mesenchymal transition and metastasis in cancer mediated by the transcriptional coactivator YAP. In this issue of Science Signaling, Palamiuc et al. demonstrate that phosphatidylinositol 5-phosphate (PI5P) enhances Hippo pathway activation and that simultaneously the Hippo pathway initiates a positive feedback loop by inhibiting the conversion of PI5P into PIP2.
{"title":"A connection between phosphatidylinositol 5-phosphate and the Hippo pathway to prevent epithelial-mesenchymal transition in cancer","authors":"Emilio Hirsch, Emanuele Fantastico, Lorenzo Prever, Federico Gulluni","doi":"10.1126/scisignal.adp3504","DOIUrl":"10.1126/scisignal.adp3504","url":null,"abstract":"<div >The Hippo pathway blocks epithelial-mesenchymal transition and metastasis in cancer mediated by the transcriptional coactivator YAP. In this issue of <i>Science Signaling</i>, Palamiuc <i>et al.</i> demonstrate that phosphatidylinositol 5-phosphate (PI5P) enhances Hippo pathway activation and that simultaneously the Hippo pathway initiates a positive feedback loop by inhibiting the conversion of PI5P into PIP<sub>2</sub>.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141162370","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}
Pub Date : 2024-05-21DOI: 10.1126/scisignal.adq4734
John F. Foley
Antibody fragments can act as pharmacological tools to modulate the functions of G protein–coupled receptors.
抗体片段可以作为药理工具，调节 G 蛋白偶联受体的功能。
{"title":"Nanobody pharmacology","authors":"John F. Foley","doi":"10.1126/scisignal.adq4734","DOIUrl":"10.1126/scisignal.adq4734","url":null,"abstract":"<div >Antibody fragments can act as pharmacological tools to modulate the functions of G protein–coupled receptors.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141077196","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}
Pub Date : 2024-05-21DOI: 10.1126/scisignal.adi9844
Renee Cusic, James M. Burke
Oligoadenylate synthetase 3 (OAS3) and ribonuclease L (RNase L) are components of a pathway that combats viral infection in mammals. Upon detection of viral double-stranded RNA (dsRNA), OAS3 synthesizes 2′-5′-oligo(A), which activates the RNase domain of RNase L by promoting the homodimerization and oligomerization of RNase L monomers. Activated RNase L rapidly degrades all cellular mRNAs, shutting off several cellular processes. We sought to understand the molecular mechanisms underlying the rapid activation of RNase L in response to viral infection. Through superresolution microscopy and live-cell imaging, we showed that OAS3 and RNase L concentrated into higher-order cytoplasmic complexes known as dsRNA-induced foci (dRIF) in response to dsRNA or infection with dengue virus, Zika virus, or West Nile virus. The concentration of OAS3 and RNase L at dRIF corresponded with the activation of RNase L–mediated RNA decay. We showed that dimerized/oligomerized RNase L concentrated in a liquid-like shell surrounding a core OAS3-dRIF structure and dynamically exchanged with the cytosol. These data establish that the condensation of dsRNA, OAS3, and RNase L into dRIF is a molecular switch that promotes the rapid activation of RNase L upon detection of dsRNA in mammalian cells.
寡聚腺苷酸合成酶 3（OAS3）和核糖核酸酶 L（RNase L）是哺乳动物体内抗病毒感染途径的组成部分。检测到病毒双链 RNA（dsRNA）后，OAS3 合成 2'-5'-醇基（A），通过促进 RNase L 单体的同源二聚化和寡聚化来激活 RNase L 的 RNase 结构域。活化的 RNase L 会迅速降解所有细胞 mRNA，从而关闭多个细胞过程。我们试图了解病毒感染时 RNase L 快速激活的分子机制。通过超分辨率显微镜和活细胞成像，我们发现在dsRNA或感染登革热病毒、寨卡病毒或西尼罗河病毒时，OAS3和RNase L会聚集成高阶细胞质复合物，即dsRNA诱导灶（dsRIF）。在 dRIF 中，OAS3 和 RNase L 的浓度与 RNase L 介导的 RNA 衰变的激活程度相对应。我们发现，二聚化/异构化的 RNase L 聚集在围绕核心 OAS3-dRIF 结构的液态外壳中，并与细胞质发生动态交换。这些数据证实，dsRNA、OAS3 和 RNase L 缩聚成 dRIF 是一种分子开关，可在哺乳动物细胞检测到 dsRNA 时促进 RNase L 的快速激活。
{"title":"Condensation of RNase L promotes its rapid activation in response to viral infection in mammalian cells","authors":"Renee Cusic, James M. Burke","doi":"10.1126/scisignal.adi9844","DOIUrl":"10.1126/scisignal.adi9844","url":null,"abstract":"<div >Oligoadenylate synthetase 3 (OAS3) and ribonuclease L (RNase L) are components of a pathway that combats viral infection in mammals. Upon detection of viral double-stranded RNA (dsRNA), OAS3 synthesizes 2′-5′-oligo(A), which activates the RNase domain of RNase L by promoting the homodimerization and oligomerization of RNase L monomers. Activated RNase L rapidly degrades all cellular mRNAs, shutting off several cellular processes. We sought to understand the molecular mechanisms underlying the rapid activation of RNase L in response to viral infection. Through superresolution microscopy and live-cell imaging, we showed that OAS3 and RNase L concentrated into higher-order cytoplasmic complexes known as dsRNA-induced foci (dRIF) in response to dsRNA or infection with dengue virus, Zika virus, or West Nile virus. The concentration of OAS3 and RNase L at dRIF corresponded with the activation of RNase L–mediated RNA decay. We showed that dimerized/oligomerized RNase L concentrated in a liquid-like shell surrounding a core OAS3-dRIF structure and dynamically exchanged with the cytosol. These data establish that the condensation of dsRNA, OAS3, and RNase L into dRIF is a molecular switch that promotes the rapid activation of RNase L upon detection of dsRNA in mammalian cells.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141077195","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}
Pub Date : 2024-05-14DOI: 10.1126/scisignal.adq3321
Wei Wong
Activation of GPR81 in white adipose tissue by lactate results in cancer-associated cachexia.
乳酸激活白色脂肪组织中的 GPR81 会导致癌症相关恶病质。
{"title":"The lactate wasteland","authors":"Wei Wong","doi":"10.1126/scisignal.adq3321","DOIUrl":"10.1126/scisignal.adq3321","url":null,"abstract":"<div >Activation of GPR81 in white adipose tissue by lactate results in cancer-associated cachexia.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140923670","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}
Pub Date : 2024-05-14DOI: 10.1126/scisignal.add5073
Haibo Zhang, Abigail Read, Christophe Cataisson, Howard H. Yang, Wei-Chun Lee, Benjamin E. Turk, Stuart H. Yuspa, Ji Luo
The Ras–mitogen-activated protein kinase (MAPK) pathway is a major target for cancer treatment. To better understand the genetic pathways that modulate cancer cell sensitivity to MAPK pathway inhibitors, we performed a CRISPR knockout screen with MAPK pathway inhibitors on a colorectal cancer (CRC) cell line carrying mutant KRAS. Genetic deletion of the catalytic subunit of protein phosphatase 6 (PP6), encoded by PPP6C, rendered KRAS- and BRAF-mutant CRC and BRAF-mutant melanoma cells more resistant to these inhibitors. In the absence of MAPK pathway inhibition, PPP6C deletion in CRC cells decreased cell proliferation in two-dimensional (2D) adherent cultures but accelerated the growth of tumor spheroids in 3D culture and tumor xenografts in vivo. PPP6C deletion enhanced the activation of nuclear factor κB (NF-κB) signaling in CRC and melanoma cells and circumvented the cell cycle arrest and decreased cyclin D1 abundance induced by MAPK pathway blockade in CRC cells. Inhibiting NF-κB activity by genetic and pharmacological means restored the sensitivity of PPP6C-deficient cells to MAPK pathway inhibition in CRC and melanoma cells in vitro and in CRC cells in vivo. Furthermore, a R264 point mutation in PPP6C conferred loss of function in CRC cells, phenocopying the enhanced NF-κB activation and resistance to MAPK pathway inhibition observed for PPP6C deletion. These findings demonstrate that PP6 constrains the growth of KRAS- and BRAF-mutant cancer cells, implicates the PP6–NF-κB axis as a modulator of MAPK pathway output, and presents a rationale for cotargeting the NF-κB pathway in PPP6C-mutant cancer cells.
{"title":"Protein phosphatase 6 activates NF-κB to confer sensitivity to MAPK pathway inhibitors in KRAS- and BRAF-mutant cancer cells","authors":"Haibo Zhang, Abigail Read, Christophe Cataisson, Howard H. Yang, Wei-Chun Lee, Benjamin E. Turk, Stuart H. Yuspa, Ji Luo","doi":"10.1126/scisignal.add5073","DOIUrl":"10.1126/scisignal.add5073","url":null,"abstract":"<div >The Ras–mitogen-activated protein kinase (MAPK) pathway is a major target for cancer treatment. To better understand the genetic pathways that modulate cancer cell sensitivity to MAPK pathway inhibitors, we performed a CRISPR knockout screen with MAPK pathway inhibitors on a colorectal cancer (CRC) cell line carrying mutant KRAS. Genetic deletion of the catalytic subunit of protein phosphatase 6 (PP6), encoded by <i>PPP6C</i>, rendered <i>KRAS</i>- and <i>BRAF</i>-mutant CRC and <i>BRAF</i>-mutant melanoma cells more resistant to these inhibitors. In the absence of MAPK pathway inhibition, <i>PPP6C</i> deletion in CRC cells decreased cell proliferation in two-dimensional (2D) adherent cultures but accelerated the growth of tumor spheroids in 3D culture and tumor xenografts in vivo. <i>PPP6C</i> deletion enhanced the activation of nuclear factor κB (NF-κB) signaling in CRC and melanoma cells and circumvented the cell cycle arrest and decreased cyclin D1 abundance induced by MAPK pathway blockade in CRC cells. Inhibiting NF-κB activity by genetic and pharmacological means restored the sensitivity of <i>PPP6C</i>-deficient cells to MAPK pathway inhibition in CRC and melanoma cells in vitro and in CRC cells in vivo. Furthermore, a R264 point mutation in PPP6C conferred loss of function in CRC cells, phenocopying the enhanced NF-κB activation and resistance to MAPK pathway inhibition observed for <i>PPP6C</i> deletion. These findings demonstrate that PP6 constrains the growth of <i>KRAS</i>- and <i>BRAF</i>-mutant cancer cells, implicates the PP6–NF-κB axis as a modulator of MAPK pathway output, and presents a rationale for cotargeting the NF-κB pathway in <i>PPP6C</i>-mutant cancer cells.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140923669","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}
Pub Date : 2024-05-07DOI: 10.1126/scisignal.adq1964
Amy E. Baek
Prostaglandins in the tumor microenvironment block IL-2–induced expansion of killer T cells.
肿瘤微环境中的前列腺素会阻碍 IL-2 诱导的杀伤性 T 细胞扩增。
{"title":"Cleanup on IL-2","authors":"Amy E. Baek","doi":"10.1126/scisignal.adq1964","DOIUrl":"10.1126/scisignal.adq1964","url":null,"abstract":"<div >Prostaglandins in the tumor microenvironment block IL-2–induced expansion of killer T cells.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140877812","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}
Pub Date : 2024-05-07DOI: 10.1126/scisignal.adj0032
Sharof Khudayberdiev, Kerstin Weiss, Anika Heinze, Dalila Colombaretti, Nathan Trausch, Uwe Linne, Marco B. Rust
Serum response factor (SRF) is an essential transcription factor for brain development and function. Here, we explored how an SRF cofactor, the actin monomer-sensing myocardin-related transcription factor MRTF, is regulated in mouse cortical neurons. We found that MRTF-dependent SRF activity in vitro and in vivo was repressed by cyclase-associated protein CAP1. Inactivation of the actin-binding protein CAP1 reduced the amount of actin monomers in the cytoplasm, which promoted nuclear MRTF translocation and MRTF-SRF activation. This function was independent of cofilin1 and actin-depolymerizing factor, and CAP1 loss of function in cortical neurons was not compensated by endogenous CAP2. Transcriptomic and proteomic analyses of cerebral cortex lysates from wild-type and Cap1 knockout mice supported the role of CAP1 in repressing MRTF-SRF–dependent signaling in vivo. Bioinformatic analysis identified likely MRTF-SRF target genes, which aligned with the transcriptomic and proteomic results. Together with our previous studies that implicated CAP1 in axonal growth cone function as well as the morphology and plasticity of excitatory synapses, our findings establish CAP1 as a crucial actin regulator in the brain relevant for formation of neuronal networks.
{"title":"The actin-binding protein CAP1 represses MRTF-SRF–dependent gene expression in mouse cerebral cortex","authors":"Sharof Khudayberdiev, Kerstin Weiss, Anika Heinze, Dalila Colombaretti, Nathan Trausch, Uwe Linne, Marco B. Rust","doi":"10.1126/scisignal.adj0032","DOIUrl":"10.1126/scisignal.adj0032","url":null,"abstract":"<div >Serum response factor (SRF) is an essential transcription factor for brain development and function. Here, we explored how an SRF cofactor, the actin monomer-sensing myocardin-related transcription factor MRTF, is regulated in mouse cortical neurons. We found that MRTF-dependent SRF activity in vitro and in vivo was repressed by cyclase-associated protein CAP1. Inactivation of the actin-binding protein CAP1 reduced the amount of actin monomers in the cytoplasm, which promoted nuclear MRTF translocation and MRTF-SRF activation. This function was independent of cofilin1 and actin-depolymerizing factor, and CAP1 loss of function in cortical neurons was not compensated by endogenous CAP2. Transcriptomic and proteomic analyses of cerebral cortex lysates from wild-type and <i>Cap1</i> knockout mice supported the role of CAP1 in repressing MRTF-SRF–dependent signaling in vivo. Bioinformatic analysis identified likely MRTF-SRF target genes, which aligned with the transcriptomic and proteomic results. Together with our previous studies that implicated CAP1 in axonal growth cone function as well as the morphology and plasticity of excitatory synapses, our findings establish CAP1 as a crucial actin regulator in the brain relevant for formation of neuronal networks.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.adj0032","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140877813","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}
Pub Date : 2024-04-30DOI: 10.1126/scisignal.adn4556
Xin Shi, Xiao-zhong Zhou, Gang Chen, Wei-feng Luo, Chengyu Zhou, Tian-ju He, Mandar T. Naik, Qin Jiang, John Marshall, Cong Cao
Signaling mediated by brain-derived neurotrophic factor (BDNF), which is supported by the postsynaptic scaffolding protein PSD-95, has antidepressant effects. Conversely, clinical depression is associated with reduced BDNF signaling. We found that peptidomimetic compounds that bind to PSD-95 promoted signaling by the BDNF receptor TrkB in the hippocampus and reduced depression-like behaviors in mice. The compounds CN2097 and Syn3 both bind to the PDZ3 domain of PSD-95, and Syn3 also binds to an α-helical region of the protein. Syn3 reduced depression-like behaviors in two mouse models of stress-induced depression; CN2097 had similar but less potent effects. In hippocampal neurons, application of Syn3 enhanced the formation of TrkB–Gαi1/3–PSD-95 complexes and potentiated downstream PI3K-Akt-mTOR signaling. In mice subjected to chronic mild stress (CMS), systemic administration of Syn3 reversed the CMS-induced, depression-associated changes in PI3K-Akt-mTOR signaling, dendrite complexity, spine density, and autophagy in the hippocampus and reduced depression-like behaviors. Knocking out Gαi1/3 in hippocampal neurons prevented the therapeutic effects of Syn3, indicating dependence of these effects on the TrkB pathway. The findings suggest that compounds that induce the formation of PSD-95–TrkB complexes have therapeutic potential to alleviate depression.
{"title":"Targeting the postsynaptic scaffolding protein PSD-95 enhances BDNF signaling to mitigate depression-like behaviors in mice","authors":"Xin Shi, Xiao-zhong Zhou, Gang Chen, Wei-feng Luo, Chengyu Zhou, Tian-ju He, Mandar T. Naik, Qin Jiang, John Marshall, Cong Cao","doi":"10.1126/scisignal.adn4556","DOIUrl":"10.1126/scisignal.adn4556","url":null,"abstract":"<div >Signaling mediated by brain-derived neurotrophic factor (BDNF), which is supported by the postsynaptic scaffolding protein PSD-95, has antidepressant effects. Conversely, clinical depression is associated with reduced BDNF signaling. We found that peptidomimetic compounds that bind to PSD-95 promoted signaling by the BDNF receptor TrkB in the hippocampus and reduced depression-like behaviors in mice. The compounds CN2097 and Syn3 both bind to the PDZ3 domain of PSD-95, and Syn3 also binds to an α-helical region of the protein. Syn3 reduced depression-like behaviors in two mouse models of stress-induced depression; CN2097 had similar but less potent effects. In hippocampal neurons, application of Syn3 enhanced the formation of TrkB–Gα<sub>i1/3</sub>–PSD-95 complexes and potentiated downstream PI3K-Akt-mTOR signaling. In mice subjected to chronic mild stress (CMS), systemic administration of Syn3 reversed the CMS-induced, depression-associated changes in PI3K-Akt-mTOR signaling, dendrite complexity, spine density, and autophagy in the hippocampus and reduced depression-like behaviors. Knocking out Gα<sub>i1/3</sub> in hippocampal neurons prevented the therapeutic effects of Syn3, indicating dependence of these effects on the TrkB pathway. The findings suggest that compounds that induce the formation of PSD-95–TrkB complexes have therapeutic potential to alleviate depression.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140819107","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}
Pub Date : 2024-04-30DOI: 10.1126/scisignal.adq0353
Annalisa M. VanHook
Displacement of the glycocalyx by membrane blebbing enables macrophages to recognize apoptotic cells.
膜裂解导致糖萼移位，使巨噬细胞能够识别凋亡细胞。
{"title":"Nude blebs expose cells to phagocytes","authors":"Annalisa M. VanHook","doi":"10.1126/scisignal.adq0353","DOIUrl":"10.1126/scisignal.adq0353","url":null,"abstract":"<div >Displacement of the glycocalyx by membrane blebbing enables macrophages to recognize apoptotic cells.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140819080","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}
Pub Date : 2024-04-30DOI: 10.1126/scisignal.adj6603
Jens Stepan, Daniel E. Heinz, Frederik Dethloff, Svenja Wiechmann, Silvia Martinelli, Kathrin Hafner, Tim Ebert, Ellen Junglas, Alexander S. Häusl, Max L. Pöhlmann, Mira Jakovcevski, Julius C. Pape, Anthony S. Zannas, Thomas Bajaj, Anke Hermann, Xiao Ma, Hermann Pavenstädt, Mathias V. Schmidt, Alexandra Philipsen, Christoph W. Turck, Jan M. Deussing, Gerhard Rammes, Andrew C. Robinson, Antony Payton, Michael C. Wehr, Valentin Stein, Christopher Murgatroyd, Joachim Kremerskothen, Bernhard Kuster, Carsten T. Wotjak, Nils C. Gassen
The localization, number, and function of postsynaptic AMPA-type glutamate receptors (AMPARs) are crucial for synaptic plasticity, a cellular correlate for learning and memory. The Hippo pathway member WWC1 is an important component of AMPAR-containing protein complexes. However, the availability of WWC1 is constrained by its interaction with the Hippo pathway kinases LATS1 and LATS2 (LATS1/2). Here, we explored the biochemical regulation of this interaction and found that it is pharmacologically targetable in vivo. In primary hippocampal neurons, phosphorylation of LATS1/2 by the upstream kinases MST1 and MST2 (MST1/2) enhanced the interaction between WWC1 and LATS1/2, which sequestered WWC1. Pharmacologically inhibiting MST1/2 in male mice and in human brain-derived organoids promoted the dissociation of WWC1 from LATS1/2, leading to an increase in WWC1 in AMPAR-containing complexes. MST1/2 inhibition enhanced synaptic transmission in mouse hippocampal brain slices and improved cognition in healthy male mice and in male mouse models of Alzheimer’s disease and aging. Thus, compounds that disrupt the interaction between WWC1 and LATS1/2 might be explored for development as cognitive enhancers.
{"title":"Inhibiting Hippo pathway kinases releases WWC1 to promote AMPAR-dependent synaptic plasticity and long-term memory in mice","authors":"Jens Stepan, Daniel E. Heinz, Frederik Dethloff, Svenja Wiechmann, Silvia Martinelli, Kathrin Hafner, Tim Ebert, Ellen Junglas, Alexander S. Häusl, Max L. Pöhlmann, Mira Jakovcevski, Julius C. Pape, Anthony S. Zannas, Thomas Bajaj, Anke Hermann, Xiao Ma, Hermann Pavenstädt, Mathias V. Schmidt, Alexandra Philipsen, Christoph W. Turck, Jan M. Deussing, Gerhard Rammes, Andrew C. Robinson, Antony Payton, Michael C. Wehr, Valentin Stein, Christopher Murgatroyd, Joachim Kremerskothen, Bernhard Kuster, Carsten T. Wotjak, Nils C. Gassen","doi":"10.1126/scisignal.adj6603","DOIUrl":"10.1126/scisignal.adj6603","url":null,"abstract":"<div >The localization, number, and function of postsynaptic AMPA-type glutamate receptors (AMPARs) are crucial for synaptic plasticity, a cellular correlate for learning and memory. The Hippo pathway member WWC1 is an important component of AMPAR-containing protein complexes. However, the availability of WWC1 is constrained by its interaction with the Hippo pathway kinases LATS1 and LATS2 (LATS1/2). Here, we explored the biochemical regulation of this interaction and found that it is pharmacologically targetable in vivo. In primary hippocampal neurons, phosphorylation of LATS1/2 by the upstream kinases MST1 and MST2 (MST1/2) enhanced the interaction between WWC1 and LATS1/2, which sequestered WWC1. Pharmacologically inhibiting MST1/2 in male mice and in human brain-derived organoids promoted the dissociation of WWC1 from LATS1/2, leading to an increase in WWC1 in AMPAR-containing complexes. MST1/2 inhibition enhanced synaptic transmission in mouse hippocampal brain slices and improved cognition in healthy male mice and in male mouse models of Alzheimer’s disease and aging. Thus, compounds that disrupt the interaction between WWC1 and LATS1/2 might be explored for development as cognitive enhancers.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140819112","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}
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