Science Signaling最新文献_第9页

DCLK1 induces a pro-tumorigenic phenotype to drive gastric cancer progression DCLK1 诱导促肿瘤表型，推动胃癌进展

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-09-17 DOI: 10.1126/scisignal.abq4888

Shoukat Afshar-Sterle, Annalisa L.E. Carli, Ryan O’Keefe, Janson Tse, Stefanie Fischer, Alexander I. Azimpour, David Baloyan, Lena Elias, Pathum Thilakasiri, Onisha Patel, Fleur M. Ferguson, Moritz F. Eissmann, Ashwini L. Chand, Nathanael S. Gray, Rita Busuttil, Alex Boussioutas, Isabelle S. Lucet, Matthias Ernst, Michael Buchert

{"title":"DCLK1 induces a pro-tumorigenic phenotype to drive gastric cancer progression","authors":"Shoukat Afshar-Sterle, Annalisa L.E. Carli, Ryan O’Keefe, Janson Tse, Stefanie Fischer, Alexander I. Azimpour, David Baloyan, Lena Elias, Pathum Thilakasiri, Onisha Patel, Fleur M. Ferguson, Moritz F. Eissmann, Ashwini L. Chand, Nathanael S. Gray, Rita Busuttil, Alex Boussioutas, Isabelle S. Lucet, Matthias Ernst, Michael Buchert","doi":"10.1126/scisignal.abq4888","DOIUrl":"10.1126/scisignal.abq4888","url":null,"abstract":"<div >Doublecortin-like kinase 1 (DCLK1) is a proposed driver of gastric cancer (GC) that phosphorylates serine and threonine residues. Here, we showed that the kinase activity of DCLK1 orchestrated cancer cell–intrinsic and–extrinsic processes that led to pro-invasive and pro-metastatic reprogramming of GC cells. Inhibition of the kinase activity of DCLK1 reduced the growth of subcutaneous xenograft tumors formed from MKN1 human gastric carcinoma cells in mice and decreased the abundance of the stromal markers α-Sma, vimentin, and collagen. Similar effects were seen in mice with xenograft tumors formed from MKN1 cells expressing a kinase-inactive DCLK1 mutant (MKN1<sup>D511N</sup>). MKN1<sup>D511N</sup> cells also had reduced in vitro migratory potential and stemness compared with control cells. Mice orthotopically grafted with MKN1 cells overexpressing DCLK1 (MKN1<sup>DCLK1</sup>) showed increased invasiveness and had a greater incidence of lung metastases compared with those grafted with control MKN1 cells. Mechanistically, we showed that the chemokine CXCL12 acted downstream of DCLK1 in cultured MKN1 cells and in mice subcutaneously implanted with gastric tumors formed by MKN1<sup>DCLK1</sup> cells. Moreover, inhibition of the kinase activity of DCLK1 or the expression of DCLK1<sup>D511N</sup> reversed the pro-tumorigenic and pro-metastatic phenotype. Together, this study establishes DCLK1 as a broadly acting and potentially targetable promoter of GC.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 854","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245154","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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Suppressing appetite with taurine 用牛磺酸抑制食欲

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-09-17 DOI: 10.1126/scisignal.adt0770

Annalisa M. VanHook

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The role of signaling pathways mediated by the GPCRs CysLTR1/2 in melanocyte proliferation and senescence GPCR CysLTR1/2 介导的信号通路在黑色素细胞增殖和衰老中的作用

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-09-17 DOI: 10.1126/scisignal.adp3967

Thomas Huber, Mizuho Horioka-Duplix, Yuanhuang Chen, Victoria R. Saca, Emilie Ceraudo, Yu Chen, Thomas P. Sakmar

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Aging and age-related disorders, cell by cell 逐个细胞看衰老和老年相关疾病

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-09-10 DOI: 10.1126/scisignal.ads9401

Leslie K. Ferrarelli

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CD98hc promotes drug resistance in extranodal natural killer/T cell lymphoma through tumor cell–derived small extracellular vesicles CD98hc 通过肿瘤细胞衍生的细胞外小泡促进结节外自然杀伤/T 细胞淋巴瘤的耐药性

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-09-10 DOI: 10.1126/scisignal.adf9388

Liming Liao, Ping Yang, Weilong Zhang, Shuyu Yu, Hongmei Jing, Xiaofeng Zheng

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Signal flow in the NMDA receptor–dependent phosphoproteome regulates postsynaptic plasticity for aversive learning 依赖于 NMDA 受体的磷酸蛋白体的信号流调节突触后的可塑性，从而促进厌恶性学习

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-09-10 DOI: 10.1126/scisignal.ado9852

Yasuhiro Funahashi, Rijwan Uddin Ahammad, Xinjian Zhang, Emran Hossen, Masahiro Kawatani, Shinichi Nakamuta, Akira Yoshimi, Minhua Wu, Huanhuan Wang, Mengya Wu, Xu Li, Md Omar Faruk, Md Hasanuzzaman Shohag, You-Hsin Lin, Daisuke Tsuboi, Tomoki Nishioka, Keisuke Kuroda, Mutsuki Amano, Yukihiko Noda, Kiyofumi Yamada, Kenji Sakimura, Taku Nagai, Takayuki Yamashita, Shigeo Uchino, Kozo Kaibuchi

{"title":"Signal flow in the NMDA receptor–dependent phosphoproteome regulates postsynaptic plasticity for aversive learning","authors":"Yasuhiro Funahashi, Rijwan Uddin Ahammad, Xinjian Zhang, Emran Hossen, Masahiro Kawatani, Shinichi Nakamuta, Akira Yoshimi, Minhua Wu, Huanhuan Wang, Mengya Wu, Xu Li, Md Omar Faruk, Md Hasanuzzaman Shohag, You-Hsin Lin, Daisuke Tsuboi, Tomoki Nishioka, Keisuke Kuroda, Mutsuki Amano, Yukihiko Noda, Kiyofumi Yamada, Kenji Sakimura, Taku Nagai, Takayuki Yamashita, Shigeo Uchino, Kozo Kaibuchi","doi":"10.1126/scisignal.ado9852","DOIUrl":"10.1126/scisignal.ado9852","url":null,"abstract":"<div >Structural plasticity of dendritic spines in the nucleus accumbens (NAc) is crucial for learning from aversive experiences. Activation of NMDA receptors (NMDARs) stimulates Ca<sup>2+</sup>-dependent signaling that leads to changes in the actin cytoskeleton, mediated by the Rho family of GTPases, resulting in postsynaptic remodeling essential for learning. We investigated how phosphorylation events downstream of NMDAR activation drive the changes in synaptic morphology that underlie aversive learning. Large-scale phosphoproteomic analyses of protein kinase targets in mouse striatal/accumbal slices revealed that NMDAR activation resulted in the phosphorylation of 194 proteins, including RhoA regulators such as ARHGEF2 and ARHGAP21. Phosphorylation of ARHGEF2 by the Ca<sup>2+</sup>-dependent protein kinase CaMKII enhanced its RhoGEF activity, thereby activating RhoA and its downstream effector Rho-associated kinase (ROCK/Rho-kinase). Further phosphoproteomic analysis identified 221 ROCK targets, including the postsynaptic scaffolding protein SHANK3, which is crucial for its interaction with NMDARs and other postsynaptic scaffolding proteins. ROCK-mediated phosphorylation of SHANK3 in the NAc was essential for spine growth and aversive learning. These findings demonstrate that NMDAR activation initiates a phosphorylation cascade crucial for learning and memory.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 853","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.ado9852","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142165826","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

Turning a negative into a positive 化消极为积极

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-09-03 DOI: 10.1126/scisignal.ads7460

John F. Foley

引用次数: 0

Structural and functional effects of phosphopriming and scaffolding in the kinase GSK-3β 激酶 GSK-3β 中磷酸化和支架的结构和功能效应。

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-09-03 DOI: 10.1126/scisignal.ado0881

Michael D. Enos, Maire Gavagan, Noel Jameson, Jesse G. Zalatan, William I. Weis

{"title":"Structural and functional effects of phosphopriming and scaffolding in the kinase GSK-3β","authors":"Michael D. Enos, Maire Gavagan, Noel Jameson, Jesse G. Zalatan, William I. Weis","doi":"10.1126/scisignal.ado0881","DOIUrl":"10.1126/scisignal.ado0881","url":null,"abstract":"<div >Glycogen synthase kinase 3β (GSK-3β) targets specific signaling pathways in response to distinct upstream signals. We used structural and functional studies to dissect how an upstream phosphorylation step primes the Wnt signaling component β-catenin for phosphorylation by GSK-3β and how scaffolding interactions contribute to this reaction. Our crystal structure of GSK-3β bound to a phosphoprimed β-catenin peptide confirmed the expected binding mode of the phosphoprimed residue adjacent to the catalytic site. An aspartate phosphomimic in the priming site of β-catenin adopted an indistinguishable structure but reacted approximately 1000-fold slower than the native phosphoprimed substrate. This result suggests that substrate positioning alone is not sufficient for catalysis and that native phosphopriming interactions are necessary. We also obtained a structure of GSK-3β with an extended peptide from the scaffold protein Axin that bound with greater affinity than that of previously crystallized Axin fragments. This structure neither revealed additional contacts that produce the higher affinity nor explained how substrate interactions in the GSK-3β active site are modulated by remote Axin binding. Together, our findings suggest that phosphopriming and scaffolding produce small conformational changes or allosteric effects, not captured in the crystal structures, that activate GSK-3β and facilitate β-catenin phosphorylation. These results highlight limitations in our ability to predict catalytic activity from structure and have potential implications for the role of natural phosphomimic mutations in kinase regulation and phosphosite evolution.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 852","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142127159","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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Protecting the liver with PKD1 用 PKD1 保护肝脏。

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-08-27 DOI: 10.1126/scisignal.ads6258

Wei Wong

引用次数: 0

Chemokine-mediated F-actin dynamics, polarity, and migration in B lymphocytes depend on WNK1 signaling 趋化因子介导的 B 淋巴细胞 F-肌动蛋白动力学、极性和迁移依赖于 WNK1 信号传导。

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-08-27 DOI: 10.1126/scisignal.ade1119

Il-Young Hwang, Ji Sung Kim, Kathleen A. Harrison, Chung Park, Chong Shan Shi, John H. Kehrl

{"title":"Chemokine-mediated F-actin dynamics, polarity, and migration in B lymphocytes depend on WNK1 signaling","authors":"Il-Young Hwang, Ji Sung Kim, Kathleen A. Harrison, Chung Park, Chong Shan Shi, John H. Kehrl","doi":"10.1126/scisignal.ade1119","DOIUrl":"10.1126/scisignal.ade1119","url":null,"abstract":"<div >Ligand-engaged chemokine receptors trigger nucleotide exchange in heterotrimeric Gα<sub>i</sub> proteins, which stimulates cytoskeletal reorganization and cell polarity changes. To better understand the signaling events responsible for these cellular changes, we focused on early changes in F-actin dynamics after engagement of the chemokine receptor CXCR5 in murine splenic B cells. Within 10 seconds of exposure to the CXCR5 ligand CXCL13, three-dimensional lamellar-like pseudopods and F-actin–rich ridges appeared. The transient F-actin increase depended on Gα<sub>i2/3</sub> signaling, the PI3K/AKT pathway, ERK activation, phospholipase C activity, and Rac1/2 activation mediated by Dock2 (dedicator of cytokinesis 2). Immunoblot analyses identified the kinase WNK1 (with no lysine kinase 1) as a potential early AKT effector. Treating B cells with specific WNK inhibitors disrupted F-actin dynamics and impaired B cell polarity, motility, and chemotaxis. These changes were mimicked in a murine B cell line by CRISPR-Cas9 gene editing of<i> Wnk1</i>, which also suggested that WNK1 contributed to B cell proliferation. Administration of a single dose of a WNK inhibitor transiently reduced B cell motility and polarity in the lymph nodes of live mice. These results indicate that WNK1 signaling maintains B cell responsiveness to CXCL13 and suggest that pharmacological inhibition of WNK1, which is involved in cancer progression and blood pressure regulation, may affect humoral immunity.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 851","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142082418","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