Pub Date : 2025-06-24DOI: 10.1126/scisignal.ads6550
Trayambak Pathak, J. Cory Benson, Martin T. Johnson, Ping Xin, Ahmed Emam Abdelnaby, Vonn Walter, Walter A. Koltun, Gregory S. Yochum, Nadine Hempel, Mohamed Trebak
The large amounts of calcium (Ca2+) stored in the endoplasmic reticulum (ER) and the controlled release of this Ca2+ store into the cytosol regulate many cellular functions, and altered ER Ca2+ homeostasis induces ER stress. Stromal-interacting molecules 1 and 2 (STIM1/2) are homologous ER-resident Ca2+ sensors that synergistically activate cytosolic Ca2+ influx through Orai channels to promote Ca2+-dependent changes in gene expression and ER Ca2+ refilling. Here, we demonstrated that reduced abundance of STIM2, but not that of STIM1, was associated with poor prognosis in colorectal cancer (CRC). STIM2-deficient CRC cells showed enhanced ER Ca2+ content in a manner dependent on the ER Ca2+ pump SERCA2, increased expression of genes associated with protein translation, and transcriptional and metabolic rewiring. STIM2 deficiency in CRC xenografts led to increased tumor size, invasion, and metastasis. STIM2 loss activated the expression of genes involved in ER stress responses in a manner dependent on the chaperone BiP and the transcription factor ATF4 and independent of Orai channels. These results suggest that loss of STIM2 may inform CRC prognosis.
{"title":"Loss of STIM2, but not of STIM1, drives colorectal cancer metastasis through metabolic reprogramming and the ATF4 ER stress pathway","authors":"Trayambak Pathak, J. Cory Benson, Martin T. Johnson, Ping Xin, Ahmed Emam Abdelnaby, Vonn Walter, Walter A. Koltun, Gregory S. Yochum, Nadine Hempel, Mohamed Trebak","doi":"10.1126/scisignal.ads6550","DOIUrl":"10.1126/scisignal.ads6550","url":null,"abstract":"<div >The large amounts of calcium (Ca<sup>2+</sup>) stored in the endoplasmic reticulum (ER) and the controlled release of this Ca<sup>2+</sup> store into the cytosol regulate many cellular functions, and altered ER Ca<sup>2+</sup> homeostasis induces ER stress. Stromal-interacting molecules 1 and 2 (STIM1/2) are homologous ER-resident Ca<sup>2+</sup> sensors that synergistically activate cytosolic Ca<sup>2+</sup> influx through Orai channels to promote Ca<sup>2+</sup>-dependent changes in gene expression and ER Ca<sup>2+</sup> refilling. Here, we demonstrated that reduced abundance of STIM2, but not that of STIM1, was associated with poor prognosis in colorectal cancer (CRC). STIM2-deficient CRC cells showed enhanced ER Ca<sup>2+</sup> content in a manner dependent on the ER Ca<sup>2+</sup> pump SERCA2, increased expression of genes associated with protein translation, and transcriptional and metabolic rewiring. STIM2 deficiency in CRC xenografts led to increased tumor size, invasion, and metastasis. STIM2 loss activated the expression of genes involved in ER stress responses in a manner dependent on the chaperone BiP and the transcription factor ATF4 and independent of Orai channels. These results suggest that loss of STIM2 may inform CRC prognosis.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 892","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144482393","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 : 2025-06-24DOI: 10.1126/scisignal.adn2044
Kaushik Chanda, Eddie Grinman, Kaylyn Clark, Abhishek Sadhu, Bindu Raveendra, Supriya Swarnkar, Sathyanarayanan V. Puthanveettil
Changes in the transcriptome are critical in shaping the structural plasticity of neurons, which underpins learning and long-term memory storage. Here, we explored the effect of two opposing, plasticity-associated pathways—cAMP second-messenger signaling and metabotropic glutamate receptor (mGluR1 and mGluR5) signaling—on the transcriptome in hippocampal neurons and how these pathways operate in distinct and coordinated manners to induce structural changes. Integration of transcriptome data and molecular pathway analysis identified central “hub” genes that were rapidly induced by cAMP and/or mGluR1/5 in hippocampal neurons. These included the long noncoding RNA (lncRNA) Gas5, whose expression was induced specifically by cAMP and which was targeted to dendrites by the kinesin motor protein KIF1A. In the dendrites, Gas5 interacted with various proteins and coding and noncoding RNAs associated with synaptic function and plasticity, and these interactions were altered by cAMP signaling. Gas5 interacted with the microRNA miR-26a-5p and sequestered it from several of its mRNA targets associated with neuronal function and whose translation was induced by cAMP. Gas5 was critical for excitatory synaptic transmission induced by cAMP but not those induced by mGluR1/5. Furthermore, Gas5 deficiency impaired dendritic branching and synapse morphology, and Gas5 abundance was decreased in the hippocampus of a mouse model of Alzheimer’s disease. Together, these findings provide insight into the transcriptional networks involved in synaptic plasticity and a lncRNA interactome that mediates dendritically localized regulation of excitatory synaptic transmission and neuronal architecture.
{"title":"The lncRNA Gas5 is an activity-responsive scaffold that mediates cAMP-dependent synaptic plasticity","authors":"Kaushik Chanda, Eddie Grinman, Kaylyn Clark, Abhishek Sadhu, Bindu Raveendra, Supriya Swarnkar, Sathyanarayanan V. Puthanveettil","doi":"10.1126/scisignal.adn2044","DOIUrl":"10.1126/scisignal.adn2044","url":null,"abstract":"<div >Changes in the transcriptome are critical in shaping the structural plasticity of neurons, which underpins learning and long-term memory storage. Here, we explored the effect of two opposing, plasticity-associated pathways—cAMP second-messenger signaling and metabotropic glutamate receptor (mGluR1 and mGluR5) signaling—on the transcriptome in hippocampal neurons and how these pathways operate in distinct and coordinated manners to induce structural changes. Integration of transcriptome data and molecular pathway analysis identified central “hub” genes that were rapidly induced by cAMP and/or mGluR1/5 in hippocampal neurons. These included the long noncoding RNA (lncRNA) Gas5, whose expression was induced specifically by cAMP and which was targeted to dendrites by the kinesin motor protein KIF1A. In the dendrites, Gas5 interacted with various proteins and coding and noncoding RNAs associated with synaptic function and plasticity, and these interactions were altered by cAMP signaling. Gas5 interacted with the microRNA miR-26a-5p and sequestered it from several of its mRNA targets associated with neuronal function and whose translation was induced by cAMP. Gas5 was critical for excitatory synaptic transmission induced by cAMP but not those induced by mGluR1/5. Furthermore, Gas5 deficiency impaired dendritic branching and synapse morphology, and Gas5 abundance was decreased in the hippocampus of a mouse model of Alzheimer’s disease. Together, these findings provide insight into the transcriptional networks involved in synaptic plasticity and a lncRNA interactome that mediates dendritically localized regulation of excitatory synaptic transmission and neuronal architecture.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 892","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.adn2044","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144482396","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 : 2025-06-24DOI: 10.1126/scisignal.adz8643
Annalisa M. VanHook
Glycosaminoglycans enable cancer cells to take up antiferroptotic lipoproteins.
糖胺聚糖能使癌细胞吸收抗铁溶脂蛋白。
{"title":"GAGging cancer cell ferroptosis","authors":"Annalisa M. VanHook","doi":"10.1126/scisignal.adz8643","DOIUrl":"10.1126/scisignal.adz8643","url":null,"abstract":"<div >Glycosaminoglycans enable cancer cells to take up antiferroptotic lipoproteins.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 892","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144482395","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 : 2025-06-17DOI: 10.1126/scisignal.adr9397
Yu-Tao Deng, Longfei Ma, Yixiao Mei, Ji-Shuai Wang, Xue-Hui Bai, Xuan-Jie Zheng, Jin-Xuan Ren, Da Zhong, Bing-Lin Zhou, Jia Dan, Xue Li, Yong-Jing Gao, Lina Yu, Min Yan, Bao-Chun Jiang
The genesis of neuropathic pain after peripheral nerve injury is associated with changes in gene expression and cell metabolism in sensory neurons and the release of inflammatory cytokines. Here, we connected glycolytic metabolism induced by the epidermal growth factor receptor (EGFR) ligand amphiregulin (AREG) to histone lactylation and changes in gene expression that promote chronic neuropathic pain. In both male and female mice subjected to peripheral nerve injury, the mRNA and protein abundance of AREG and its receptor EGFR was increased in dorsal root ganglia (DRGs). AREG-EGFR signaling induced glycolytic metabolism by activating the kinase PKM2. An increase in the glycolytic byproduct lactate facilitated lactylation of the histone lysines H3K18 and H4K12 by the lactyltransferase p300 in DRG neurons. These modifications promoted the expression of genes encoding various proinflammatory and pronociceptive proteins that contribute to the development and maintenance of pain. Deletion or knockdown of AREG or pharmacologically inhibiting EGFR, PKM2, or p300 alleviated neuropathic pain in mice and attenuated the injury-induced hyperexcitability of nociceptive neurons. Targeting this metabolically driven epigenetic mechanism may be a way to treat neuropathic pain in patients.
{"title":"Amphiregulin contributes to neuropathic pain by enhancing glycolysis that stimulates histone lactylation in sensory neurons","authors":"Yu-Tao Deng, Longfei Ma, Yixiao Mei, Ji-Shuai Wang, Xue-Hui Bai, Xuan-Jie Zheng, Jin-Xuan Ren, Da Zhong, Bing-Lin Zhou, Jia Dan, Xue Li, Yong-Jing Gao, Lina Yu, Min Yan, Bao-Chun Jiang","doi":"10.1126/scisignal.adr9397","DOIUrl":"10.1126/scisignal.adr9397","url":null,"abstract":"<div >The genesis of neuropathic pain after peripheral nerve injury is associated with changes in gene expression and cell metabolism in sensory neurons and the release of inflammatory cytokines. Here, we connected glycolytic metabolism induced by the epidermal growth factor receptor (EGFR) ligand amphiregulin (AREG) to histone lactylation and changes in gene expression that promote chronic neuropathic pain. In both male and female mice subjected to peripheral nerve injury, the mRNA and protein abundance of AREG and its receptor EGFR was increased in dorsal root ganglia (DRGs). AREG-EGFR signaling induced glycolytic metabolism by activating the kinase PKM2. An increase in the glycolytic byproduct lactate facilitated lactylation of the histone lysines H3K18 and H4K12 by the lactyltransferase p300 in DRG neurons. These modifications promoted the expression of genes encoding various proinflammatory and pronociceptive proteins that contribute to the development and maintenance of pain. Deletion or knockdown of AREG or pharmacologically inhibiting EGFR, PKM2, or p300 alleviated neuropathic pain in mice and attenuated the injury-induced hyperexcitability of nociceptive neurons. Targeting this metabolically driven epigenetic mechanism may be a way to treat neuropathic pain in patients.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 891","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309181","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 : 2025-06-17DOI: 10.1126/scisignal.adt2678
Julia Christine Gutjahr, Elin Hub, Caroline Amy Anderson, Maryna Samus, Katharina Artinger, Esteban A. Gomez, Christoph Ratswohl, Natalie Wickli, Mandy Raum, Neil Dufton, Jesmond Dalli, Jemima J. Burden, Johan Duchene, Antal Rot
The chemokine CXCL12 signals through its receptor CXCR4 to induce the migration of all leukocyte types and multiple other cell types. Here, we report that CXCR4 is expressed in mouse erythroblasts, the bone marrow erythroid precursors, in which it stimulates erythrocyte generation instead of chemotaxis. CXCR4 signaling promoted homeostatic erythroblast maturation and increased the expression of genes mainly involved in metabolism and chromatin organization. Consequently, genetic depletion of CXCR4 in erythroblasts inhibited late erythropoiesis and diminished bone marrow erythroid outputs. Binding of CXCL12 to CXCR4 stimulated its rapid endocytosis and translocation together with Gαi or phosphorylated β-arrestin1 into distinct intracellular compartments, including the nuclear envelope and nucleus. CXCL12 signaling promoted erythroblast elongation and the condensation and excentric positioning of nuclei and stimulated rapid perinuclear Ca2+ transients that immediately preceded erythroblast enucleation. These findings highlight previously uncharacterized physiological roles for CXCR4 and bone marrow–derived CXCL12 in erythropoiesis.
{"title":"Intracellular and nuclear CXCR4 signaling promotes terminal erythroblast differentiation and enucleation","authors":"Julia Christine Gutjahr, Elin Hub, Caroline Amy Anderson, Maryna Samus, Katharina Artinger, Esteban A. Gomez, Christoph Ratswohl, Natalie Wickli, Mandy Raum, Neil Dufton, Jesmond Dalli, Jemima J. Burden, Johan Duchene, Antal Rot","doi":"10.1126/scisignal.adt2678","DOIUrl":"10.1126/scisignal.adt2678","url":null,"abstract":"<div >The chemokine CXCL12 signals through its receptor CXCR4 to induce the migration of all leukocyte types and multiple other cell types. Here, we report that CXCR4 is expressed in mouse erythroblasts, the bone marrow erythroid precursors, in which it stimulates erythrocyte generation instead of chemotaxis. CXCR4 signaling promoted homeostatic erythroblast maturation and increased the expression of genes mainly involved in metabolism and chromatin organization. Consequently, genetic depletion of CXCR4 in erythroblasts inhibited late erythropoiesis and diminished bone marrow erythroid outputs. Binding of CXCL12 to CXCR4 stimulated its rapid endocytosis and translocation together with Gα<sub>i</sub> or phosphorylated β-arrestin1 into distinct intracellular compartments, including the nuclear envelope and nucleus. CXCL12 signaling promoted erythroblast elongation and the condensation and excentric positioning of nuclei and stimulated rapid perinuclear Ca<sup>2+</sup> transients that immediately preceded erythroblast enucleation. These findings highlight previously uncharacterized physiological roles for CXCR4 and bone marrow–derived CXCL12 in erythropoiesis.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 891","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309182","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 : 2025-06-10DOI: 10.1126/scisignal.adz5144
John F. Foley
The cryo-EM structures of human sweet taste receptors reveal the molecular basis of sweet taste detection.
人类甜味受体的低温电镜结构揭示了甜味检测的分子基础。
{"title":"Sweet structures","authors":"John F. Foley","doi":"10.1126/scisignal.adz5144","DOIUrl":"10.1126/scisignal.adz5144","url":null,"abstract":"<div >The cryo-EM structures of human sweet taste receptors reveal the molecular basis of sweet taste detection.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 890","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144256614","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 : 2025-06-10DOI: 10.1126/scisignal.adt1936
Qinghu Yang, Huan Ma, Liang Yang, Ming Jiang, Xia Liu, Zhantao Bai
Lysosomes are versatile organelles that play pivotal roles in cellular recycling and signal transduction. They are crucial for the autophagic degradation and recycling of macromolecules, which facilitates the efficient turnover of cellular components. Beyond their intracellular roles, lysosomes also regulate the degradation and assembly of extracellular matrix (ECM) constituents, affecting ECM remodeling and the processing of signaling molecules essential for cellular communication and adaptation to the microenvironment. Conversely, the ECM regulates key lysosomal functions, including biogenesis, acidification, and subcellular positioning. In this Review, we discuss the bidirectional interaction between lysosomes and the ECM and explore its implications in the development and treatment of neurodegenerative disease.
{"title":"Decoding extracellular matrix–lysosome cross-talk and its implications for neurodegenerative diseases","authors":"Qinghu Yang, Huan Ma, Liang Yang, Ming Jiang, Xia Liu, Zhantao Bai","doi":"10.1126/scisignal.adt1936","DOIUrl":"10.1126/scisignal.adt1936","url":null,"abstract":"<div >Lysosomes are versatile organelles that play pivotal roles in cellular recycling and signal transduction. They are crucial for the autophagic degradation and recycling of macromolecules, which facilitates the efficient turnover of cellular components. Beyond their intracellular roles, lysosomes also regulate the degradation and assembly of extracellular matrix (ECM) constituents, affecting ECM remodeling and the processing of signaling molecules essential for cellular communication and adaptation to the microenvironment. Conversely, the ECM regulates key lysosomal functions, including biogenesis, acidification, and subcellular positioning. In this Review, we discuss the bidirectional interaction between lysosomes and the ECM and explore its implications in the development and treatment of neurodegenerative disease.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 890","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144256592","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 : 2025-06-10DOI: 10.1126/scisignal.adt4606
Frederick C. Baker, Jacob Harman, Trevor Jordan, Breana Walton, Amber Ajamu-Johnson, Rama F. Alashqar, Simran Bhikot, Gary Struhl, Paul D. Langridge
Notch proteins are single-pass transmembrane receptors activated by sequential extracellular and intramembrane cleavages to release the cytosolic domains that function as transcription factors. Transmembrane ligands of the Delta/Serrate/LAG-2 (DSL) family activate Notch on neighboring cells by exerting a pulling force across the intercellular ligand-receptor bridge. This force is generated by Epsin-mediated endocytosis of the ligand into the signal-sending cell and results in the extracellular cleavage of the force-sensing negative regulatory region (NRR) of the receptor by an ADAM10 protease on the signal-receiving cell. Here, we used chimeric Notch and DSL proteins to screen for other domains that could function as ligand-dependent proteolytic switches in place of the NRR in the developing Drosophila melanogaster wing. The domains that could functionally substitute for the NRR in vivo derived from diverse source proteins, varied in sequence, and had different predicted structures, yet all depended on cleavage that was catalyzed by the Drosophila ADAM10 homolog Kuzbanian (Kuz) and stimulated by Epsin-mediated ligand endocytosis. The large sequence space of protein domains that can serve as force-sensing proteolytic switches suggests a widespread potential role for force-dependent, ADAM10-mediated proteolysis in other cell contact–dependent signaling mechanisms.
{"title":"An in vivo screen identifies diverse domains that can act as force-dependent proteolytic switches for Notch activation","authors":"Frederick C. Baker, Jacob Harman, Trevor Jordan, Breana Walton, Amber Ajamu-Johnson, Rama F. Alashqar, Simran Bhikot, Gary Struhl, Paul D. Langridge","doi":"10.1126/scisignal.adt4606","DOIUrl":"10.1126/scisignal.adt4606","url":null,"abstract":"<div >Notch proteins are single-pass transmembrane receptors activated by sequential extracellular and intramembrane cleavages to release the cytosolic domains that function as transcription factors. Transmembrane ligands of the Delta/Serrate/LAG-2 (DSL) family activate Notch on neighboring cells by exerting a pulling force across the intercellular ligand-receptor bridge. This force is generated by Epsin-mediated endocytosis of the ligand into the signal-sending cell and results in the extracellular cleavage of the force-sensing negative regulatory region (NRR) of the receptor by an ADAM10 protease on the signal-receiving cell. Here, we used chimeric Notch and DSL proteins to screen for other domains that could function as ligand-dependent proteolytic switches in place of the NRR in the developing <i>Drosophila melanogaster</i> wing. The domains that could functionally substitute for the NRR in vivo derived from diverse source proteins, varied in sequence, and had different predicted structures, yet all depended on cleavage that was catalyzed by the <i>Drosophila</i> ADAM10 homolog Kuzbanian (Kuz) and stimulated by Epsin-mediated ligand endocytosis. The large sequence space of protein domains that can serve as force-sensing proteolytic switches suggests a widespread potential role for force-dependent, ADAM10-mediated proteolysis in other cell contact–dependent signaling mechanisms.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 890","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.adt4606","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144256613","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 : 2025-06-03DOI: 10.1126/scisignal.adv4579
Zejiao Li, Fengwei Gao, Xuesha Liu, Shijie Fan, Yucheng Qi, Mingzhu He, Xiushuang Luo, Xiaoyun Nie, Jia Wang, Yajun Wang, Zhi-Xiong Jim Xiao, Chenghua Li
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor and frequently has mutations in the transcription factor p53. TAp63α is a member of the p53 protein family that is generally tumor suppressive in various other p53-mutant or p53-deficient cancers. Here, we found that TAp63α inhibited cell proliferation, epithelial-mesenchymal transition (EMT), and migration in several p53-mutant PDAC cell lines. TAp63α transcriptionally repressed IL20RB (which encodes a subunit of the interleukin-20 receptor), potentially by inducing the methylation of its promoter. However, mutations in p53 or KRAS that are common in PDAC increased the abundance of the E3 ligase TRIM21, which promoted the ubiquitin-dependent degradation of TAp63α. Thus, the degradation of TAp63α enabled increases in IL20RB expression and formation of IL-20 receptors, resulting in the activation of downstream JAK1-STAT3 signaling that stimulated the proliferation, EMT, migration, and in vivo metastatic seeding of PDAC cells. Our findings identify a signaling axis involving TRIM21, TAp63α, and IL-20RB in PDAC progression.
{"title":"The E3 ligase TRIM21 promotes progression of pancreatic ductal adenocarcinoma by down-regulating TAp63α and derepressing IL20RB","authors":"Zejiao Li, Fengwei Gao, Xuesha Liu, Shijie Fan, Yucheng Qi, Mingzhu He, Xiushuang Luo, Xiaoyun Nie, Jia Wang, Yajun Wang, Zhi-Xiong Jim Xiao, Chenghua Li","doi":"10.1126/scisignal.adv4579","DOIUrl":"10.1126/scisignal.adv4579","url":null,"abstract":"<div >Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor and frequently has mutations in the transcription factor p53. TAp63α is a member of the p53 protein family that is generally tumor suppressive in various other p53-mutant or p53-deficient cancers. Here, we found that TAp63α inhibited cell proliferation, epithelial-mesenchymal transition (EMT), and migration in several p53-mutant PDAC cell lines. TAp63α transcriptionally repressed <i>IL20RB</i> (which encodes a subunit of the interleukin-20 receptor), potentially by inducing the methylation of its promoter. However, mutations in p53 or KRAS that are common in PDAC increased the abundance of the E3 ligase TRIM21, which promoted the ubiquitin-dependent degradation of TAp63α. Thus, the degradation of TAp63α enabled increases in <i>IL20RB</i> expression and formation of IL-20 receptors, resulting in the activation of downstream JAK1-STAT3 signaling that stimulated the proliferation, EMT, migration, and in vivo metastatic seeding of PDAC cells. Our findings identify a signaling axis involving TRIM21, TAp63α, and IL-20RB in PDAC progression.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 889","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207116","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 : 2025-06-03DOI: 10.1126/scisignal.adq4238
Hannah Gerninghaus, Jörg Isensee, Lea Kennel, Fangyuan Zhou, Anja Kaiser, Tilman Gross, Cathrin Flauaus, Patrick Engel, Christoph Jacobs, Jonas Petersen, Wiebke Kallenborn-Gerhardt, Ruirui Lu, Katharina Metzner, Julia Adler, Peter Ruth, Robert Lukowski, Tim Hucho, Hannes Schmidt, Achim Schmidtko
Natriuretic peptide receptor 2 (Npr2; also termed guanylyl cyclase B) is a transmembrane guanylyl cyclase that is highly abundant in nociceptors. Here, we investigated the role of production of cyclic GMP (cGMP) by Npr2 in pain processing. Adult mice with a deletion of Npr2 specifically in nociceptive sensory neurons exhibited deficits in noxious heat sensing, which can activate the nonselective cation channels TRPV1 and TRPA1. In parallel, Npr2-deficient mice showed a reduction in TRPV1-mediated nocifensive behavior and Ca2+ influx into sensory neurons. Furthermore, Npr2-deficient mice had considerably reduced hypersensitivity after hindpaw injection of TRPA1 and TRPV1 activators or after hindpaw injection of complete Freund adjuvant, a model of persistent inflammatory pain. These results indicate that Npr2 contributes to the pain sensitization that can lead to chronic pain. Patch-clamp recordings revealed that the endogenous Npr2 ligand, C-type natriuretic peptide (CNP), enhanced the excitability of nociceptive sensory neurons through Npr2. CNP/Npr2 signaling led to the phosphorylation of cysteine-rich LIM-only protein 4 (CRP4), a substrate of cGMP-dependent protein kinase I. Behavioral and electrophysiological analyses using CRP4-deficient mice revealed that CRP4 limited CNP/Npr2-mediated pain sensitization. Our findings reveal a role for CNP/Npr2 signaling in sensory neurons in acute nociceptive and chronic pain and suggest that CRP4 is a downstream target that attenuates pain sensitization.
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