Pub Date : 2025-11-25DOI: 10.1126/scisignal.aee0649
Wei Wong
Stem cells in hair follicles can be activated after skin injury by fatty acids released from adipocytes.
皮肤损伤后毛囊干细胞可被脂肪细胞释放的脂肪酸激活。
{"title":"The fatty acid method for regrowing hair","authors":"Wei Wong","doi":"10.1126/scisignal.aee0649","DOIUrl":"10.1126/scisignal.aee0649","url":null,"abstract":"<div >Stem cells in hair follicles can be activated after skin injury by fatty acids released from adipocytes.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 914","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145595397","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 : 2025-11-25DOI: 10.1126/scisignal.aea2788
Brianna R. Daley, Patricia L. Theard, Jacob M. Hughes, Bridget A. Finniff, Marco H. Hofmann, Kaja Kostyrko, Robyn L. Schenk, Heidi M. Vieira, James W. Askew, Robert E. Lewis, Robert L. Kortum
Osimertinib is the mainstay of therapy for patients with non–small cell lung cancer (NSCLC) driven by the receptor tyrosine kinase (RTK) EGFR. In most patients, however, therapeutic pressure promotes RTK-dependent mechanisms that support tumor cell survival and the emergence of osimertinib resistance. Here, we found that inhibiting the proximal RTK signaling intermediate SOS1 promoted continued osimertinib efficacy in sensitive cells and restored sensitivity in cells with acquired resistance. In three-dimensional spheroid cultures of naïve NSCLC cells, SOS1 inhibition enhanced osimertinib potency by limiting the reactivation of RTK-dependent adaptive Ras effectors. SOS1 inhibition resensitized drug-tolerant persister cells to osimertinib, and knockout or inhibition of SOS1 reduced the frequency of tumor-initiating cells to curb spheroid growth in situ and tumorigenesis in vivo. SOS1 inhibition further limited the development of acquired osimertinib resistance and resensitized resistant cells to osimertinib. In mice, tumors regressed nearly completely when treated with either osimertinib or a combination of osimertinib and a SOS1 inhibitor, with the combination providing a slightly greater effect. However, only the combination delayed tumor regrowth after treatment removal. Our data provide a mechanistic rationale for the clinical investigation of combining SOS1 inhibitors with osimertinib to achieve more durable responses and suppress resistance in NSCLC.
{"title":"SOS1 inhibition suppresses the emergence of osimertinib resistance to generate a durable response in EGFR-mutant lung cancer","authors":"Brianna R. Daley, Patricia L. Theard, Jacob M. Hughes, Bridget A. Finniff, Marco H. Hofmann, Kaja Kostyrko, Robyn L. Schenk, Heidi M. Vieira, James W. Askew, Robert E. Lewis, Robert L. Kortum","doi":"10.1126/scisignal.aea2788","DOIUrl":"10.1126/scisignal.aea2788","url":null,"abstract":"<div >Osimertinib is the mainstay of therapy for patients with non–small cell lung cancer (NSCLC) driven by the receptor tyrosine kinase (RTK) EGFR. In most patients, however, therapeutic pressure promotes RTK-dependent mechanisms that support tumor cell survival and the emergence of osimertinib resistance. Here, we found that inhibiting the proximal RTK signaling intermediate SOS1 promoted continued osimertinib efficacy in sensitive cells and restored sensitivity in cells with acquired resistance. In three-dimensional spheroid cultures of naïve NSCLC cells, SOS1 inhibition enhanced osimertinib potency by limiting the reactivation of RTK-dependent adaptive Ras effectors. SOS1 inhibition resensitized drug-tolerant persister cells to osimertinib, and knockout or inhibition of SOS1 reduced the frequency of tumor-initiating cells to curb spheroid growth in situ and tumorigenesis in vivo. SOS1 inhibition further limited the development of acquired osimertinib resistance and resensitized resistant cells to osimertinib. In mice, tumors regressed nearly completely when treated with either osimertinib or a combination of osimertinib and a SOS1 inhibitor, with the combination providing a slightly greater effect. However, only the combination delayed tumor regrowth after treatment removal. Our data provide a mechanistic rationale for the clinical investigation of combining SOS1 inhibitors with osimertinib to achieve more durable responses and suppress resistance in NSCLC.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 914","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145595399","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 : 2025-11-18DOI: 10.1126/scisignal.ady0398
Davide Cinat, Ryan van der Wal, Mirjam Baanstra, Abel Soto-Gamez, Rufina Maturi, Anne L. Jellema-de Bruin, Uilke Brouwer, Marc-Jan van Goethem, Marcel A. T. M. van Vugt, Lara Barazzuol, Rob P. Coppes
The goal of radiotherapy in cancer treatment is to maximize DNA damage in tumors while minimizing harm to surrounding healthy tissues, especially to stem and progenitor cells essential for tissue regeneration and organ function. Here, we investigated the molecular responses to photon and proton irradiation, two key modalities in head and neck cancer treatment. Multiomics and in vitro analyses revealed that both photon and proton irradiation of mouse salivary gland organoids induced similar early responses, including DNA damage, micronuclei formation, increased amounts of the cytosolic DNA sensor cGAS, and type I interferon (IFN-I) signaling. In addition, both types of radiation induced comparable increases in the release of mitochondrial DNA (mtDNA) into the cytoplasm and stimulated the production of ZBP1, a cytosolic nucleic acid sensor involved in mtDNA recognition. However, proton irradiation resulted in a more pronounced loss of heterochromatin regulators and derepression of transposable elements at later times after irradiation, which was accompanied by increased accumulation of intracellular double-stranded RNA (dsRNA) and an enhanced RIG-I–mediated IFN-I response. Genetic and pharmacological modulation demonstrated its critical role for IFN-I signaling in enhancing salivary gland stem and progenitor cell activity after irradiation in vitro and in vivo. Our findings reveal more pronounced molecular changes after proton irradiation as compared with photon irradiation and uncover a proregenerative role of IFN-I signaling in the salivary gland, suggesting this pathway as a promising therapeutic target to mitigate radiation-induced side effects.
{"title":"IFN-I signaling enhances salivary gland stem and progenitor cell activity after irradiation","authors":"Davide Cinat, Ryan van der Wal, Mirjam Baanstra, Abel Soto-Gamez, Rufina Maturi, Anne L. Jellema-de Bruin, Uilke Brouwer, Marc-Jan van Goethem, Marcel A. T. M. van Vugt, Lara Barazzuol, Rob P. Coppes","doi":"10.1126/scisignal.ady0398","DOIUrl":"10.1126/scisignal.ady0398","url":null,"abstract":"<div >The goal of radiotherapy in cancer treatment is to maximize DNA damage in tumors while minimizing harm to surrounding healthy tissues, especially to stem and progenitor cells essential for tissue regeneration and organ function. Here, we investigated the molecular responses to photon and proton irradiation, two key modalities in head and neck cancer treatment. Multiomics and in vitro analyses revealed that both photon and proton irradiation of mouse salivary gland organoids induced similar early responses, including DNA damage, micronuclei formation, increased amounts of the cytosolic DNA sensor cGAS, and type I interferon (IFN-I) signaling. In addition, both types of radiation induced comparable increases in the release of mitochondrial DNA (mtDNA) into the cytoplasm and stimulated the production of ZBP1, a cytosolic nucleic acid sensor involved in mtDNA recognition. However, proton irradiation resulted in a more pronounced loss of heterochromatin regulators and derepression of transposable elements at later times after irradiation, which was accompanied by increased accumulation of intracellular double-stranded RNA (dsRNA) and an enhanced RIG-I–mediated IFN-I response. Genetic and pharmacological modulation demonstrated its critical role for IFN-I signaling in enhancing salivary gland stem and progenitor cell activity after irradiation in vitro and in vivo. Our findings reveal more pronounced molecular changes after proton irradiation as compared with photon irradiation and uncover a proregenerative role of IFN-I signaling in the salivary gland, suggesting this pathway as a promising therapeutic target to mitigate radiation-induced side effects.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 913","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145538107","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 : 2025-11-18DOI: 10.1126/scisignal.aeb6151
Yoshiaki Sato, Jian Yu
Innate immune signaling is important for tissue regeneration. In this issue of Science Signaling, Cinat et al. report that a cell-intrinsic type I interferon (IFN-I) response drives salivary gland organoid regeneration after radiation and that proton irradiation induces a stronger regenerative response than photon irradiation because it amplifies the IFN-I response.
{"title":"Jump-starting IFN-I responses and epithelial regeneration","authors":"Yoshiaki Sato, Jian Yu","doi":"10.1126/scisignal.aeb6151","DOIUrl":"10.1126/scisignal.aeb6151","url":null,"abstract":"<div >Innate immune signaling is important for tissue regeneration. In this issue of <i>Science Signaling</i>, Cinat <i>et al</i>. report that a cell-intrinsic type I interferon (IFN-I) response drives salivary gland organoid regeneration after radiation and that proton irradiation induces a stronger regenerative response than photon irradiation because it amplifies the IFN-I response.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 913","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145538108","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 : 2025-11-18DOI: 10.1126/scisignal.ads8396
Alekhya Kandoor, Gabrielle Martinez, Julianna M. Hitchcock, Savannah Angel, Logan Campbell, Saqib Rizvi, Kristen M. Naegle
Protein domains are conserved structural and functional units that serve as the building blocks of proteins. Through evolutionary expansion, domain families are represented by multiple members in diverse configurations with other domains, evolving new specificities for their interacting partners. Here, we developed a structure-based interface analysis to map domain interfaces from experimental and predicted structures, including interfaces with macromolecules and intraprotein interfaces. We hypothesized that contact mapping of domains could yield insights into domain selectivity and the conservation of domain-domain interfaces across proteins and identify conserved posttranslational modifications (PTMs) relative to interaction interfaces, enabling the inference of specific effects as a result of PTMs or mutations. We designed this modular approach as an open-source Python package called Comprehensive Domain Interface Analysis of Contacts (CoDIAC) and applied it to the family of human Src homology 2 (SH2) domains, a modular unit central to phosphotyrosine-mediated signaling. CoDIAC revealed coordinated regulation of SH2 domain binding interfaces by tyrosine and serine/threonine phosphorylation and acetylation that may underlie binding selectivity. These findings suggest that multiple signaling systems can regulate protein activity and SH2 domain interactions in a coordinated manner. Applying CoDIAC to the study of other protein domains should provide insights into their binding interfaces and molecular interactions.
{"title":"CoDIAC: A comprehensive approach for interaction analysis provides insights into SH2 domain function and regulation","authors":"Alekhya Kandoor, Gabrielle Martinez, Julianna M. Hitchcock, Savannah Angel, Logan Campbell, Saqib Rizvi, Kristen M. Naegle","doi":"10.1126/scisignal.ads8396","DOIUrl":"10.1126/scisignal.ads8396","url":null,"abstract":"<div >Protein domains are conserved structural and functional units that serve as the building blocks of proteins. Through evolutionary expansion, domain families are represented by multiple members in diverse configurations with other domains, evolving new specificities for their interacting partners. Here, we developed a structure-based interface analysis to map domain interfaces from experimental and predicted structures, including interfaces with macromolecules and intraprotein interfaces. We hypothesized that contact mapping of domains could yield insights into domain selectivity and the conservation of domain-domain interfaces across proteins and identify conserved posttranslational modifications (PTMs) relative to interaction interfaces, enabling the inference of specific effects as a result of PTMs or mutations. We designed this modular approach as an open-source Python package called Comprehensive Domain Interface Analysis of Contacts (CoDIAC) and applied it to the family of human Src homology 2 (SH2) domains, a modular unit central to phosphotyrosine-mediated signaling. CoDIAC revealed coordinated regulation of SH2 domain binding interfaces by tyrosine and serine/threonine phosphorylation and acetylation that may underlie binding selectivity. These findings suggest that multiple signaling systems can regulate protein activity and SH2 domain interactions in a coordinated manner. Applying CoDIAC to the study of other protein domains should provide insights into their binding interfaces and molecular interactions.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 913","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145538109","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 : 2025-11-11DOI: 10.1126/scisignal.adt3018
Papa Kobina Van Dyck, Luke Piszkin, Elijah A. Gorski, Eduarda Tartarella Nascimento, Joshua A. Abebe, Logan M. Hoffmann, Jeffrey W. Peng, Katharine A. White
Intracellular pH dynamics regulate many cell biological processes. We developed a computational pipeline to identify pH-sensitive proteins and the molecular mechanisms that regulate their pH-dependent activity. By applying the pipeline to the phosphatase SHP2, which regulates signaling pathways that control pH-dependent cellular processes, we found that SHP2 phosphatase activity was sensitive to pH in vitro and in cells and that mutation of His116 and Glu252 abolished SHP2 pH-sensitive activity. We also found that the activity of the kinase SRC was pH dependent and that mutations in a network of ionizable amino acids abolished pH-sensitive activity. Furthermore, we found that SRC kinase activity was pH sensitive even in the presence of the growth factor EGF, which stimulates SRC activity in a phosphorylation-dependent manner, or with a phosphomimetic substitution (Y527E) that promotes SRC autoinhibition. These data suggest that pH-sensitive regulation functions in concert with established phosphorylation-dependent mechanisms to regulate SRC kinase activity. Constant pH molecular dynamics simulations performed on both SHP2 and SRC supported allosteric regulation mediated by pH-dependent binding of inhibitory SH2 domains to the respective catalytic domain in each protein. We also identified evolutionarily conserved putative pH-sensing networks in other SH2 domain–containing signaling proteins. Together, our computational, biophysical, and cellular analyses reveal a role for intracellular pH dynamics in allosterically regulating the activities of modular SH2 signaling proteins to control cell biology.
{"title":"Ionizable networks mediate pH-dependent allostery in the SH2 domain–containing signaling proteins SHP2 and SRC","authors":"Papa Kobina Van Dyck, Luke Piszkin, Elijah A. Gorski, Eduarda Tartarella Nascimento, Joshua A. Abebe, Logan M. Hoffmann, Jeffrey W. Peng, Katharine A. White","doi":"10.1126/scisignal.adt3018","DOIUrl":"10.1126/scisignal.adt3018","url":null,"abstract":"<div >Intracellular pH dynamics regulate many cell biological processes. We developed a computational pipeline to identify pH-sensitive proteins and the molecular mechanisms that regulate their pH-dependent activity. By applying the pipeline to the phosphatase SHP2, which regulates signaling pathways that control pH-dependent cellular processes, we found that SHP2 phosphatase activity was sensitive to pH in vitro and in cells and that mutation of His<sup>116</sup> and Glu<sup>252</sup> abolished SHP2 pH-sensitive activity. We also found that the activity of the kinase SRC was pH dependent and that mutations in a network of ionizable amino acids abolished pH-sensitive activity. Furthermore, we found that SRC kinase activity was pH sensitive even in the presence of the growth factor EGF, which stimulates SRC activity in a phosphorylation-dependent manner, or with a phosphomimetic substitution (Y527E) that promotes SRC autoinhibition. These data suggest that pH-sensitive regulation functions in concert with established phosphorylation-dependent mechanisms to regulate SRC kinase activity. Constant pH molecular dynamics simulations performed on both SHP2 and SRC supported allosteric regulation mediated by pH-dependent binding of inhibitory SH2 domains to the respective catalytic domain in each protein. We also identified evolutionarily conserved putative pH-sensing networks in other SH2 domain–containing signaling proteins. Together, our computational, biophysical, and cellular analyses reveal a role for intracellular pH dynamics in allosterically regulating the activities of modular SH2 signaling proteins to control cell biology.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 912","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145487126","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 : 2025-11-11DOI: 10.1126/scisignal.adv4112
Aurora Callahan, Xinyan Zhang, Amber Wang, Aisharja Mojumdar, Longhui Zeng, Xiaolei Su, Arthur R. Salomon
Chimeric antigen receptor (CAR) T cells have demonstrated unprecedented success in treating relapsed or refractory blood cancers. Previous studies of the mechanisms underlying the interactions and responses of CAR T cells and their targets have largely ignored the responses of tumors to CAR ligation. We compared the signaling of a second-generation, ligand-based CAR built from colony-stimulating factor 1 (CSF1) to target the CSF1 receptor (CSF1R) on target cells with a conventional, single-chain variable fragment–based CAR against the B cell antigen CD19. Using SILAC coculture with phosphotyrosine enrichment and LC-MS/MS analysis, we showed that ligation of CSF1R-expressing THP-1 cells with CSF1R-CAR T cells stimulated CSF1R-like signaling in the THP-1 cells. In contrast, no target cell signaling response was observed after the ligation of CD19-CAR T cells with target Raji cells. Using small-molecule inhibitors of the tyrosine kinase Lck, actin polymerization, and CSF1R, we found that CAR-induced CSF1R signaling in THP-1 cells depended exclusively on the kinase activity of CSF1R with no participation from T cell activation. Consistently, CSF1R-CAR T cells promoted THP-1 cell proliferation at low effector-to-target ratios but prevented THP-1 cell proliferation at high effector-to-target ratios. Our data provide evidence for CAR-induced signaling in target cells, an unintended consequence of CARs that may have implications for the choice of CAR antigen for optimal clinical efficacy.
{"title":"CSF1R-CAR T cells induce CSF1R signaling and can promote target cell proliferation","authors":"Aurora Callahan, Xinyan Zhang, Amber Wang, Aisharja Mojumdar, Longhui Zeng, Xiaolei Su, Arthur R. Salomon","doi":"10.1126/scisignal.adv4112","DOIUrl":"10.1126/scisignal.adv4112","url":null,"abstract":"<div >Chimeric antigen receptor (CAR) T cells have demonstrated unprecedented success in treating relapsed or refractory blood cancers. Previous studies of the mechanisms underlying the interactions and responses of CAR T cells and their targets have largely ignored the responses of tumors to CAR ligation. We compared the signaling of a second-generation, ligand-based CAR built from colony-stimulating factor 1 (CSF1) to target the CSF1 receptor (CSF1R) on target cells with a conventional, single-chain variable fragment–based CAR against the B cell antigen CD19. Using SILAC coculture with phosphotyrosine enrichment and LC-MS/MS analysis, we showed that ligation of CSF1R-expressing THP-1 cells with CSF1R-CAR T cells stimulated CSF1R-like signaling in the THP-1 cells. In contrast, no target cell signaling response was observed after the ligation of CD19-CAR T cells with target Raji cells. Using small-molecule inhibitors of the tyrosine kinase Lck, actin polymerization, and CSF1R, we found that CAR-induced CSF1R signaling in THP-1 cells depended exclusively on the kinase activity of CSF1R with no participation from T cell activation. Consistently, CSF1R-CAR T cells promoted THP-1 cell proliferation at low effector-to-target ratios but prevented THP-1 cell proliferation at high effector-to-target ratios. Our data provide evidence for CAR-induced signaling in target cells, an unintended consequence of CARs that may have implications for the choice of CAR antigen for optimal clinical efficacy.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 912","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.adv4112","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145487124","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 : 2025-11-11DOI: 10.1126/scisignal.aed6498
Leslie K. Ferrarelli
Citrullination enhances the tumor-suppressor function of p53 by redirecting its gene target selectivity.
瓜氨酸化通过重定向p53基因的靶标选择性来增强p53的肿瘤抑制功能。
{"title":"Skewing p53 to tumor-suppressor targets","authors":"Leslie K. Ferrarelli","doi":"10.1126/scisignal.aed6498","DOIUrl":"10.1126/scisignal.aed6498","url":null,"abstract":"<div >Citrullination enhances the tumor-suppressor function of p53 by redirecting its gene target selectivity.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 912","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145487125","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 : 2025-11-04DOI: 10.1126/scisignal.adr0235
Véronique Calleja, Jack C. Henry, Mathias Cobbaut, Joanne Sewell, Karine Rizzoti, Francesca Houghton, Stefan Boeing, Nneka Anyanwu, Sunita Varsani-Brown, Thomas Snoeks, Alejandro Suárez-Bonnet, Simon L. Priestnall, Neil Q. McDonald, Angus J. M. Cameron, Peter J. Parker
The penetrant D463H mutation in PRKCA, which encodes the kinase PKCα, is a biomarker and driver of chordoid glioma, a type of brain cancer. Here, we found that heterozygous knock-in expression of the D463H mutant in mice elicited the development of chondrosarcomas. The mutant protein kinase was catalytically inactive, but no such oncogenic phenotype was observed for the related inactivating mutation D463N, indicating that the lack of activity per se was not the cause of the oncogenicity of the D463H mutant. In cultured glioma cells, the behavior of the D463H mutant closely mirrored that of wild-type PKCα and retained ATP binding, unlike the related D463N mutant. Mechanistically, PKCα D463H displayed quantitative alterations in its interactome compared with that of the wild-type kinase, with enhanced association with epigenetic regulators. This change in the interactome aligned with transcriptomic changes that resembled an increased PKCα-induced expression program, with enhanced gene signatures mediated by BRD4, MYC, and TGF-β. D463H expression reduced the sensitivity of cells to the BET inhibitors JQ1 and AZD5153, indicating the functional importance of these pathways. The findings indicate that D463H is a dominant gain-of-function oncogenic mutant that operates through a noncatalytic allosteric mechanism.
{"title":"The chordoid glioma PRKCA D463H mutation is a kinase inactive, gain-of-function allele that induces early-onset chondrosarcoma in mice","authors":"Véronique Calleja, Jack C. Henry, Mathias Cobbaut, Joanne Sewell, Karine Rizzoti, Francesca Houghton, Stefan Boeing, Nneka Anyanwu, Sunita Varsani-Brown, Thomas Snoeks, Alejandro Suárez-Bonnet, Simon L. Priestnall, Neil Q. McDonald, Angus J. M. Cameron, Peter J. Parker","doi":"10.1126/scisignal.adr0235","DOIUrl":"10.1126/scisignal.adr0235","url":null,"abstract":"<div >The penetrant D463H mutation in <i>PRKCA</i>, which encodes the kinase PKCα, is a biomarker and driver of chordoid glioma, a type of brain cancer. Here, we found that heterozygous knock-in expression of the D463H mutant in mice elicited the development of chondrosarcomas. The mutant protein kinase was catalytically inactive, but no such oncogenic phenotype was observed for the related inactivating mutation D463N, indicating that the lack of activity per se was not the cause of the oncogenicity of the D463H mutant. In cultured glioma cells, the behavior of the D463H mutant closely mirrored that of wild-type PKCα and retained ATP binding, unlike the related D463N mutant. Mechanistically, PKCα D463H displayed quantitative alterations in its interactome compared with that of the wild-type kinase, with enhanced association with epigenetic regulators. This change in the interactome aligned with transcriptomic changes that resembled an increased PKCα-induced expression program, with enhanced gene signatures mediated by BRD4, MYC, and TGF-β. D463H expression reduced the sensitivity of cells to the BET inhibitors JQ1 and AZD5153, indicating the functional importance of these pathways. The findings indicate that D463H is a dominant gain-of-function oncogenic mutant that operates through a noncatalytic allosteric mechanism.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 911","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145436561","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 : 2025-11-04DOI: 10.1126/scisignal.adr0011
Megan J. Priestley, Anna K. Hains, Iashia Z. Mulholland, Sam Spijkers-Shaw, Joshua C. Müller, Gareth Howell, Amanda J. L. Ridley, H. Davies-Strickleton, Rebecca L. Miller, Max Nobis, Olga V. Zubkova, Amy E. Saunders, Douglas P. Dyer
The glycocalyx is a proteoglycan-rich layer present on the surface of all mammalian cells and is particularly prevalent on endothelial cells lining the vasculature. The glycocalyx is thought to affect leukocyte migration by masking adhesion molecules and reducing leukocyte adhesion to the endothelium. Leukocyte recruitment is a key driver of inflammatory diseases, including psoriasis. Here, we found that leukocytes had the glycocalyx component heparan sulfate on their cell surface and that it was lost in response to psoriasis-like skin inflammation. In contrast, endothelial heparan sulfate was not affected. Treatment with a heparan sulfate mimetic during psoriasis-like skin inflammation in mice protected heparan sulfate from cleavage by myeloid cell–derived heparanase and resulted in reduced leukocyte accumulation in the skin. However, clinical signs of inflammation were increased because of the reduced numbers of T regulatory cells that were recruited. These findings refine our understanding of immune cell recruitment by revealing the presence and function of a heparan sulfate glycocalyx on immune cells and highlight the complex effects of heparanase inhibitors on the immune response in this context.
{"title":"Leukocytes have a heparan sulfate glycocalyx that regulates recruitment during psoriasis-like skin inflammation","authors":"Megan J. Priestley, Anna K. Hains, Iashia Z. Mulholland, Sam Spijkers-Shaw, Joshua C. Müller, Gareth Howell, Amanda J. L. Ridley, H. Davies-Strickleton, Rebecca L. Miller, Max Nobis, Olga V. Zubkova, Amy E. Saunders, Douglas P. Dyer","doi":"10.1126/scisignal.adr0011","DOIUrl":"10.1126/scisignal.adr0011","url":null,"abstract":"<div >The glycocalyx is a proteoglycan-rich layer present on the surface of all mammalian cells and is particularly prevalent on endothelial cells lining the vasculature. The glycocalyx is thought to affect leukocyte migration by masking adhesion molecules and reducing leukocyte adhesion to the endothelium. Leukocyte recruitment is a key driver of inflammatory diseases, including psoriasis. Here, we found that leukocytes had the glycocalyx component heparan sulfate on their cell surface and that it was lost in response to psoriasis-like skin inflammation. In contrast, endothelial heparan sulfate was not affected. Treatment with a heparan sulfate mimetic during psoriasis-like skin inflammation in mice protected heparan sulfate from cleavage by myeloid cell–derived heparanase and resulted in reduced leukocyte accumulation in the skin. However, clinical signs of inflammation were increased because of the reduced numbers of T regulatory cells that were recruited. These findings refine our understanding of immune cell recruitment by revealing the presence and function of a heparan sulfate glycocalyx on immune cells and highlight the complex effects of heparanase inhibitors on the immune response in this context.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 911","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145436560","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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