The transcriptional coactivator YAP1 regulates numerous biological processes, including organ size control and tissue homeostasis. Although its hyperactivity promotes tumor development and progression, YAP1 itself is not yet druggable. Here, we found that the poly(ADP-ribose) polymerase PARP1 promoted the transcriptional activity of YAP1-TEAD4 complexes that mediate breast cancer cell stemness, metastatic behavior, and evasion of antitumor immunity. This PARP1-mediated mechanism was independent of its role in the DNA damage response. Specifically, PARP1 directly interacted with and promoted the formation of the YAP1-TEAD4 complex by PARylating TEAD4 at a conserved Arg-Lys sequence. This PARP1-enhanced YAP1-TEAD4 binding attenuated the interaction between YAP1 and the E3 ubiquitin ligase CRL4DCAF12, thus preventing its ubiquitylation and degradation. Furthermore, the abundance of PARP1 protein correlated with that of YAP1 and the immune checkpoint protein PD-L1 in breast cancer tissues and cell lines. In a mouse model of triple-negative breast cancer, pharmacological inhibition of PARP1 enhanced the ability of antibody blockade of PD-L1 to increase cytolytic and tumor-suppressive T cell infiltration and reduce tumor growth. The findings reveal a mechanism that promotes YAP1-TEAD4 transcriptional activity and immune escape in breast cancer cells and is targetable with clinically approved therapies.
{"title":"PARP1-mediated PARylation of TEAD4 stabilizes the YAP1-TEAD4 complex and promotes growth and immune evasion in breast cancer cells","authors":"Yibo Guo, Gaoqing Song, Hailin Zou, Liangxin Lu, Xuyin Dai, Chuannan Sun, Haoming Chen, Tongyu Tong, Mengjun Huang, Mengyuan Zhu, Liang Deng, Yulong He, Changhua Zhang, Juan Luo, Peng Li","doi":"10.1126/scisignal.adx2532","DOIUrl":"10.1126/scisignal.adx2532","url":null,"abstract":"<div >The transcriptional coactivator YAP1 regulates numerous biological processes, including organ size control and tissue homeostasis. Although its hyperactivity promotes tumor development and progression, YAP1 itself is not yet druggable. Here, we found that the poly(ADP-ribose) polymerase PARP1 promoted the transcriptional activity of YAP1-TEAD4 complexes that mediate breast cancer cell stemness, metastatic behavior, and evasion of antitumor immunity. This PARP1-mediated mechanism was independent of its role in the DNA damage response. Specifically, PARP1 directly interacted with and promoted the formation of the YAP1-TEAD4 complex by PARylating TEAD4 at a conserved Arg-Lys sequence. This PARP1-enhanced YAP1-TEAD4 binding attenuated the interaction between YAP1 and the E3 ubiquitin ligase CRL4<sup>DCAF12</sup>, thus preventing its ubiquitylation and degradation. Furthermore, the abundance of PARP1 protein correlated with that of YAP1 and the immune checkpoint protein PD-L1 in breast cancer tissues and cell lines. In a mouse model of triple-negative breast cancer, pharmacological inhibition of PARP1 enhanced the ability of antibody blockade of PD-L1 to increase cytolytic and tumor-suppressive T cell infiltration and reduce tumor growth. The findings reveal a mechanism that promotes YAP1-TEAD4 transcriptional activity and immune escape in breast cancer cells and is targetable with clinically approved therapies.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 909","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145335953","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 : 2025-10-14DOI: 10.1126/scisignal.adv1529
Bo Lu, Feng Cong
Ligands of the WNT family induce formation of the WNT receptor signalosome and promote stabilization of the transcriptional coactivator β-catenin. The homologous transmembrane E3 ubiquitin ligases ZNRF3 and RNF43 inhibit WNT-dependent stabilization of β-catenin by stimulating the degradation of the WNT receptor FZD, whereas the secreted R-spondin proteins promote the stabilization of FZD by inducing the degradation of ZNRF3 and RNF43. Here, we report that the R-spondin–induced stabilization of β-catenin in HEK293 cells was not mimicked by FZD overexpression, highlighting a gap in our understanding of this important regulatory mechanism. Contrary to the conventional view that ZNRF3 constitutively mediates the ubiquitylation and degradation of FZD, we found that ZNRF3-induced FZD degradation depended on endogenous WNT and that ZNRF3 selectively degraded WNT-engaged FZD. WNT enhanced the association between FZD and the intracellular adaptor protein DVL, and DVL subsequently recruited ZNRF3 to FZD to promote FZD degradation. Our data suggest that WNT signaling actively restricts itself through ZNRF3-dependent degradation of WNT-engaged FZD and that R-spondin enhances WNT signaling by prolonging the action of the WNT-engaged FZD complex, rather than by simply increasing the abundance of FZD on the cell surface.
{"title":"The E3 ubiquitin ligase ZNRF3 restricts WNT receptor complex activity by stimulating the selective degradation of WNT-engaged FZD","authors":"Bo Lu, Feng Cong","doi":"10.1126/scisignal.adv1529","DOIUrl":"10.1126/scisignal.adv1529","url":null,"abstract":"<div >Ligands of the WNT family induce formation of the WNT receptor signalosome and promote stabilization of the transcriptional coactivator β-catenin. The homologous transmembrane E3 ubiquitin ligases ZNRF3 and RNF43 inhibit WNT-dependent stabilization of β-catenin by stimulating the degradation of the WNT receptor FZD, whereas the secreted R-spondin proteins promote the stabilization of FZD by inducing the degradation of ZNRF3 and RNF43. Here, we report that the R-spondin–induced stabilization of β-catenin in HEK293 cells was not mimicked by FZD overexpression, highlighting a gap in our understanding of this important regulatory mechanism. Contrary to the conventional view that ZNRF3 constitutively mediates the ubiquitylation and degradation of FZD, we found that ZNRF3-induced FZD degradation depended on endogenous WNT and that ZNRF3 selectively degraded WNT-engaged FZD. WNT enhanced the association between FZD and the intracellular adaptor protein DVL, and DVL subsequently recruited ZNRF3 to FZD to promote FZD degradation. Our data suggest that WNT signaling actively restricts itself through ZNRF3-dependent degradation of WNT-engaged FZD and that R-spondin enhances WNT signaling by prolonging the action of the WNT-engaged FZD complex, rather than by simply increasing the abundance of FZD on the cell surface.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 908","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145285015","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 : 2025-10-14DOI: 10.1126/scisignal.adv8801
Alice Billie Libri, Jinglong Wang, Timea Marton, Wei Yu, François Dossin, Gabriel Balmus, Bernardo Reina-San-Martin, Richard Frock, Chloé Lescale, Ludovic Deriano
Antigen receptor diversity depends on the assembly of variable (V), diverse (D), and joining (J) exons in genes encoding immunoglobulins (Igs) and T cell receptors (TCRs). During V(D)J recombination, DNA double-strand breaks (DSBs) introduced by the RAG1/2 nuclease complex are repaired by the process of nonhomologous end-joining (NHEJ). We hypothesized that functional redundancies between NHEJ and the chromatin DSB response, which depends on the kinase ATM, potentially masked the activity of additional factors that regulate V(D)J recombination. We performed targeted CRISPR-Cas9 knockout screens for genes implicated in V(D)J recombination in pro-B cells that were either untreated or treated with an ATM inhibitor. We found that loss of the RNA/DNA helicase senataxin (SETX) impaired V(D)J recombination and led to the formation of aberrant hybrid joints between coding ends and signal ends, both in vitro and in mice. The loss of SETX in a background deficient in the NHEJ factor XLF or in which ATM was inhibited led to substantial impairment of V(D)J recombination and to the presence of unsealed coding ends. SETX limited aberrant activation-induced cytidine deaminase (AID)–induced DNA end-joining between Igh-containing alleles during the process of class-switch recombination. Together, our findings reveal a previously uncharacterized role for SETX in promoting recombination fidelity during antigen receptor gene diversification.
{"title":"Senataxin promotes recombination fidelity during antigen receptor gene diversification","authors":"Alice Billie Libri, Jinglong Wang, Timea Marton, Wei Yu, François Dossin, Gabriel Balmus, Bernardo Reina-San-Martin, Richard Frock, Chloé Lescale, Ludovic Deriano","doi":"10.1126/scisignal.adv8801","DOIUrl":"10.1126/scisignal.adv8801","url":null,"abstract":"<div >Antigen receptor diversity depends on the assembly of variable (V), diverse (D), and joining (J) exons in genes encoding immunoglobulins (Igs) and T cell receptors (TCRs). During V(D)J recombination, DNA double-strand breaks (DSBs) introduced by the RAG1/2 nuclease complex are repaired by the process of nonhomologous end-joining (NHEJ). We hypothesized that functional redundancies between NHEJ and the chromatin DSB response, which depends on the kinase ATM, potentially masked the activity of additional factors that regulate V(D)J recombination. We performed targeted CRISPR-Cas9 knockout screens for genes implicated in V(D)J recombination in pro-B cells that were either untreated or treated with an ATM inhibitor. We found that loss of the RNA/DNA helicase senataxin (SETX) impaired V(D)J recombination and led to the formation of aberrant hybrid joints between coding ends and signal ends, both in vitro and in mice. The loss of SETX in a background deficient in the NHEJ factor XLF or in which ATM was inhibited led to substantial impairment of V(D)J recombination and to the presence of unsealed coding ends. SETX limited aberrant activation-induced cytidine deaminase (AID)–induced DNA end-joining between <i>Igh</i>-containing alleles during the process of class-switch recombination. Together, our findings reveal a previously uncharacterized role for SETX in promoting recombination fidelity during antigen receptor gene diversification.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 908","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.adv8801","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145285014","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 : 2025-10-07DOI: 10.1126/scisignal.adu6357
Sarah E. Catheline, Christina Mundy, Cheri Saunders, Sadhana Ramesh, Kelly A. Shaughnessy, Juliet Chung, Eiki Koyama, Maurizio Pacifici
Osteochondromas characterize the rare pediatric disorder hereditary multiple osteochondromas (HMO). The tumors originate from the growth plate perichondrium along skeletal elements, appear first as ectopic cartilage, and then grow unidirectionally, colliding with and damaging surrounding structures. HMO is caused by mutations that affect the heparan sulfate (HS) synthases EXT1 or EXT2, leading to HS deficiency and aberrant activity of HS-binding growth factors. We investigated the signaling pathways and mechanisms underlying tumor growth in HMO using mice with conditional Ext1 deficiency in the growth plate and perichondrium. Developing tumors displayed active Hedgehog (Hh) signaling within their cartilaginous moiety and the presence of parathyroid hormone–related protein (PTHrP) at their distal edge, generating an ectopic Hh-PTHrP axis orthogonal to the one directing normal bone lengthening at the adjacent growth plate. In Ext1 mutants, loss of the Hh signaling effector Smoothened (Smo) reduced tumor growth, whereas heterozygous loss of the Smo inhibitor Patched1 (Ptch1) increased tumor growth. Two HS-binding growth factors that promote normal cartilage growth in the growth plate, BMP2 and activin A, did not exert their normal prochondrogenic activity when Hh signaling was blocked, demonstrating that Hh signaling is essential for chondrogenesis. Together, our findings show that osteochondromas usurp a physiological signaling mechanism to guide and propel their directional outgrowth, enabling them to damage surrounding tissues, and suggest potential targets for therapeutic intervention.
{"title":"An ectopic Hedgehog signaling axis drives directional tumor outgrowth in a mouse model of hereditary multiple osteochondromas","authors":"Sarah E. Catheline, Christina Mundy, Cheri Saunders, Sadhana Ramesh, Kelly A. Shaughnessy, Juliet Chung, Eiki Koyama, Maurizio Pacifici","doi":"10.1126/scisignal.adu6357","DOIUrl":"10.1126/scisignal.adu6357","url":null,"abstract":"<div >Osteochondromas characterize the rare pediatric disorder hereditary multiple osteochondromas (HMO). The tumors originate from the growth plate perichondrium along skeletal elements, appear first as ectopic cartilage, and then grow unidirectionally, colliding with and damaging surrounding structures. HMO is caused by mutations that affect the heparan sulfate (HS) synthases EXT1 or EXT2, leading to HS deficiency and aberrant activity of HS-binding growth factors. We investigated the signaling pathways and mechanisms underlying tumor growth in HMO using mice with conditional <i>Ext1</i> deficiency in the growth plate and perichondrium. Developing tumors displayed active Hedgehog (Hh) signaling within their cartilaginous moiety and the presence of parathyroid hormone–related protein (PTHrP) at their distal edge, generating an ectopic Hh-PTHrP axis orthogonal to the one directing normal bone lengthening at the adjacent growth plate. In <i>Ext1</i> mutants, loss of the Hh signaling effector Smoothened (Smo) reduced tumor growth, whereas heterozygous loss of the Smo inhibitor Patched1 (Ptch1) increased tumor growth. Two HS-binding growth factors that promote normal cartilage growth in the growth plate, BMP2 and activin A, did not exert their normal prochondrogenic activity when Hh signaling was blocked, demonstrating that Hh signaling is essential for chondrogenesis. Together, our findings show that osteochondromas usurp a physiological signaling mechanism to guide and propel their directional outgrowth, enabling them to damage surrounding tissues, and suggest potential targets for therapeutic intervention.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 907","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145237421","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 : 2025-10-07DOI: 10.1126/scisignal.adx3087
Rachel Sue Zhen Yee, Chang Seok Lee, Ting Chang, Sung Yun Jung, Omar Yousif, Courtney Cavazos, John Colyer, Filip Van Petegem, George G. Rodney, Susan L. Hamilton
Ryanodine receptor 1 (RYR1) is the sarcoplasmic reticulum (SR) Ca2+ release channel required for both skeletal muscle contraction and Ca2+ leak. Mutations in RYR1 cause malignant hyperthermia susceptibility (MHS) and enhanced sensitivity to heat stroke (ESHS), which can result in death due to excessive skeletal muscle thermogenesis upon exposure to volatile anesthetics or heat. Here, we investigated the molecular and physiological functions of phosphorylation of RYR1 at Ser2902 by the kinase striated muscle preferentially expressed protein (SPEG). Muscle from SPEG-deficient mice expressing RYR1 with a Ser2902→Asp2902 (S2902D) point mutation to mimic phosphorylation by SPEG showed decreased SR Ca2+ sparks. Muscle from mice homozygous for the S2902D point mutation had reduced SR Ca2+ transients and small changes in force generation but overall mild phenotypic changes. YS mice, which are heterozygous for a Tyr524→Ser524 point mutation in RYR1, show increased Ca2+ leak and are a model of MHS and ESHS. Crossing YS mice with S2902D mice led to decreased SR Ca2+ leak and desensitized the mice to both volatile anesthetics and heat. Thus, SPEG inhibits SR Ca2+ leak in skeletal muscle by phosphorylating Ser2902 on RYR1, and mutation of Ser2902 to Asp2902 to mimic this phosphorylation event rescues YS mice from heat-induced death.
{"title":"Phosphorylation of RYR1 at Ser2902 decreases Ca2+ leak in skeletal muscle and susceptibility to malignant hyperthermia and heat stroke","authors":"Rachel Sue Zhen Yee, Chang Seok Lee, Ting Chang, Sung Yun Jung, Omar Yousif, Courtney Cavazos, John Colyer, Filip Van Petegem, George G. Rodney, Susan L. Hamilton","doi":"10.1126/scisignal.adx3087","DOIUrl":"10.1126/scisignal.adx3087","url":null,"abstract":"<div >Ryanodine receptor 1 (RYR1) is the sarcoplasmic reticulum (SR) Ca<sup>2+</sup> release channel required for both skeletal muscle contraction and Ca<sup>2+</sup> leak. Mutations in <i>RYR1</i> cause malignant hyperthermia susceptibility (MHS) and enhanced sensitivity to heat stroke (ESHS), which can result in death due to excessive skeletal muscle thermogenesis upon exposure to volatile anesthetics or heat. Here, we investigated the molecular and physiological functions of phosphorylation of RYR1 at Ser<sup>2902</sup> by the kinase striated muscle preferentially expressed protein (SPEG). Muscle from SPEG-deficient mice expressing RYR1 with a Ser<sup>2902</sup>→Asp<sup>2902</sup> (S2902D) point mutation to mimic phosphorylation by SPEG showed decreased SR Ca<sup>2+</sup> sparks. Muscle from mice homozygous for the S2902D point mutation had reduced SR Ca<sup>2+</sup> transients and small changes in force generation but overall mild phenotypic changes. YS mice, which are heterozygous for a Tyr<sup>524</sup>→Ser<sup>524</sup> point mutation in RYR1, show increased Ca<sup>2+</sup> leak and are a model of MHS and ESHS. Crossing YS mice with S2902D mice led to decreased SR Ca<sup>2+</sup> leak and desensitized the mice to both volatile anesthetics and heat. Thus, SPEG inhibits SR Ca<sup>2+</sup> leak in skeletal muscle by phosphorylating Ser<sup>2902</sup> on RYR1, and mutation of Ser<sup>2902</sup> to Asp<sup>2902</sup> to mimic this phosphorylation event rescues YS mice from heat-induced death.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 907","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145237422","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 : 2025-09-30DOI: 10.1126/scisignal.ado8924
Irene Estadella, María Navarro-Pérez, Magalí Colomer-Molera, Michael L. Dustin, Alexander Sorkin, Jesusa Capera, Antonio Felipe
The voltage-gated potassium channel Kv1.3 contributes to action potential conduction in sensory neurons and to sustained increases in cytoplasmic Ca2+ that activate immune cells. Here, we found that two distinct endocytosis-inducing stimuli acted through the same residues in Kv1.3 to control surface abundance and activity of the channel. Upon stimulation of the growth factor receptor EGFR, which stimulates Tyr-directed kinases and is important in neuronal differentiation, or of the Ser/Thr kinase PKC, which participates in the down-regulation of inflammatory responses, Kv1.3 underwent ubiquitination-dependent endocytosis that routed channel proteins to lysosomes for degradation. We mapped two lysine clusters in the N and C termini of Kv1.3, both of which became ubiquitinated upon activation of either Tyr or Ser/Thr kinases and whose combined mutation had an additive effect in reducing ubiquitination and endocytosis. Manipulations that prevented the ubiquitination or decreased the endocytosis of Kv1.3 resulted in increased Kv1.3 abundance at the immunological synapse and activity in primary human T cells. Prolonged channel accumulation at this location would be expected to increase Kv1.3-dependent leukocyte activation and lead to chronic inflammatory pathologies. Thus, ubiquitination fine-tunes cell biology by inducing the endocytosis and turnover of Kv1.3 in response to biological stimuli and insults.
{"title":"Molecular determinants for the endocytosis of the voltage-gated K+ channel Kv1.3","authors":"Irene Estadella, María Navarro-Pérez, Magalí Colomer-Molera, Michael L. Dustin, Alexander Sorkin, Jesusa Capera, Antonio Felipe","doi":"10.1126/scisignal.ado8924","DOIUrl":"10.1126/scisignal.ado8924","url":null,"abstract":"<div >The voltage-gated potassium channel Kv1.3 contributes to action potential conduction in sensory neurons and to sustained increases in cytoplasmic Ca<sup>2+</sup> that activate immune cells. Here, we found that two distinct endocytosis-inducing stimuli acted through the same residues in Kv1.3 to control surface abundance and activity of the channel. Upon stimulation of the growth factor receptor EGFR, which stimulates Tyr-directed kinases and is important in neuronal differentiation, or of the Ser/Thr kinase PKC, which participates in the down-regulation of inflammatory responses, Kv1.3 underwent ubiquitination-dependent endocytosis that routed channel proteins to lysosomes for degradation. We mapped two lysine clusters in the N and C termini of Kv1.3, both of which became ubiquitinated upon activation of either Tyr or Ser/Thr kinases and whose combined mutation had an additive effect in reducing ubiquitination and endocytosis. Manipulations that prevented the ubiquitination or decreased the endocytosis of Kv1.3 resulted in increased Kv1.3 abundance at the immunological synapse and activity in primary human T cells. Prolonged channel accumulation at this location would be expected to increase Kv1.3-dependent leukocyte activation and lead to chronic inflammatory pathologies. Thus, ubiquitination fine-tunes cell biology by inducing the endocytosis and turnover of Kv1.3 in response to biological stimuli and insults.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 906","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197363","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 : 2025-09-30DOI: 10.1126/scisignal.adu7145
Priya S. Hibshman, Clint A. Stalnecker, Jeffrey A. Klomp, Kristina Drizyte-Miller, Jennifer E. Klomp, A. Cole Edwards, Lily M. Pita, Richard G. Hodge, J. Nathaniel Diehl, Ryan D. Mouery, Brandon L. Mouery, Kayla R. Snare, Andrew M. Waters, Sen Peng, Natalie K. Barker, Mariaelena Pierobon, Naim U. Rashid, Nhan L. Tran, Laura A. Herring, Lee M. Graves, Emanuel F. Petricoin III, Kirsten L. Bryant, Adrienne D. Cox, Channing J. Der
Of the thousands of genes and substrates identified in KRAS-mutant signaling networks in pancreatic ductal adenocarcinoma (PDAC), more than 200 are transcription factors, implying extensive and complex transcriptional regulation. However, we observed that genetic suppression of the transcription factor MYC alone was sufficient to phenocopy the effect of KRAS suppression in signaling, growth, and metabolic processes in PDAC cells. We determined the gene transcription changes caused by acute suppression of MYC function in KRAS-mutant PDAC cell lines and performed dependency map and pathway analyses on the affected gene sets. The expression of 1685 genes was increased upon suppression of MYC, and this gene set may comprise the bulk of the MYC-regulated genes essential for PDAC growth. In contrast, the 1325 genes whose expression was inhibited may comprise a compensatory response to oncogenic stress, mediated in part by the GTPase RHO. MYC-dependent transcriptional activity was largely ERK dependent, and almost one-third of ERK-regulated genes were also regulated by MYC in PDAC cells. Furthermore, chemical proteomic profiling revealed MYC-regulated protein kinases that can be targeted therapeutically. Together, these data provide a molecular portrait of MYC-dependent signaling that encompasses potentially exploitable mechanisms for treating PDAC.
{"title":"Defining the MYC-regulated transcriptome and kinome that support KRAS- and ERK-dependent growth of pancreatic cancer","authors":"Priya S. Hibshman, Clint A. Stalnecker, Jeffrey A. Klomp, Kristina Drizyte-Miller, Jennifer E. Klomp, A. Cole Edwards, Lily M. Pita, Richard G. Hodge, J. Nathaniel Diehl, Ryan D. Mouery, Brandon L. Mouery, Kayla R. Snare, Andrew M. Waters, Sen Peng, Natalie K. Barker, Mariaelena Pierobon, Naim U. Rashid, Nhan L. Tran, Laura A. Herring, Lee M. Graves, Emanuel F. Petricoin III, Kirsten L. Bryant, Adrienne D. Cox, Channing J. Der","doi":"10.1126/scisignal.adu7145","DOIUrl":"10.1126/scisignal.adu7145","url":null,"abstract":"<div >Of the thousands of genes and substrates identified in KRAS-mutant signaling networks in pancreatic ductal adenocarcinoma (PDAC), more than 200 are transcription factors, implying extensive and complex transcriptional regulation. However, we observed that genetic suppression of the transcription factor MYC alone was sufficient to phenocopy the effect of KRAS suppression in signaling, growth, and metabolic processes in PDAC cells. We determined the gene transcription changes caused by acute suppression of MYC function in <i>KRAS</i>-mutant PDAC cell lines and performed dependency map and pathway analyses on the affected gene sets. The expression of 1685 genes was increased upon suppression of MYC, and this gene set may comprise the bulk of the MYC-regulated genes essential for PDAC growth. In contrast, the 1325 genes whose expression was inhibited may comprise a compensatory response to oncogenic stress, mediated in part by the GTPase RHO. MYC-dependent transcriptional activity was largely ERK dependent, and almost one-third of ERK-regulated genes were also regulated by MYC in PDAC cells. Furthermore, chemical proteomic profiling revealed MYC-regulated protein kinases that can be targeted therapeutically. Together, these data provide a molecular portrait of MYC-dependent signaling that encompasses potentially exploitable mechanisms for treating PDAC.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 906","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.adu7145","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197362","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 : 2025-09-23DOI: 10.1126/scisignal.adr3177
Gina Papadopoulou, Dimitrios Valakos, Ioanna Polydouri, Afroditi Moulara, Giannis Vatsellas, Stefano Angiari, Marah C. Runtsch, Marc Foretz, Benoit Viollet, Antonino Cassotta, Luke A. J. O’Neill, Georgina Xanthou
Metabolic reprogramming controls protective and pathogenic T helper 17 (TH17) cell responses. When naïve T cells are differentiated into TH17 cells in vitro, the presence of the cytokine activin A promotes their maturation into a nonpathogenic state. Here, we found that nonpathogenic TH17 cells induced by activin A displayed reduced aerobic glycolysis and increased oxidative phosphorylation (OXPHOS). In response to activin A, signaling through the adenosine A2A receptor (A2AR) and AMP-activated protein kinase (AMPK) enhanced OXPHOS and reprogrammed pathogenic TH17 cells toward nonpathogenic states that did not induce central nervous system autoimmunity in a mouse model of multiple sclerosis. In pathogenic TH17 cells, the transcriptional coactivator p300/CBP-associated factor (PCAF) increased acetylation at histone 3 Lys9 (H3K9ac) of genes involved in aerobic glycolysis and TH17 pathogenic programs. In contrast, in nonpathogenic activin A–treated TH17 cells, AMPK signaling suppressed PCAF-mediated H3K9ac modification of genes involved in aerobic metabolism and enhanced H3K9ac modification of genes involved in OXPHOS and nonpathogenic TH17 programs. Together, our findings uncover A2AR-AMPK signaling as a central metabolic checkpoint that suppresses TH17 cell pathogenicity.
{"title":"Adenosine 2A receptor–dependent activation of AMPK represses TH17 cell pathogenicity through epigenetic and metabolic reprogramming","authors":"Gina Papadopoulou, Dimitrios Valakos, Ioanna Polydouri, Afroditi Moulara, Giannis Vatsellas, Stefano Angiari, Marah C. Runtsch, Marc Foretz, Benoit Viollet, Antonino Cassotta, Luke A. J. O’Neill, Georgina Xanthou","doi":"10.1126/scisignal.adr3177","DOIUrl":"10.1126/scisignal.adr3177","url":null,"abstract":"<div >Metabolic reprogramming controls protective and pathogenic T helper 17 (T<sub>H</sub>17) cell responses. When naïve T cells are differentiated into T<sub>H</sub>17 cells in vitro, the presence of the cytokine activin A promotes their maturation into a nonpathogenic state. Here, we found that nonpathogenic T<sub>H</sub>17 cells induced by activin A displayed reduced aerobic glycolysis and increased oxidative phosphorylation (OXPHOS). In response to activin A, signaling through the adenosine A<sub>2A</sub> receptor (A<sub>2A</sub>R) and AMP-activated protein kinase (AMPK) enhanced OXPHOS and reprogrammed pathogenic T<sub>H</sub>17 cells toward nonpathogenic states that did not induce central nervous system autoimmunity in a mouse model of multiple sclerosis. In pathogenic T<sub>H</sub>17 cells, the transcriptional coactivator p300/CBP-associated factor (PCAF) increased acetylation at histone 3 Lys<sup>9</sup> (H3K9ac) of genes involved in aerobic glycolysis and T<sub>H</sub>17 pathogenic programs. In contrast, in nonpathogenic activin A–treated T<sub>H</sub>17 cells, AMPK signaling suppressed PCAF-mediated H3K9ac modification of genes involved in aerobic metabolism and enhanced H3K9ac modification of genes involved in OXPHOS and nonpathogenic T<sub>H</sub>17 programs. Together, our findings uncover A<sub>2A</sub>R-AMPK signaling as a central metabolic checkpoint that suppresses T<sub>H</sub>17 cell pathogenicity.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 905","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145123759","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 : 2025-09-23DOI: 10.1126/scisignal.aec3820
Wei Wong
Mitochondrial stress drives brown fat whitening through a pathway involving reduced nuclear stiffness.
线粒体压力通过降低核硬度的途径驱动棕色脂肪变白。
{"title":"Softer nuclei for whiter brown fat","authors":"Wei Wong","doi":"10.1126/scisignal.aec3820","DOIUrl":"10.1126/scisignal.aec3820","url":null,"abstract":"<div >Mitochondrial stress drives brown fat whitening through a pathway involving reduced nuclear stiffness.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 905","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145123760","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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