Pub Date : 2026-01-17DOI: 10.1016/j.bbamcr.2026.120114
Yulia Okulova , Maxim Filatov , Ekaterina Varlamova , Anna Tvorogova , Evgeniy Korshunov , Yulia Silaeva , Victor Tatarskiy , Alexandra Bruter
CDK8/19 are transcriptional cyclin dependent kinases, which do not directly control cell cycle progression. CDK8/19 are involved in regulation of multiple processes in embryogenesis, cancer progression, immune activation and others. Previously we demonstrated that CDK8/19 are critical for spermatogenesis in mice. Here we report that CDK8/19 activity is also required for oocyte maturation playing a significant role in meiosis resumption in mouse oocytes. Two chemically distinct CDK8/19 inhibitors – Senexin B and Snx631 prevented nuclear envelope breakdown and first polar body extrusion, blocking key molecular events required for exiting the dictyate - inhibition of PKA activity and activation of the CDK1/Cyclin B complex. This effect did not cause cytotoxicity, and oocytes could resume progression upon transfer into fresh media. Inhibition of CDK8/19 also prevented meiotic-specific mitochondrial expansion and clustering. Notably, these effects appear to be independent of roles of CDK8/19 in transcription, which is not required for resumption of meiosis. These findings for the first time demonstrate the roles of CDK8/19 activity in oocyte maturation, through its role in transcription-independent regulation of PKA activity.
{"title":"Cyclin dependent kinases CDK8/19 are required for PKA inactivation during meiosis resumption","authors":"Yulia Okulova , Maxim Filatov , Ekaterina Varlamova , Anna Tvorogova , Evgeniy Korshunov , Yulia Silaeva , Victor Tatarskiy , Alexandra Bruter","doi":"10.1016/j.bbamcr.2026.120114","DOIUrl":"10.1016/j.bbamcr.2026.120114","url":null,"abstract":"<div><div>CDK8/19 are transcriptional cyclin dependent kinases, which do not directly control cell cycle progression. CDK8/19 are involved in regulation of multiple processes in embryogenesis, cancer progression, immune activation and others. Previously we demonstrated that CDK8/19 are critical for spermatogenesis in mice. Here we report that CDK8/19 activity is also required for oocyte maturation playing a significant role in meiosis resumption in mouse oocytes. Two chemically distinct CDK8/19 inhibitors – Senexin B and Snx631 prevented nuclear envelope breakdown and first polar body extrusion, blocking key molecular events required for exiting the dictyate - inhibition of PKA activity and activation of the CDK1/Cyclin B complex. This effect did not cause cytotoxicity, and oocytes could resume progression upon transfer into fresh media. Inhibition of CDK8/19 also prevented meiotic-specific mitochondrial expansion and clustering. Notably, these effects appear to be independent of roles of CDK8/19 in transcription, which is not required for resumption of meiosis. These findings for the first time demonstrate the roles of CDK8/19 activity in oocyte maturation, through its role in transcription-independent regulation of PKA activity.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 3","pages":"Article 120114"},"PeriodicalIF":3.7,"publicationDate":"2026-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146002960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Accurate quantification of Yes-associated protein (YAP) and its paralog TAZ is critical for understanding their biological functions, however, existing reporter systems are constrained by their reliance on endogenous TEAD transcription factors. Here, we developed an endogenous TEAD-independent reporter system for YAP/TAZ activity, based on the GAL4-UAS system. The construct consists of the GAL4 DNA-binding domain (DBD) fused to the YAP-binding domain (YBD) of TEAD4, with the native TEAD DNA-binding domain (TEA) removed. Structural modeling of the G-TEAD4(217) fusion protein confirmed high similarity to experimentally resolved TEAD4-YAP or GAL4-DNA bound structures and revealed surface properties consistent with functional domain separation. Functional assays showed that the reporter reliably responded to both YAP knockdown and overexpression. Compared to the conventional 8 × GTIIC reporter, G-TEAD4(217) exhibited higher sensitivity and remained unaffected by TEAD4 silencing, confirming reporter specificity and TEAD independence. In addition, the system demonstrated its suitability for compound screening by validating known YAP inhibitors across a number of high-YAP cancer cell lines. A single-plasmid lentiviral version LV-G-TEAD4(217) was also developed to enable stable transduction and potential in vivo use. Together, these findings demonstrate that G-TEAD4(217) represents a sensitive, specific, and modular reporter platform for analyzing YAP/TAZ transcriptional activity in diverse biological settings.
{"title":"Development of a TEAD-independent reporter system for specific and sensitive measurement of YAP/TAZ activity","authors":"Jiuge Zhang , Wenqian Yang , Qiuyun Yuan , Fei Huang , Die Lv , Yixin Zhang , Xiaoqiang Xia , Yuan Yue , Xiaodong Feng","doi":"10.1016/j.bbamcr.2026.120111","DOIUrl":"10.1016/j.bbamcr.2026.120111","url":null,"abstract":"<div><div>Accurate quantification of Yes-associated protein (YAP) and its paralog TAZ is critical for understanding their biological functions, however, existing reporter systems are constrained by their reliance on endogenous TEAD transcription factors. Here, we developed an endogenous TEAD-independent reporter system for YAP/TAZ activity, based on the GAL4-UAS system. The construct consists of the GAL4 DNA-binding domain (DBD) fused to the YAP-binding domain (YBD) of TEAD4, with the native TEAD DNA-binding domain (TEA) removed. Structural modeling of the G-TEAD4(217) fusion protein confirmed high similarity to experimentally resolved TEAD4-YAP or GAL4-DNA bound structures and revealed surface properties consistent with functional domain separation. Functional assays showed that the reporter reliably responded to both YAP knockdown and overexpression. Compared to the conventional 8 × GTIIC reporter, G-TEAD4(217) exhibited higher sensitivity and remained unaffected by TEAD4 silencing, confirming reporter specificity and TEAD independence. In addition, the system demonstrated its suitability for compound screening by validating known YAP inhibitors across a number of high-YAP cancer cell lines. A single-plasmid lentiviral version LV-G-TEAD4(217) was also developed to enable stable transduction and potential in vivo use. Together, these findings demonstrate that G-TEAD4(217) represents a sensitive, specific, and modular reporter platform for analyzing YAP/TAZ transcriptional activity in diverse biological settings.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 3","pages":"Article 120111"},"PeriodicalIF":3.7,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145974086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-12DOI: 10.1016/j.bbamcr.2026.120112
Yan Yu , Aaron Babendreyer , Alessa Pabst , Anna Michely , Marie Tauscher , Christian Martin , Mark P. Kühnel , Danny D. Jonigk , Stefan Düsterhöft , Andreas Ludwig
Angiotensin-converting enzyme (ACE) is expressed on lung endothelium and can promote hypertension and cardiovascular diseases. By the activity of the metalloproteinase ADAM10 ACE can be constitutively released from the cell membrane as soluble protease. The aim of this study was to further investigate the mechanisms underlying the enhanced production of soluble ACE under pathological conditions. Using in vitro models of primary human pulmonary microvascular endothelial cells (HPMECs) and primary human umbilical vein endothelial cells (HUVECs), as well as ex vivo models of human and murine precision-cut lung slices (PCLS), we examined ACE release in response to inflammatory stimuli, hypoxia, and protein kinase C (PKC) activation, in the presence or absence of ADAM10 and ADAM17 inhibitors. Our findings demonstrate that ADAM10 is the primary sheddase responsible for inducible ACE release, while ADAM17 contributes to ACE shedding via paracrine transcriptional induction through soluble mediators. Moreover, ACE release was differentially induced by lipopolysaccharide (LPS) and hypoxia in a manner dependent on the cellular or tissue context and exhibited species-specific differences in response to the tested stimuli. Importantly, inducibly released ACE displays enhanced catalytic activity attributable to its increased extracellular concentration. Collectively, our data reveal, for the first time, that inducible ACE release is directly mediated by ADAM10, indirectly facilitated by ADAM17, and is influenced by tissue-, context-, and species-dependent factors. This complex regulation of soluble ACE release in pathological settings may be involved in fine tuning vascular pathologies.
{"title":"ADAM10 and ADAM17 differently mediate induced pulmonary ACE release by either direct proteolysis or indirect upregulation protein synthesis","authors":"Yan Yu , Aaron Babendreyer , Alessa Pabst , Anna Michely , Marie Tauscher , Christian Martin , Mark P. Kühnel , Danny D. Jonigk , Stefan Düsterhöft , Andreas Ludwig","doi":"10.1016/j.bbamcr.2026.120112","DOIUrl":"10.1016/j.bbamcr.2026.120112","url":null,"abstract":"<div><div>Angiotensin-converting enzyme (ACE) is expressed on lung endothelium and can promote hypertension and cardiovascular diseases. By the activity of the metalloproteinase ADAM10 ACE can be constitutively released from the cell membrane as soluble protease. The aim of this study was to further investigate the mechanisms underlying the enhanced production of soluble ACE under pathological conditions. Using in vitro models of primary human pulmonary microvascular endothelial cells (HPMECs) and primary human umbilical vein endothelial cells (HUVECs), as well as ex vivo models of human and murine precision-cut lung slices (PCLS), we examined ACE release in response to inflammatory stimuli, hypoxia, and protein kinase C (PKC) activation, in the presence or absence of ADAM10 and ADAM17 inhibitors. Our findings demonstrate that ADAM10 is the primary sheddase responsible for inducible ACE release, while ADAM17 contributes to ACE shedding via paracrine transcriptional induction through soluble mediators. Moreover, ACE release was differentially induced by lipopolysaccharide (LPS) and hypoxia in a manner dependent on the cellular or tissue context and exhibited species-specific differences in response to the tested stimuli. Importantly, inducibly released ACE displays enhanced catalytic activity attributable to its increased extracellular concentration. Collectively, our data reveal, for the first time, that inducible ACE release is directly mediated by ADAM10, indirectly facilitated by ADAM17, and is influenced by tissue-, context-, and species-dependent factors. This complex regulation of soluble ACE release in pathological settings may be involved in fine tuning vascular pathologies.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 3","pages":"Article 120112"},"PeriodicalIF":3.7,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145984376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-09DOI: 10.1016/j.bbamcr.2026.120109
Stefan Rose-John
Interleukin-6 is a protein of 184 amino acids and belongs to the four-helical family of cytokines. Interleukin-6 is a major inflammatory mediator and an important target in the treatment of autoimmune diseases. In addition, Interleukin-6 has regenerative and protective functions in many organs such as the liver, the intestine and the central nervous system. Interleukin-6 binds to the Interleukin-6 receptor and this complex associates with the signaling receptor subunit gp130 to initiate intracellular signaling. The Interleukin-6 receptor occurs in membrane-bound and soluble form. Recent work has demonstrated that the house-keeping functions of Interleukin-6 are mediated via the membrane-bound Interleukin-6 receptor whereas the pro-inflammatory activities are brought about via the soluble Interleukin-6 receptor. Here, the biology of the Interleukin-6 receptor and consequences of blockade of Interleukin-6 activity are reviewed. Furthermore, it is speculated that soluble cytokine receptors might play an important role in the biology of other cytokines.
{"title":"Insights from Interleukin-6 trans-signaling and implications for the control of cytokine activity","authors":"Stefan Rose-John","doi":"10.1016/j.bbamcr.2026.120109","DOIUrl":"10.1016/j.bbamcr.2026.120109","url":null,"abstract":"<div><div>Interleukin-6 is a protein of 184 amino acids and belongs to the four-helical family of cytokines. Interleukin-6 is a major inflammatory mediator and an important target in the treatment of autoimmune diseases. In addition, Interleukin-6 has regenerative and protective functions in many organs such as the liver, the intestine and the central nervous system. Interleukin-6 binds to the Interleukin-6 receptor and this complex associates with the signaling receptor subunit gp130 to initiate intracellular signaling. The Interleukin-6 receptor occurs in membrane-bound and soluble form. Recent work has demonstrated that the house-keeping functions of Interleukin-6 are mediated via the membrane-bound Interleukin-6 receptor whereas the pro-inflammatory activities are brought about via the soluble Interleukin-6 receptor. Here, the biology of the Interleukin-6 receptor and consequences of blockade of Interleukin-6 activity are reviewed. Furthermore, it is speculated that soluble cytokine receptors might play an important role in the biology of other cytokines.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 3","pages":"Article 120109"},"PeriodicalIF":3.7,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145951254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-09DOI: 10.1016/j.bbamcr.2026.120110
Giulia Fianco , Irene Taddei , Veronica Oropallo , Claudia Contadini , Alessandra Ferri , Laura Coculo , Stefano A. Serapian , Giorgio Colombo , Venturina Stagni , Daniela Barilà
Heat Shock Protein 90 (HSP90) is an essential molecular chaperone whose activity is regulated not only by co-chaperones but also by distinct post-translational modifications. Interestingly, its chaperone activity is essential for the stability of several oncogenes, among which the receptor tyrosine kinase HER2. HER2 is overexpressed in 20–30% of breast and ovarian cancers. Its overexpression triggers proliferative and transforming pathways aberrant activation and therefore frequently correlates with invasive and poor prognostic features, and associates with shorter patient survival. Of note, HSP90 inhibitors have been studied in HER2-positive breast cancer and have shown promising results. Unexpectedly, we previously reported that ATM promotes the interaction of HER2 with HSP90 therefore sustaining HER2 protein stability and tumorigenicity.
To further investigate the interplay between HER2-HSP90 and ATM, we tested the hypothesis that ATM could phosphorylate HSP90. We confirmed that ATM activation can induce the phosphorylation of HSP90 in HER2 positive breast cancer models. Point mutagenesis showed that T297 is the major site targeted by ATM kinase and importantly the unphosphorylatable mutant HSP90-T297A displays a reduced ability to interact with HER2, and to prevent its ubiquitination and degradation. Consistently, the overexpression of HSP90-T297A impinges on the viability of HER2-overexpressing cells, further supporting a role of this phosphorylation in the modulation of HER2 tumorigenicity. T297 is located in the middle domain of HSP90, a region that is involved in the interaction of HSP90 with clients. Consistently, structural studies indicate that T297 phosphorylation can indeed favor the chaperone's interaction with HER2, further supporting our hypothesis.
{"title":"ATM kinase phosphorylates HSP90 on T297 changing its conformation dynamics and promoting its interaction with HER2 receptor tyrosine kinase","authors":"Giulia Fianco , Irene Taddei , Veronica Oropallo , Claudia Contadini , Alessandra Ferri , Laura Coculo , Stefano A. Serapian , Giorgio Colombo , Venturina Stagni , Daniela Barilà","doi":"10.1016/j.bbamcr.2026.120110","DOIUrl":"10.1016/j.bbamcr.2026.120110","url":null,"abstract":"<div><div>Heat Shock Protein 90 (HSP90) is an essential molecular chaperone whose activity is regulated not only by co-chaperones but also by distinct post-translational modifications. Interestingly, its chaperone activity is essential for the stability of several oncogenes, among which the receptor tyrosine kinase HER2. HER2 is overexpressed in 20–30% of breast and ovarian cancers. Its overexpression triggers proliferative and transforming pathways aberrant activation and therefore frequently correlates with invasive and poor prognostic features, and associates with shorter patient survival. Of note, HSP90 inhibitors have been studied in HER2-positive breast cancer and have shown promising results. Unexpectedly, we previously reported that ATM promotes the interaction of HER2 with HSP90 therefore sustaining HER2 protein stability and tumorigenicity.</div><div>To further investigate the interplay between HER2-HSP90 and ATM, we tested the hypothesis that ATM could phosphorylate HSP90. We confirmed that ATM activation can induce the phosphorylation of HSP90 in HER2 positive breast cancer models. Point mutagenesis showed that T297 is the major site targeted by ATM kinase and importantly the unphosphorylatable mutant HSP90-T297A displays a reduced ability to interact with HER2, and to prevent its ubiquitination and degradation. Consistently, the overexpression of HSP90-T297A impinges on the viability of HER2-overexpressing cells, further supporting a role of this phosphorylation in the modulation of HER2 tumorigenicity. T297 is located in the middle domain of HSP90, a region that is involved in the interaction of HSP90 with clients. Consistently, structural studies indicate that T297 phosphorylation can indeed favor the chaperone's interaction with HER2, further supporting our hypothesis.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 3","pages":"Article 120110"},"PeriodicalIF":3.7,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145951138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hepatocellular carcinoma (HCC) remains a lethal malignancy with limited therapeutic options. While ubiquitin-specific peptidase 49 (USP49) has been implicated in various cancers, its role in HCC is unclear. Here, we found that USP49 is upregulated in HCC tissues and associated with poor prognosis. Functional assays demonstrated that USP49 promotes HCC proliferation and migration both in vitro and in vivo. Mechanistically, USP49 directly interacts with and deubiquitinates RACK1, thereby stabilizing it. This stabilization leads to RACK1-driven transcriptional activation of key fatty acid metabolic enzymes, enhancing triglyceride synthesis and fueling tumor growth through metabolic reprogramming. Collectively, our study identifies the USP49/RACK1 axis as a critical driver of HCC progression and nominates USP49 as a promising therapeutic target.
{"title":"USP49 regulates lipid metabolism in hepatocellular carcinoma by stabilizing RACK1 to promote tumor proliferation and migration","authors":"Weikang Xu , Jijun Shan , Jifei Wang , Yudi Zhou , Yiming Ouyang , Yananlan Chen , Qiyang Zhou","doi":"10.1016/j.bbamcr.2026.120107","DOIUrl":"10.1016/j.bbamcr.2026.120107","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) remains a lethal malignancy with limited therapeutic options. While ubiquitin-specific peptidase 49 (USP49) has been implicated in various cancers, its role in HCC is unclear. Here, we found that USP49 is upregulated in HCC tissues and associated with poor prognosis. Functional assays demonstrated that USP49 promotes HCC proliferation and migration both in vitro and in vivo. Mechanistically, USP49 directly interacts with and deubiquitinates RACK1, thereby stabilizing it. This stabilization leads to RACK1-driven transcriptional activation of key fatty acid metabolic enzymes, enhancing triglyceride synthesis and fueling tumor growth through metabolic reprogramming. Collectively, our study identifies the USP49/RACK1 axis as a critical driver of HCC progression and nominates USP49 as a promising therapeutic target.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 3","pages":"Article 120107"},"PeriodicalIF":3.7,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-07DOI: 10.1016/j.bbamcr.2026.120106
Mariah C.J. Rozier, Danielle N. Adjei, Rachel A. Radtke, Deborah N. Chadee
Mixed lineage kinase 3 (MLK3) is a serine/threonine mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K) that activates MAPK signaling pathways and promotes cell proliferation, migration and invasion. E-cadherin is an essential cell adhesion protein that mediates cell-cell interactions in epithelial adherens junctions and is crucial for the integrity of tissues and organs. Here, we demonstrate that MLK3 siRNA knockdown or kinase inhibition significantly impaired spheroid formation in SKOV3, TOV112D and OVCAR3 ovarian cancer cells, that was rescued by overexpression of E-cadherin. Endogenous MLK3 and E-cadherin were co-immunoprecipitated from ovarian cancer cell lysates; and recombinant MLK3 and E-cadherin directly interacted in vitro. MLK3 phosphorylates E-cadherin and has a positive regulatory effect on E-cadherin protein stability. Like E-cadherin, MLK3 is localized to the plasma membrane at regions of cell-cell contact, and MLK3 also has cytoplasmic and nuclear localization. Neither the MLK3-E-cadherin interaction nor the plasma membrane localization of MLK3 is dependent on β-catenin. Collectively, these results indicate a novel function for MLK3 in regulating E-cadherin protein stability, cell adhesion, and ovarian cancer spheroid formation.
混合谱系激酶3 （MLK3）是一种丝氨酸/苏氨酸丝裂原活化蛋白激酶（MAPK）激酶激酶（MAP3K），激活MAPK信号通路，促进细胞增殖、迁移和侵袭。e -钙粘蛋白是一种重要的细胞粘附蛋白，在上皮粘附连接中介导细胞间相互作用，对组织和器官的完整性至关重要。在这里，我们证明MLK3 siRNA敲低或激酶抑制显著损害SKOV3， TOV112D和OVCAR3卵巢癌细胞的球形形成，这是通过E-cadherin的过表达来拯救的。从卵巢癌细胞裂解液中共免疫沉淀内源性MLK3和E-cadherin；重组MLK3与E-cadherin在体外直接相互作用。MLK3磷酸化E-cadherin，对E-cadherin蛋白稳定性有正向调节作用。与E-cadherin一样，MLK3定位于细胞-细胞接触区域的质膜上，MLK3也具有细胞质和细胞核定位。MLK3- e -cadherin相互作用和MLK3的质膜定位都不依赖于β-catenin。总之，这些结果表明MLK3在调节E-cadherin蛋白稳定性、细胞粘附和卵巢癌球体形成方面具有新的功能。
{"title":"Regulation of E-cadherin by mixed lineage kinase 3 (MLK3) mediates cell adhesion in ovarian cancer spheroids","authors":"Mariah C.J. Rozier, Danielle N. Adjei, Rachel A. Radtke, Deborah N. Chadee","doi":"10.1016/j.bbamcr.2026.120106","DOIUrl":"10.1016/j.bbamcr.2026.120106","url":null,"abstract":"<div><div>Mixed lineage kinase 3 (MLK3) is a serine/threonine mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K) that activates MAPK signaling pathways and promotes cell proliferation, migration and invasion. E-cadherin is an essential cell adhesion protein that mediates cell-cell interactions in epithelial adherens junctions and is crucial for the integrity of tissues and organs. Here, we demonstrate that MLK3 siRNA knockdown or kinase inhibition significantly impaired spheroid formation in SKOV3, TOV112D and OVCAR3 ovarian cancer cells, that was rescued by overexpression of E-cadherin. Endogenous MLK3 and E-cadherin were co-immunoprecipitated from ovarian cancer cell lysates; and recombinant MLK3 and E-cadherin directly interacted <em>in vitro</em>. MLK3 phosphorylates E-cadherin and has a positive regulatory effect on E-cadherin protein stability. Like E-cadherin, MLK3 is localized to the plasma membrane at regions of cell-cell contact, and MLK3 also has cytoplasmic and nuclear localization. Neither the MLK3-E-cadherin interaction nor the plasma membrane localization of MLK3 is dependent on β-catenin. Collectively, these results indicate a novel function for MLK3 in regulating E-cadherin protein stability, cell adhesion, and ovarian cancer spheroid formation.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 3","pages":"Article 120106"},"PeriodicalIF":3.7,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145923181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-07DOI: 10.1016/j.bbamcr.2026.120108
Yuan Jin , Chao Hu , Dianfu Pang
Colorectal cancer (CRC) exhibits altered lipid metabolism associated with therapy resistance. FOXA2, a lipid metabolism activator, mediates fatty acid β-oxidation in CRC, but its role in irinotecan (CPT-11) resistance remains unclear. Through bioinformatics analysis, clinical sample assessment, and cell line validation, we confirmed the expression of FOXA2 in CRC. The impact of FOXA2 on the viability and CPT-11 sensitivity of CRC cells was tested via CCK-8 assay. DNA damage was evaluated using the comet assay and monitoring of γ-H2AX foci. Assay kits determined the concentrations of triglycerides, cholesterol, and phospholipids, as well as the rate of fatty acid β-oxidation. Protein expression related to lipid metabolism (ACLY, SCD1) was identified by WB. Bioinformatic tools were used to analyze the potential transcriptional control of Aldolase B (ALDOB) by FOXA2 and to scrutinize ALDOB expression in CRC. The molecular interaction was substantiated by dual-luciferase and CHIP assays. IHC was performed on an xenograft tumor model in mice to measure FOXA2, ALDOB, and Ki67 expression. Oil Red O staining was applied to detect triglyceride presence, and TUNEL was used to gauge apoptosis. The results showed that FOXA2 overexpression correlated with CPT-11 resistance in CRC. FOXA2 transcriptionally activated ALDOB, enhancing fatty acid β-oxidation and suppressing drug sensitivity. FOXA2 inhibition sensitized CRC cells to CPT-11 in vitro/vivo, while ALDOB overexpression restored resistance. These findings indicate that FOXA2 promotes CPT-11 resistance by upregulating ALDOB-mediated fatty acid β-oxidation. Targeting the FOXA2/ALDOB axis may overcome chemoresistance in CRC.
{"title":"FOXA2/ALDOB axis modulation of fatty acid beta-oxidation influences irinotecan resistance in colorectal cancer","authors":"Yuan Jin , Chao Hu , Dianfu Pang","doi":"10.1016/j.bbamcr.2026.120108","DOIUrl":"10.1016/j.bbamcr.2026.120108","url":null,"abstract":"<div><div>Colorectal cancer (CRC) exhibits altered lipid metabolism associated with therapy resistance. FOXA2, a lipid metabolism activator, mediates fatty acid β-oxidation in CRC, but its role in irinotecan (CPT-11) resistance remains unclear. Through bioinformatics analysis, clinical sample assessment, and cell line validation, we confirmed the expression of FOXA2 in CRC. The impact of FOXA2 on the viability and CPT-11 sensitivity of CRC cells was tested <em>via</em> CCK-8 assay. DNA damage was evaluated using the comet assay and monitoring of γ-H2AX foci. Assay kits determined the concentrations of triglycerides, cholesterol, and phospholipids, as well as the rate of fatty acid β-oxidation. Protein expression related to lipid metabolism (ACLY, SCD1) was identified by WB. Bioinformatic tools were used to analyze the potential transcriptional control of Aldolase B (ALDOB) by <em>FOXA2</em> and to scrutinize <em>ALDOB</em> expression in CRC. The molecular interaction was substantiated by dual-luciferase and CHIP assays. IHC was performed on an xenograft tumor model in mice to measure FOXA2, ALDOB, and Ki67 expression. Oil Red O staining was applied to detect triglyceride presence, and TUNEL was used to gauge apoptosis. The results showed that FOXA2 overexpression correlated with CPT-11 resistance in CRC. FOXA2 transcriptionally activated ALDOB, enhancing fatty acid β-oxidation and suppressing drug sensitivity. FOXA2 inhibition sensitized CRC cells to CPT-11 <em>in vitro</em>/vivo, while ALDOB overexpression restored resistance. These findings indicate that FOXA2 promotes CPT-11 resistance by upregulating ALDOB-mediated fatty acid β-oxidation. Targeting the FOXA2/ALDOB axis may overcome chemoresistance in CRC.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 3","pages":"Article 120108"},"PeriodicalIF":3.7,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145942380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Adenosine-to-inosine (A-to-I) RNA editing catalyzed by adenosine deaminase acting on RNA (ADAR) 1 is the most abundant RNA modification in humans. We noticed that there are multiple A-to-I RNA editing sites in the 3′-UTR of cytochrome c (CYCS), a mitochondrial protein involved in the initiation of apoptosis. We aimed to clarify the impact of ADAR1 on the regulation of CYCS expression, its mechanism, and its biological and pharmacological significance. In human hepatocellular carcinoma-derived HepG2 or Huh-7 cells, siRNA-mediated knockdown of ADAR1 (siADAR1) reduced CYCS protein levels without affecting mRNA levels, suggesting that ADAR1 facilitates CYCS translation. Sanger sequence analysis showed that multiple adenosines in the 3′-UTR of CYCS are highly edited by ADAR1. The CYCS protein level in HepG2 CYCS 3′-UTR-deleted cells in which the 3′-UTR of CYCS was deleted by the CRISPR/Cas9 system was not decreased by siADAR1, indicating that the 3′-UTR is required for ADAR1-dependent translational regulation. The pulldown assay revealed that siADAR1 increases the binding of CYCS mRNA to RNA-binding proteins with disordered regions, suggesting that stress granules, a membrane-less organelle formed by such proteins with intrinsically disordered regions, might trap CYCS mRNA and suppress its translation. Treatment with ISRIB, an inhibitor of stress granule formation, attenuated the siADAR1-mediated decrease in CYCS protein levels. Interestingly, sorafenib-induced apoptosis in HepG2 cells was repressed by siADAR1, but this repression was not observed in HepG2 CYCS 3′-UTR-deleted cells. Collectively, this study clarified that ADAR1 upregulates CYCS translation by inhibiting stress granule formation and thereby can facilitate anticancer agent-induced apoptosis.
{"title":"ADAR1 upregulates the translation of cytochrome c via the inhibition of translocation into stress granules, facilitating apoptosis by an anticancer agent","authors":"Motoki Isono , Tomoka Yamakawa , Kyoka Nagaoka , Masataka Nakano , Tatsuki Fukami , Miki Nakajima","doi":"10.1016/j.bbamcr.2025.120104","DOIUrl":"10.1016/j.bbamcr.2025.120104","url":null,"abstract":"<div><div>Adenosine-to-inosine (A-to-I) RNA editing catalyzed by adenosine deaminase acting on RNA (ADAR) 1 is the most abundant RNA modification in humans. We noticed that there are multiple A-to-I RNA editing sites in the 3′-UTR of cytochrome <em>c</em> (CYCS), a mitochondrial protein involved in the initiation of apoptosis. We aimed to clarify the impact of ADAR1 on the regulation of CYCS expression, its mechanism, and its biological and pharmacological significance. In human hepatocellular carcinoma-derived HepG2 or Huh-7 cells, siRNA-mediated knockdown of ADAR1 (siADAR1) reduced CYCS protein levels without affecting mRNA levels, suggesting that ADAR1 facilitates CYCS translation. Sanger sequence analysis showed that multiple adenosines in the 3′-UTR of CYCS are highly edited by ADAR1. The CYCS protein level in HepG2 <sup><em>CYCS 3′-UTR-deleted</em></sup> cells in which the 3′-UTR of CYCS was deleted by the CRISPR/Cas9 system was not decreased by siADAR1, indicating that the 3′-UTR is required for ADAR1-dependent translational regulation. The pulldown assay revealed that siADAR1 increases the binding of CYCS mRNA to RNA-binding proteins with disordered regions, suggesting that stress granules, a membrane-less organelle formed by such proteins with intrinsically disordered regions, might trap CYCS mRNA and suppress its translation. Treatment with ISRIB, an inhibitor of stress granule formation, attenuated the siADAR1-mediated decrease in CYCS protein levels. Interestingly, sorafenib-induced apoptosis in HepG2 cells was repressed by siADAR1, but this repression was not observed in HepG2 <sup><em>CYCS 3′-UTR-deleted</em></sup> cells. Collectively, this study clarified that ADAR1 upregulates CYCS translation by inhibiting stress granule formation and thereby can facilitate anticancer agent-induced apoptosis.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 3","pages":"Article 120104"},"PeriodicalIF":3.7,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145931913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-05DOI: 10.1016/j.bbamcr.2026.120105
Isabel Ramón Roth , Jana I. Führing , Christoph Garbers
Cytokines activate their target cells via binding to specific receptors on the cell surface. The receptor glycoprotein 130 (gp130) is ubiquitously expressed throughout the human body and used by nine members of the interleukin-6 (IL-6) family of cytokines to facilitate the initiation of intracellular signalling cascades. Although these cytokines share the same protein fold, gp130 requires substantial promiscuity in order to bind such diverse proteins. In this review, we summarize what is currently known about the structural features of gp130 that allow this flexibility towards its binding partners. We compare this to the other non-signalling α-receptors and signal-transducing β-receptors of the family and discuss how IL-6 family cytokines form signalling complexes at the cell surface that lead to the activation of intracellular signalling cascades. We further show how mutations found in human patients influence gp130 signalling, and describe how such knowledge can be used to create tailor-made designer proteins that can be used as next-generation therapeutics for the treatment of inflammatory diseases.
{"title":"Understanding complex formation of gp130 cytokines for the design of selective therapeutics","authors":"Isabel Ramón Roth , Jana I. Führing , Christoph Garbers","doi":"10.1016/j.bbamcr.2026.120105","DOIUrl":"10.1016/j.bbamcr.2026.120105","url":null,"abstract":"<div><div>Cytokines activate their target cells via binding to specific receptors on the cell surface. The receptor glycoprotein 130 (gp130) is ubiquitously expressed throughout the human body and used by nine members of the interleukin-6 (IL-6) family of cytokines to facilitate the initiation of intracellular signalling cascades. Although these cytokines share the same protein fold, gp130 requires substantial promiscuity in order to bind such diverse proteins. In this review, we summarize what is currently known about the structural features of gp130 that allow this flexibility towards its binding partners. We compare this to the other non-signalling α-receptors and signal-transducing β-receptors of the family and discuss how IL-6 family cytokines form signalling complexes at the cell surface that lead to the activation of intracellular signalling cascades. We further show how mutations found in human patients influence gp130 signalling, and describe how such knowledge can be used to create tailor-made designer proteins that can be used as next-generation therapeutics for the treatment of inflammatory diseases.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 3","pages":"Article 120105"},"PeriodicalIF":3.7,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145916918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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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