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• LPA promotes the migration of skeletal muscle-isolated FAPs through LPA 1 signaling. • YAP activity is required for LPA-induced migration of FAPs. • FAPs isolated from dystrophic muscle possess an enhanced migration response to LPA, behavior which can be blocked by inhibiting LPA 1/3 or YAP activity. Skeletal muscle fibrosis is defined as the excessive accumulation of extracellular matrix (ECM) components and is a hallmark of muscular dystrophies. Fibro-adipogenic progenitors (FAPs) are the main source of ECM, and thus have been strongly implicated in fibrogenesis. In skeletal muscle fibrotic models, including muscular dystrophies, FAPs undergo dysregulations in terms of proliferation, differentiation, and apoptosis, however few studies have explored the impact of FAPs migration. Here, we studied fibroblast and FAPs migration and identified lysophosphatidic acid (LPA), a signaling lipid central to skeletal muscle fibrogenesis, as a significant migration inductor. We identified LPA receptor 1 (LPA 1) mediated signaling as crucial for this effect through a mechanism dependent on the Hippo pathway, another pathway implicated in fibrosis across diverse tissues. This cross-talk favors the activation of the Yes-associated protein 1 (YAP) and Transcriptional coactivator with PDZ-binding motif (TAZ), leading to increased expression of fibrosis-associated genes. This study reveals the role of YAP in LPA-mediated fibrotic responses as inhibition of YAP transcriptional coactivator activity hinders LPA-induced migration in fibroblasts and FAPs. Moreover, we found that FAPs derived from the mdx 4cv mice, a murine model of Duchenne muscular dystrophy, display a heightened migratory phenotype due to enhanced LPA signaling compared to wild-type FAPs. Remarkably, we found that the inhibition of LPA 1 or YAP transcriptional coactivator activity in mdx 4cv FAPs reverts this phenotype. In summary, the identified LPA-LPA 1 -YAP pathway emerges as a critical driver of skeletal muscle FAPs migration and provides insights into potential novel targets to mitigate fibrosis in muscular dystrophies. [ABSTRACT FROM AUTHOR]

Intraflagellar transport (IFT) proteins have been reported to regulate cell growth and differentiation as the essential functional component of primary cilia. The effects of IFT80 on early bone healing of extraction sockets have not been well studied. To investigate whether deletion of Ift80 in alveolar bone‐derived mesenchymal stem cells (aBMSCs) affected socket bone healing, we generated a mouse model of specific knockout of Ift80 in Prx1 mesenchymal lineage cells (Prx1Cre;IFT80f/f). Our results demonstrated that deletion of IFT80 in Prx1 lineage cells decreased the trabecular bone volume, ALP‐positive osteoblastic activity, TRAP‐positive osteoclastic activity, and OSX‐/COL I‐/OCN‐positive areas in tooth extraction sockets of Prx1Cre; IFT80f/f mice compared with IFT80f/f littermates. Furthermore, aBMSCs from Prx1Cre; IFT80f/f mice showed significantly decreased osteogenic markers and downregulated migration and proliferation capacity. Importantly, the overexpression of TAZ recovered significantly the expressions of osteogenic markers and migration capacity of aBMSCs. Lastly, the local administration of lentivirus for TAZ enhanced the expression of RUNX2 and OSX and promoted early bone healing of extraction sockets from Prx1Cre; IFT80f/f mice. Thus, IFT80 promotes osteogenesis and early bone healing of tooth sockets through the activation of TAZ/RUNX2 pathway. [ABSTRACT FROM AUTHOR]

Pulmonary fibrosis (PF) is a severe, irreversible lung disease characterized by progressive scarring, with idiopathic pulmonary fibrosis (IPF) being the most prevalent form. IPF's pathogenesis involves repetitive lung epithelial injury leading to fibroblast activation and excessive extracellular matrix (ECM) deposition. The prognosis for IPF is poor, with limited therapeutic options like nintedanib and pirfenidone offering only modest benefits. Emerging research highlights the dysregulation of the yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) signaling pathway as a critical factor in PF. YAP and TAZ, components of the Hippo pathway, play significant roles in cell proliferation, differentiation, and fibrosis by modulating gene expression through interactions with TEA domain (TEAD) transcription factors. The aberrant activation of YAP/TAZ in lung tissue promotes fibroblast activation and ECM accumulation. Targeting the YAP/TAZ pathway offers a promising therapeutic avenue. Preclinical studies have identified potential treatments, such as trigonelline, dopamine receptor D1 (DRD1) agonists, and statins, which inhibit YAP/TAZ activity and demonstrate antifibrotic effects. These findings underscore the importance of YAP/TAZ in PF pathogenesis and the potential of novel therapies aimed at this pathway, suggesting a new direction for improving IPF treatment outcomes. Further research is needed to validate these approaches and translate them into clinical practice. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) and inflammatory bowel disease (IBD) are escalating global health concerns. Despite their distinct clinical presentations, both disorders share intricate genetic and molecular interactions. The Hippo signaling pathway plays a crucial role in regulating cell processes and is implicated in the pathogenesis of IBD and CRC. Circular RNAs (circRNAs) have gained attention for their roles in various diseases, including IBD and CRC. However, a comprehensive understanding of specific circRNAs involved in both IBD and CRC, and their functional roles is lacking. Here, it is found that circHIPK2 (hsa_circRNA_104507) is a bona fide circRNA consistently upregulated in both IBD and CRC suggesting its potential as a biomarker. Furthermore, silencing of circHIPK2 suppressed the growth of CRC cells in vitro and in vivo. Interestingly, decreased circHipk2 potentiated dextran sulfate sodium (DSS)‐induced colitis but alleviated colitis‐associated tumorigenesis. Most significantly, mechanistic investigations further unveil that circHIPK2, mediated by FUS, interacting with EIF4A3 to promote the translation of TAZ, ultimately increasing the transcription of downstream target genes CCN1 and CCN2. Taken together, circHIPK2 emerges as a key player in the shared mechanisms of IBD and CRC, modulating the Hippo signaling pathway. CircHIPK2‐EIF4A3 axis contributes to cell growth in intestinal epithelial of colitis and CRC by enhancing TAZ translation. [ABSTRACT FROM AUTHOR]

Background: Ischemic stroke leads a primary cause of mortality in human diseases, with a high disability rate worldwide. This study aims to investigate the function of β‐1,4‐galactosyltransferase 1 (B4galt1) in mouse brain ischemia/reperfusion (I/R) injury. Methods: Recombinant human B4galt1 (rh‐B4galt1) was intranasally administered to the mice model of middle cerebral artery occlusion (MCAO)/reperfusion. In this study, the impact of rh‐B4galt1 on cerebral injury assessed using multiple methods, including the neurological disability status scale, 2,3,5‐triphenyltetrazolium chloride (TTC), Nissl and TUNEL staining. This study utilized laser speckle Doppler flowmeter to monitor the cerebral blood flow. Western blotting was performed to assess the protein expression levels, and fluorescence‐labeled dihydroethidium method was performed to determine the superoxide anion generation. Assay kits were used for the measurement of iron, malondialdehyde (MDA) and glutathione (GSH) levels. Results: We demonstrated that rh‐B4galt1 markedly improved neurological function, reduced cerebral infarct volume and preserved the completeness of blood–brain barrier (BBB) for preventing damage. These findings further illustrated that rh‐B4galt1 alleviated oxidative stress, lipid peroxidation, as well as iron deposition induced by I/R. The vital role of ferroptosis was proved in brain injury. Furthermore, the rh‐B4galt1 could increase the levels of TAZ, Nrf2 and HO‐1 after I/R. And TAZ‐siRNA and ML385 reversed the neuroprotective effects of rh‐B4galt1. Conclusions: The results indicated that rh‐B4galt1 implements neuroprotective effects by modulating ferroptosis, primarily via upregulating TAZ/Nrf2/HO‐1 pathway. Thus, B4galt1 could be seen as a promising novel objective for ischemic stroke therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: The YAP/TAZ signaling pathways, which is involved in tumor development and proliferation in a variety of solid tumors, inhibits hypoxia-induced cell death, increases and stabilizes angiogenesis, and activates tumor proliferation, both independently and in conjunction with HIF in hypoxic tumors. It also promotes tumor metastasis by regulating different TME environments. Therefore, understanding the activity of YAP/TAZ as a mechanism of tumor development may lead to the development of novel therapeutic strategies. In solid tumors such as hepatocellular carcinoma (HCC), hypoxia is one of the important mechanisms of cancer development that closely influences cancer development, survival, and metastasis. The development of treatments for cancer was temporarily revolutionized by immunotherapy but continues to be constrained by limited response rates and the resistance and high costs required for the development of new and innovative strategies. In particular, solid tumors, including HCC, a multi-vascular tumor type, are sensitive to hypoxia and generate many blood vessels for metastasis and development, making it difficult to treat HCC, not only with immunotherapy but also with drugs targeting blood vessels. Therefore, in order to develop a treatment strategy for hypoxic tumors, various mechanisms must be explored and analyzed to treat these impregnable solid tumors. To date, tumor growth mechanisms linked to hypoxia are known to be complex and coexist with various signal pathways, but recently, mechanisms related to the Hippo signal pathway are emerging. Interestingly, Hippo YAP/TAZ, which appear during early tumor and normal tumor growth, and YAP/TAZ, which appear during hypoxia, help tumor growth and proliferation in different directions. Peculiarly, YAP/TAZ, which have different phosphorylation directions in the hypoxic environment of tumors, are involved in cancer proliferation and metastasis in various carcinomas, including HCC. Analyzing the mechanisms that regulate the function and expression of YAP in addition to HIF in the complex hypoxic environment of tumors may lead to a variety of anti-cancer strategies and combining HIF and YAP/TAZ may develop the potential to change the landscape of cancer treatment. [ABSTRACT FROM AUTHOR]

Introduction: Transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo signaling pathway effector, maintains the balance of cell proliferation, differentiation, and death. However, the role of TAZ in tubular cell survival and acute kidney injury (AKI) remains largely unknown. Methods: We used the RNA-seq database, Western blot, and immunohistochemistry to examine TAZ expression in kidneys from cisplatin-induced AKI. We generated tubular-specific TAZ knockout mice to assess the role of TAZ in cisplatin-induced renal toxicity. Immunoprecipitation-mass spectrometry followed standard procedures. Results: TAZ was activated in tubular cells in kidneys injected with cisplatin. Conditional deletion of TAZ in tubular cells confers ferroptosis resistance and protects kidneys from cisplatin-induced AKI, whereas overexpression of TAZ(S89A) exacerbates cisplatin-induced ferroptosis. Inhibition of ferroptosis with ferrostatin-1 potently preserves renal function and alleviates morphological injury and tubular cell ferroptosis induced by cisplatin. Mechanistically, in a PPARδ-dependent manner, but not TEAD, TAZ reduces the expression of glutathione peroxidase 4 (GPX4), thus exacerbating cisplatin-induced ferroptosis. Conclusions: Our findings show that cisplatin-induced AKI and tubular cell ferroptosis are mediated by TAZ-PPARδ interaction through regulation of GPX4, highlighting TAZ as a potential therapeutic candidate for AKI.

Abstract Background Human periodontal ligament stem cells (hPDLSCs) are important candidate seed cells for periodontal tissue engineering, but the presence of lipopolysaccharide(LPS) in periodontal tissues inhibits the self-renewal and osteogenic differentiation of hPDLSCs. Our previous studies demonstrated that TAZ is a positive regulator of osteogenic differentiation of hPDLSCs, but whether TAZ can protect hPDLSCs from LPS is still unknown. The present study aimed to explore the regulatory effect of TAZ on the osteogenic differentiation of hPDLSCs in an LPS-induced inflammatory model, and to preliminarily reveal the molecular mechanisms related to the NF-κB signaling pathway. Methods LPS was added to the culture medium of hPDLSCs. The influence of LPS on hPDLSC proliferation was analyzed by CCK-8 assays. The effects of LPS on hPDLSC osteogenic differentiation were detected by Alizarin Red staining, ALP staining, Western Blot and qRT-PCR analysis of osteogenesis-related genes. The effects of LPS on the osteogenic differentiation of hPDLSCs with TAZ overexpressed or knocked down via lentivirus were analyzed. NF-κB signaling in hPDLSCs was analyzed by Western Blot and immunofluorescence. Results LPS inhibited the osteogenic differentiation of hPDLSCs, inhibited TAZ expression, and activated the NF-κB signaling pathway. Overexpressing TAZ in hPDLSCs partly reversed the negative effects of LPS on osteogenic differentiation and inhibited the activation of the NF-κB pathway by LPS. TAZ knockdown enhanced the inhibitory effects of LPS on osteogenesis. Conclusion Overexpressing TAZ could partly reverse the inhibitory effects of LPS on the osteogenic differentiation of hPDLSCs, possibly through inhibiting the NF-κB signaling pathway. TAZ is a potential target for improving hPDLSC-based periodontal tissue regeneration in inflammatory environments.

Background: Brain–lung–thyroid syndrome (BLTS) is caused by NKX2-1 haploinsufficiency, resulting in chorea/choreoathetosis, respiratory problems, and hypothyroidism. Genes interacting with NKX2-1 mutants influence its phenotypic variability. We report a novel NKX2-1 missense variant and the modifier function of TAZ/WWTR1 in BLTS. Methods: A child with BLTS underwent next-generation sequencing panel testing for thyroid disorders. His family was genotyped for NKX2-1 variants and screened for germline mosaicism. Mutant NKX2-1 was generated, and transactivation assays were performed on three NKX2-1 target gene promoters. DNA binding capacity and protein–protein interaction were analyzed. Results: The patient had severe BLTS and carried a novel missense variant c.632A>G (p.N211S) in NKX2-1, which failed to bind to specific DNA promoters, reducing their transactivation. TAZ cotransfection did not significantly increase transcription of these genes, although the variant retained its ability to bind to TAZ. Conclusions: We identify a novel pathogenic NKX2-1 variant that causes severe BLTS and is inherited through germline mosaicism. The mutant lacks DNA-binding capacity, impairing transactivation and suggesting that NKX2-1 binding to DNA is essential for TAZ-mediated transcriptional rescue. [ABSTRACT FROM AUTHOR]

Hippo signaling in Drosophila and mammals is prominent in regulating cell proliferation, death and differentiation. Hippo signaling effectors (YAP and TAZ; also known as YAP1 and WWTR1, respectively) exhibit crosstalk with transforming growth factor-β (TGF-β)--Smad and Wnt/β-catenin pathways. Previously, we implicated Smad7 and β-catenin in mammalian myogenesis. Therefore, we assessed a potential role of TAZ on the Smad7--β-catenin complex in muscle cells. Here, we document functional interactions between Smad7, TAZ and β-catenin in mouse myogenic cells. Ectopic TAZ expression resulted in repression of the muscle-specific creatine kinase muscle (Ckm) gene promoter and its corresponding protein level. Depletion of endogenous TAZ enhanced Ckm promoter activation. Ectopic TAZ, while potently active on a TEAD reporter (HIP-HOP), repressed myogenin (Myog) and Myod1 enhancer regions and myogenin protein level. Additionally, a Wnt/β-catenin readout (TOP flash) demonstrated TAZ-mediated inhibition of β-catenin activity. In myoblasts, TAZ was predominantly localized in nuclear speckles, while in differentiation conditions TAZ was hyperphosphorylated at Ser89, leading to enhanced cytoplasmic sequestration. Finally, live-cell imaging indicated that TAZ exhibits properties of liquid--liquid phase separation (LLPS). These observations indicate that TAZ, as an effector of Hippo signaling, suppresses the myogenic differentiation machinery. [ABSTRACT FROM AUTHOR]

The liver plays a crucial role in maintaining whole-body homeostasis in both health and disease, engaging in important communication with other organs. The coordination of multiple signaling pathways is essential for facilitating such interorgan communication. Among these pathways, the transforming growth factor-ß (TGF-ß) and HIPPO signaling pathways serve critical functions as tumor suppressors, exerting pivotal control over liver development, size, and tissue regeneration. In the normal hepatic context, these pathways exhibit significant crosstalk through various molecular mechanisms. This interaction is context-dependent within the hepatic microenvironment, regulating diverse cellular processes from development to adulthood. Disruptions in the regulation of these pathways and their crosstalk contribute to the onset of liver diseases. This review delves into the intricate interplay between the canonical pathways of TGF-ß and HIPPO, exploring their involvement in liver development and various pathologies such as fibrosis, cirrhosis, and tumorigenesis. Special attention is given to their impact on the epithelial-to-mesenchymal transition process, a crucial element associated with liver wound healing and cancer metastasis. By addressing these molecular interactions, the review aimed to provide insights into the underlying mechanisms that influence liver physiology and pathology, offering potential avenues for therapeutic interventions. [ABSTRACT FROM AUTHOR]

Background: Human periodontal ligament stem cells (hPDLSCs) are important candidate seed cells for periodontal tissue engineering, but the presence of lipopolysaccharide(LPS) in periodontal tissues inhibits the self-renewal and osteogenic differentiation of hPDLSCs. Our previous studies demonstrated that TAZ is a positive regulator of osteogenic differentiation of hPDLSCs, but whether TAZ can protect hPDLSCs from LPS is still unknown. The present study aimed to explore the regulatory effect of TAZ on the osteogenic differentiation of hPDLSCs in an LPS-induced inflammatory model, and to preliminarily reveal the molecular mechanisms related to the NF-κB signaling pathway. Methods: LPS was added to the culture medium of hPDLSCs. The influence of LPS on hPDLSC proliferation was analyzed by CCK-8 assays. The effects of LPS on hPDLSC osteogenic differentiation were detected by Alizarin Red staining, ALP staining, Western Blot and qRT-PCR analysis of osteogenesis-related genes. The effects of LPS on the osteogenic differentiation of hPDLSCs with TAZ overexpressed or knocked down via lentivirus were analyzed. NF-κB signaling in hPDLSCs was analyzed by Western Blot and immunofluorescence. Results: LPS inhibited the osteogenic differentiation of hPDLSCs, inhibited TAZ expression, and activated the NF-κB signaling pathway. Overexpressing TAZ in hPDLSCs partly reversed the negative effects of LPS on osteogenic differentiation and inhibited the activation of the NF-κB pathway by LPS. TAZ knockdown enhanced the inhibitory effects of LPS on osteogenesis. Conclusion: Overexpressing TAZ could partly reverse the inhibitory effects of LPS on the osteogenic differentiation of hPDLSCs, possibly through inhibiting the NF-κB signaling pathway. TAZ is a potential target for improving hPDLSC-based periodontal tissue regeneration in inflammatory environments. [ABSTRACT FROM AUTHOR]

Abstract Colorectal cancer (CRC) and inflammatory bowel disease (IBD) are escalating global health concerns. Despite their distinct clinical presentations, both disorders share intricate genetic and molecular interactions. The Hippo signaling pathway plays a crucial role in regulating cell processes and is implicated in the pathogenesis of IBD and CRC. Circular RNAs (circRNAs) have gained attention for their roles in various diseases, including IBD and CRC. However, a comprehensive understanding of specific circRNAs involved in both IBD and CRC, and their functional roles is lacking. Here, it is found that circHIPK2 (hsa_circRNA_104507) is a bona fide circRNA consistently upregulated in both IBD and CRC suggesting its potential as a biomarker. Furthermore, silencing of circHIPK2 suppressed the growth of CRC cells in vitro and in vivo. Interestingly, decreased circHipk2 potentiated dextran sulfate sodium (DSS)‐induced colitis but alleviated colitis‐associated tumorigenesis. Most significantly, mechanistic investigations further unveil that circHIPK2, mediated by FUS, interacting with EIF4A3 to promote the translation of TAZ, ultimately increasing the transcription of downstream target genes CCN1 and CCN2. Taken together, circHIPK2 emerges as a key player in the shared mechanisms of IBD and CRC, modulating the Hippo signaling pathway. CircHIPK2‐EIF4A3 axis contributes to cell growth in intestinal epithelial of colitis and CRC by enhancing TAZ translation.

PurposeWe sought to define the role of Wwtr1 in murine ocular structure and function and determine the role of mechanotransduction in Fuchs' endothelial corneal dystrophy (FECD), with emphasis on interactions between corneal endothelial cells (CEnCs) and Descemet's membrane (DM).MethodsA Wwtr1 deficient mouse colony was established, and advanced ocular imaging, atomic force microscope (AFM), and histology/immunofluorescence were performed. Corneal endothelial wound healing was assessed using cryoinjury and phototherapeutic keratectomy in Wwtr1 deficient mice. Expression of WWTR1/TAZ was determined in the corneal endothelium from normal and FECD-affected patients; WWTR1 was screened for coding sequence variants in this FECD cohort.ResultsMice deficient in Wwtr1 had reduced CEnC density, abnormal CEnC morphology, softer DM, and thinner corneas versus wildtype controls by 2 months of age. Additionally, CEnCs had altered expression and localization of Na/K-ATPase and ZO-1. Further, Wwtr1 deficient mice had impaired CEnC wound healing. The WWTR1 transcript was highly expressed in healthy human CEnCs comparable to other genes implicated in FECD pathogenesis. Although WWTR1 mRNA expression was comparable between healthy and FECD-affected patients, WWTR1/TAZ protein concentrations were higher and localized to the nucleus surrounding guttae. No genetic associations were found in WWTR1 and FECD in a patient cohort compared to controls.ConclusionsThere are common phenotypic abnormalities seen between Wwtr1 deficient and FECD-affected patients, suggesting that Wwtr1 deficient mice could function as a murine model of late-onset FECD. Despite the lack of a genetic association between FECD and WWTR1, aberrant WWTR1/TAZ protein subcellular localization and degradation may play critical roles in the pathogenesis of FECD.

MESH1 is the metazoan homolog of bacterial SpoT, the main phosphatase that dephosphorylates and degrades (p)ppGpp, the alarmone involved in the bacterial stringent response. The functional role of MESH1 in human cells is unknown. To define the global transcriptional response to MESH1 knockdown, we employed microarrays to perform transcriptome analysis of H1975 when the MESH1 was knocked down using three independent siRNAs targeting MESH1. The changes of each gene were derived by zero-transformation, followed by filtering to derive the genes affected by MESH1 knockdown. These datasets showed the transcriptional features of the mammalian stringent response and identified a prominent TAZ repression. Thus, we performed a second experiment to determine the contribution of TAZ repression to the transcriptional response of MESH1 knockdown by comparing the effects of MESH1-knockdown gene signatures in H1975 cells transduced with control or constitutive active TAZ (TAZS89A). The transcriptional response of these two cells to MESH1 was derived by zero transformation, followed by the effects of TAZ restoration to define the contribution of TAZ repression to the transcriptome features of human stringent response. The transcriptome data will be useful for the mechanistic understanding of the functional role of MESH1 in human cancer cells.

Abstract A cell is a dynamic system in which various processes occur simultaneously. In particular, intra- and intercellular signaling pathway crosstalk has a significant impact on a cell’s life cycle, differentiation, proliferation, growth, regeneration, and, consequently, on the normal functioning of an entire organ. Hippo signaling and YAP/TAZ nucleocytoplasmic shuttling play a pivotal role in normal development, homeostasis, and tissue regeneration, particularly in lung cells. Intersignaling communication has a significant impact on the core components of the Hippo pathway and on YAP/TAZ localization. This review describes the crosstalk between Hippo signaling and key lung signaling pathways (WNT, SHH, TGFβ, Notch, Rho, and mTOR) using lung cells as an example and highlights the remaining unanswered questions.

Abstract YAP and TAZ, the Hippo pathway terminal transcriptional activators, are frequently upregulated in cancers. In tumor cells, they have been mainly associated with increased tumorigenesis controlling different aspects from cell cycle regulation, stemness, or resistance to chemotherapies. In fewer cases, they have also been shown to oppose cancer progression, including by promoting cell death through the action of the p73/YAP transcriptional complex, in particular after chemotherapeutic drug exposure. Using HCT116 cells, we show here that oxaliplatin treatment led to core Hippo pathway down-regulation and nuclear accumulation of TAZ. We further show that TAZ was required for the increased sensitivity of HCT116 cells to oxaliplatin, an effect that appeared independent of p73, but which required the nuclear relocalization of TAZ. Accordingly, Verteporfin and CA3, two drugs affecting the activity of YAP and TAZ, showed antagonistic effects with oxaliplatin in co-treatments. Importantly, using several colorectal cell lines, we show that the sensitizing action of TAZ to oxaliplatin is dependent on the p53 status of the cells. Our results support thus an early action of TAZ to sensitize cells to oxaliplatin, consistent with a model in which nuclear TAZ in the context of DNA damage and p53 activity pushes cells towards apoptosis.

Abstract Background Transcriptional coactivator with PDZ-biding motif (TAZ) is widely expressed in most tissues and interacts with several transcription factors to regulate cell proliferation, differentiation, and death, thereby influencing organ development and size control. However, very little is known about the function of TAZ in the immune system and its association with inflammatory skin diseases, so we investigated the role of TAZ in the pathogenesis of psoriasis. Results Interestingly, TAZ was expressed in mast cells associated, particularly in lysosomes, and co-localized with histamine-releasing factor (HRF). TAZ deficiency promoted mast cell maturation and increased HRF expression and secretion by mast cells. The upregulation of HRF in TAZ deficiency was not due to increased transcription but to protein stabilization, and TAZ restoration into TAZ-deficient cells reduced HRF protein. Interestingly, imiquimod (IMQ)-induced psoriasis, in which HRF serves as a major pro-inflammatory factor, was more severe in TAZ KO mice than in WT control. HRF expression and secretion were increased by IMQ treatment and were more pronounced in TAZ KO mice treated with IMQ. Conclusions Thus, as HRF expression was stabilized in TAZ KO mice, psoriatic pathogenesis progressed more rapidly, indicating that TAZ plays an important role in preventing psoriasis by regulating HRF protein stability. Graphical Abstract

Background: Cancer metastasis is dependent on cell migration. Several mechanisms, including epithelial-to-mesenchymal transition (EMT) and actin fiber formation, could be involved in cancer cell migration. As a downstream effector of the Hippo signaling pathway, transcriptional coactivator with PDZbinding motif (TAZ) is recognized as a key mediator of the metastatic ability of breast cancer cells. We aimed to examine whether TAZ affects the migration of breast cancer cells through the regulation of EMT or actin cytoskeleton. Methods: MCF-7 and MDA-MB-231 cells were treated with siRNA to attenuate TAZ abundance. Transwell migration assay and scratch wound healing assay were performed to study the effects of TAZ knockdown on cancer cell migration. Fluorescence microscopy was conducted to examine the vinculin and phalloidin. Semiquantitative immunoblotting and quantitative real-time PCR were performed to study the expression of small GTPases and kinases. Changes in the expression of genes associated with cell migration were examined through next-generation sequencing. Results: TAZ-siRNA treatment reduced TAZ abundance in MCF-7 and MDA-MB-231 breast cancer cells, which was associated with a significant decrease in cell migration. TAZ knockdown increased the expression of fibronectin, but it did not exhibit the typical pattern of EMT progression. TGF-b treatment in MDA-MB-231 cells resulted in a reduction in TAZ and an increase in fibronectin levels. However, it paradoxically promoted cell migration, suggesting that EMT is unlikely to be involved in the decreased migration of breast cancer cells in response to TAZ suppression. RhoA, a small Rho GTPase protein, was significantly reduced in response to TAZ knockdown. This caused a decrease in the expression of the Rho-dependent downstream pathway, i.e., LIM kinase 1 (LIMK1), phosphorylated LIMK1/2, and phosphorylated cofilin, leading to actin depolymerization. Furthermore, myosin light chain kinase (MLCK) and phosphorylated MLC2 were significantly decreased in MDA-MB-231 cells with TAZ knockdown, inhibiting the assembly of stress fibers and focal adhesions. Conclusion: TAZ knockdown inhibits the migration of breast cancer cells by regulating the intracellular actin cytoskeletal organization. This is achieved, in part, by reducing the abundance of RhoA and Rho-dependent downstream kinase proteins, which results in actin depolymerization and the disassembly of stress fibers and focal adhesions. [ABSTRACT FROM AUTHOR]

YAP and TAZ, the Hippo pathway terminal transcriptional activators, are frequently upregulated in cancers. In tumor cells, they have been mainly associated with increased tumorigenesis controlling different aspects from cell cycle regulation, stemness, or resistance to chemotherapies. In fewer cases, they have also been shown to oppose cancer progression, including by promoting cell death through the action of the p73/YAP transcriptional complex, in particular after chemotherapeutic drug exposure. Using HCT116 cells, we show here that oxaliplatin treatment led to core Hippo pathway down-regulation and nuclear accumulation of TAZ. We further show that TAZ was required for the increased sensitivity of HCT116 cells to oxaliplatin, an effect that appeared independent of p73, but which required the nuclear relocalization of TAZ. Accordingly, Verteporfin and CA3, two drugs affecting the activity of YAP and TAZ, showed antagonistic effects with oxaliplatin in co-treatments. Importantly, using several colorectal cell lines, we show that the sensitizing action of TAZ to oxaliplatin is dependent on the p53 status of the cells. Our results support thus an early action of TAZ to sensitize cells to oxaliplatin, consistent with a model in which nuclear TAZ in the context of DNA damage and p53 activity pushes cells towards apoptosis. [ABSTRACT FROM AUTHOR]

WWdomain-containing transcription regulator 1 (WWTR1, referred to here as TAZ) and Yes-associated protein (YAP, also known as YAP1) are transcriptional co-activators traditionally studied together as a part of the Hippo pathway, and are best known for their roles in stem cell proliferation and differentiation. Despite their similarities, TAZ and YAP can exert divergent cellular effects by differentially interacting with other signaling pathways that regulate stem cell maintenance or differentiation. In this study, we show in mouse neural stem and progenitor cells (NPCs) that TAZ regulates astrocytic differentiation and maturation, and that TAZ mediates some, but not all, of the effects of bone morphogenetic protein (BMP) signaling on astrocytic development. By contrast, both TAZ and YAP mediate the effects on NPC fate of β1-integrin (ITGB1) and integrin-linked kinase signaling, and these effects are dependent on extracellular matrix cues. These findings demonstrate that TAZ and YAP perform divergent functions in the regulation of astrocyte differentiation, where YAP regulates cell cycle states of astrocytic progenitors and TAZ regulates differentiation and maturation from astrocytic progenitors into astrocytes. [ABSTRACT FROM AUTHOR]

Bone mechanotransduction is a critical process during skeletal development in embryogenesis and organogenesis. At the same time, the type and level of mechanical loading regulates bone remodeling throughout the adult life. The aberrant mechanosensing of bone cells has been implicated in the development and progression of bone loss disorders, but also in the bone-specific aspect of other clinical entities, such as the tumorigenesis of solid organs. Novel treatment options have come into sight that exploit the mechanosensitivity of osteoblasts, osteocytes, and chondrocytes to achieve efficient bone regeneration. In this regard, runt-related transcription factor 2 (Runx2) has emerged as a chief skeletal-specific molecule of differentiation, which is prominent to induction by mechanical stimuli. Polycystins represent a family of mechanosensitive proteins that interact with Runx2 in mechano-induced signaling cascades and foster the regulation of alternative effectors of mechanotransuction. In the present narrative review, we employed a PubMed search to extract the literature concerning Runx2, polycystins, and their association from 2000 to March 2024. The keywords stated below were used for the article search. We discuss recent advances regarding the implication of Runx2 and polycystins in bone remodeling and regeneration and elaborate on the targeting strategies that may potentially be applied for the treatment of patients with bone loss diseases. [ABSTRACT FROM AUTHOR]

Background: Transcriptional coactivator with PDZ-biding motif (TAZ) is widely expressed in most tissues and interacts with several transcription factors to regulate cell proliferation, differentiation, and death, thereby influencing organ development and size control. However, very little is known about the function of TAZ in the immune system and its association with inflammatory skin diseases, so we investigated the role of TAZ in the pathogenesis of psoriasis. Results: Interestingly, TAZ was expressed in mast cells associated, particularly in lysosomes, and co-localized with histamine-releasing factor (HRF). TAZ deficiency promoted mast cell maturation and increased HRF expression and secretion by mast cells. The upregulation of HRF in TAZ deficiency was not due to increased transcription but to protein stabilization, and TAZ restoration into TAZ-deficient cells reduced HRF protein. Interestingly, imiquimod (IMQ)-induced psoriasis, in which HRF serves as a major pro-inflammatory factor, was more severe in TAZ KO mice than in WT control. HRF expression and secretion were increased by IMQ treatment and were more pronounced in TAZ KO mice treated with IMQ. Conclusions: Thus, as HRF expression was stabilized in TAZ KO mice, psoriatic pathogenesis progressed more rapidly, indicating that TAZ plays an important role in preventing psoriasis by regulating HRF protein stability. Highlights: HRF is expressed in lysosomes and associated with TAZ expression. HRF expression is increased in TAZ-deficient immune cells. HRF protein stability is controlled by TAZ, resulting in stabilized HRF in TAZ deficiency. TAZ deficiency promotes susceptibility to IMQ-induced psoriasis, leading to exacerbated psoriatic inflammation. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the effect of yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) on connective tissue growth factor (CTGF) expression in adult retinal pigment epithelial (ARPE)-19 cells. We also studied the inhibitory effect of K-975, a new pan-transcriptional enhanced associate domain (TEAD) inhibitor, and luteolin, a plant-derived flavonoid on CTGF expression. Methods: ARPE-19 cells were transfected with either YAP or TAZ overexpression plasmid or treated with transforming growth factor (TGF)-β2. The cells were cultured either with or without K-975 or luteolin. The expression of YAP, TAZ, and CTGF was examined using real-time PCR. Results: ARPE-19 cells overexpressing YAP or TAZ exhibited significantly increased CTGF expression. This increase was attenuated by K-975 or luteolin alone. TGF-β2 treatment significantly raised the expression of not just YAP and TAZ, but also CTGF in ARPE-19 cells. TGF-β2 treatment-enhanced CTGF expression was considerably lowered by the addition of K-975 or luteolin. Conclusions: Overexpression of YAP or TAZ and treatment with TGF-β2 led to an increase in the expression of CTGF in ARPE-19 cells. These increases were attenuated by treatment with K-975 and luteolin. These findings suggest that YAP and TAZ may be related to the expression of CTGF in ARPE-19 cells and that K-975 and luteolin can be explored as potential therapeutic agents for preventing CTGF production in vitreoretinal fibrosis. [ABSTRACT FROM AUTHOR]

The Hippo signalling pathway, an evolutionarily conserved kinase cascade, has been shown to be crucial for cell fate determination, homeostasis and tissue regeneration. Recent experimental and clinical studies have demonstrated that the Hippo signalling pathway is involved in the pathophysiology of ocular diseases. This article provides the first systematic review of studies on the regulatory and functional roles of mammalian Hippo signalling systems in eye diseases. More comprehensive studies on this pathway are required for a better understanding of the pathophysiology of eye diseases and the development of effective therapies. [ABSTRACT FROM AUTHOR]

The Hippo pathway plays crucial roles in governing various biological processes during tumorigenesis and metastasis. Within this pathway, upstream signaling stimuli activate a core kinase cascade, involving MST1/2 and LATS1/2, that subsequently phosphorylates and inhibits the transcriptional co-activators YAP and its paralog TAZ. This inhibition modulates the transcriptional regulation of downstream target genes, impacting cell proliferation, migration, and death. Despite the acknowledged significance of protein kinases in the Hippo pathway, the regulatory influence of protein phosphatases remains largely unexplored. In this study, we conducted the first gain-of-functional screen for protein tyrosine phosphatases (PTPs) regulating the Hippo pathway. Utilizing a LATS kinase biosensor (LATS-BS), a YAP/TAZ activity reporter (STBS-Luc), and a comprehensive PTP library, we identified numerous novel PTPs that play regulatory roles in the Hippo pathway. Subsequent experiments validated PTPN12, a master regulator of oncogenic receptor tyrosine kinases (RTKs), as a previously unrecognized negative regulator of the Hippo pathway effectors, oncogenic YAP/TAZ, influencing breast cancer cell proliferation and migration. In summary, our findings offer valuable insights into the roles of PTPs in the Hippo signaling pathway, significantly contributing to our understanding of breast cancer biology and potential therapeutic strategies. [ABSTRACT FROM AUTHOR]

In skeletal muscle, the Hippo effector Yap promotes satellite cell, myoblast, and rhabdomyoblast proliferation but prevents myogenic differentiation into multinucleated muscle fibres. We previously noted that Yap drives expression of the first enzyme of the serine biosynthesis pathway, phosphoglycerate dehydrogenase (Phgdh). Here, we examined the regulation and function of Phgdh in satellite cells and myoblasts and found that Phgdh protein increased during satellite cell activation. Analysis of published data reveal that Phgdh mRNA in mouse tibialis anterior muscle was highly expressed at day 3 of regeneration after cardiotoxin injection, when markers of proliferation are also robustly expressed and in the first week of synergist-ablated muscle. Finally, siRNA-mediated knockdown of PHGDH significantly reduced myoblast numbers and the proliferation rate. Collectively, our data suggest that Phgdh is a proliferation-enhancing metabolic enzyme that is induced when quiescent satellite cells become activated. [ABSTRACT FROM AUTHOR]

Exposure to bisphenol A (BPA) during gestation leads to fetal growth restriction (FGR), whereby the underlying mechanisms remain unknown. Here, we found that FGR patients showed higher levels of BPA in the urine, serum, and placenta; meanwhile, trophoblast ferroptosis was observed in FGR placentas, as indicated by accumulated intracellular iron, impaired antioxidant molecules, and increased lipid peroxidation products. To investigate the role of ferroptosis in placental and fetal growth, BPA stimulation was performed both in vivo and in vitro. BPA exposure during gestation was associated with FGR in mice; also, it induces ferroptosis in mouse placentas and human placental trophoblast. Pretreatment with ferroptosis inhibitor ferritin-1 (Fer-1) alleviated BPA-induced oxidative damage and cell death. Notably, BPA reduced the trophoblastic expression of Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), which regulated tissue growth and organ size. YAP or TAZ siRNA enhanced BPA-induced ferroptosis, suggesting that trophoblast ferroptosis is dependent on YAP/TAZ downregulation after BPA stimulation. Consistently, the protein levels of YAP/TAZ were also reduced in FGR placentas. Further results revealed that silencing YAP/TAZ promoted BPA-induced ferroptosis through autophagy. Pretreatment with autophagy inhibitor chloroquine (CQ) attenuated BPA-induced trophoblast ferroptosis. Ferritinophagy, an autophagic degradation of ferritin (FTH1), was observed in FGR placentas. Similarly, BPA reduced the protein level of FTH1 in placental trophoblast. Pretreatment with iron chelator desferrioxamine (DFO) and NCOA4 (an autophagy cargo receptor) siRNA weakened the ferroptosis of trophoblast after exposure to BPA, indicating that autophagy mediates ferroptosis in BPA-stimulated trophoblast by degrading ferritin. In summary, ferroptosis was featured in BPA-associated FGR and trophoblast injury; the regulation of ferroptosis involved the YAP/TAZ-autophagy-ferritin axis. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to investigate the clinical and prognostic relevance of the Hippo‐YAP transactivators YAP1 and TAZ in oral squamous cell carcinoma, and their possible relationship with PI3K/mTOR pathway activation. Materials and Methods: Immunohistochemical analysis of YAP1, TAZ, PIK3CA (p110α), p‐AKT (Ser473), and p‐S6 (Ser235) was performed in paraffin‐embedded tissue specimens from 165 OSCC patients. Correlations between protein expression and clinical data were further assessed. Results: YAP1 expression was detected in both cytoplasm and nucleus of tumor cells, whereas TAZ expression was only found in the nucleus. Nuclear YAP1 was significantly associated with tumor size (p = 0.03), neck lymph node metastasis (p = 0.02), TNM stage (p = 0.02), and poor differentiation (p = 0.04). Nuclear TAZ was associated with tobacco (p = 0.03) and alcohol consumption (p = 0.04), and poor tumor differentiation (p = 0.04). There was a positive significant correlation between nuclear and cytoplasmic YAP1, nuclear TAZ, p110α expression, and mTORC1 activation p‐S6 (S235). Combined expression of nuclear and cytoplasmic YAP1 was prognostic in both univariate and multivariate analyses. Active nuclear YAP1 was significantly and independently associated with poor disease‐specific (p = 0.005, HR = 2.520; 95% CI = 1.319–4.816) and overall survival (p = 0.015, HR = 2.126; 95% CI = 1.155–3.916). Conclusion: Nuclear YAP1 is an independent predictor of poor survival in oral squamous cell carcinoma. [ABSTRACT FROM AUTHOR]

Simple Summary: Most cancer treatments poison cells non-specifically and can therefore also impact other cells in the body, causing adverse side effects. Targeted therapies block specific proteins that are more essential for cancer cells than for normal cells, limiting side effects. However, targeted therapies are only effective against tumors that rely on the targeted protein for growth or survival. Therefore, it is essential to develop tests that can help predict if a patient's cancer is dependent upon the targeted protein. Drugs that inhibit the TEAD proteins are currently in clinical trials in cancer patients because many cancers require TEAD function. The goal of our study was to identify genes that are regulated by TEADs in cancer cells and determine if the expression levels of these genes can be used to predict if a cancer is dependent upon TEAD proteins. We identified a set of genes regulated by TEADs in cancer cells and found that the levels of these genes could predict if the cancer cells require TEADs for survival and growth. Targeted therapies are effective cancer treatments when accompanied by accurate diagnostic tests that can help identify patients that will respond to those therapies. The YAP/TAZ-TEAD axis is activated and plays a causal role in several cancer types, and TEAD inhibitors are currently in early-phase clinical trials in cancer patients. However, a lack of a reliable way to identify tumors with YAP/TAZ-TEAD activation for most cancer types makes it difficult to determine which tumors will be susceptible to TEAD inhibitors. Here, we used a combination of RNA-seq and bioinformatic analysis of metastatic melanoma cells to develop a YAP/TAZ gene signature. We found that the genes in this signature are TEAD-dependent in several melanoma cell lines, and that their expression strongly correlates with YAP/TAZ activation in human melanomas. Using DepMap dependency data, we found that this YAP/TAZ signature was predictive of melanoma cell dependence upon YAP/TAZ or TEADs. Importantly, this was not limited to melanoma because this signature was also predictive when tested on a panel of over 1000 cancer cell lines representing numerous distinct cancer types. Our results suggest that YAP/TAZ gene signatures like ours may be effective tools to predict tumor cell dependence upon YAP/TAZ-TEAD, and thus potentially provide a means to identify patients likely to benefit from TEAD inhibitors. [ABSTRACT FROM AUTHOR]

This review examined how Hippo cell signaling and heparan sulfate (HS)-proteoglycans (HSPGs) regulate tissue form and function. Despite being a nonweight-bearing tissue, the brain is regulated by Hippo mechanoresponsive cell signaling pathways during embryonic development. HS-proteoglycans interact with growth factors, morphogens, and extracellular matrix components to regulate development and pathology. Pikachurin and Eyes shut (Eys) interact with dystroglycan to stabilize the photoreceptor axoneme primary cilium and ribbon synapse facilitating phototransduction and neurotransduction with bipolar retinal neuronal networks in ocular vision, the primary human sense. Another HSPG, Neurexin interacts with structural and adaptor proteins to stabilize synapses and ensure specificity of neural interactions, and aids in synaptic potentiation and plasticity in neurotransduction. HSPGs also stabilize the blood-brain barrier and motor neuron basal structures in the neuromuscular junction. Agrin and perlecan localize acetylcholinesterase and its receptors in the neuromuscular junction essential for neuromuscular control. The primary cilium is a mechanosensory hub on neurons, utilized by YES associated protein (YAP)-transcriptional coactivator with PDZ-binding motif (TAZ) Hippo, Hh, Wnt, transforming growth factor (TGF)-b/bone matrix protein (BMP) receptor tyrosine kinase cell signaling. Members of the glypican HSPG proteoglycan family interact with Smoothened and Patched G-protein coupled receptors on the cilium to regulate Hh and Wnt signaling during neuronal development. Control of glycosyl sulfotransferases and endogenous protease expression by Hippo TAZ YAP represents a mechanism whereby the fine structure of HS-proteoglycans can be potentially modulated spatiotemporally to regulate tissue morphogenesis in a similar manner to how Hippo signaling controls sialyltransferase expression and mediation of cell-cell recognition, dysfunctional sialic acid expression is a feature of many tumors. [ABSTRACT FROM AUTHOR]

Tankyrase inhibitors are increasingly considered for therapeutic use in malignancies that are characterized by high intrinsic β-catenin activity. However, how tankyrase inhibition affects the endothelium after systemic application remains poorly understood. In this study, we aimed to investigate how the tankyrase inhibitor XAV939 affects endothelial cell function and the underlying mechanism involved. Endothelial cell function was analyzed using sprouting angiogenesis, endothelial cell migration, junctional dynamics, and permeability using human umbilical vein endothelial cells (HUVEC) and explanted mouse retina. Underlying signaling was studied using western blot, immunofluorescence, and qPCR in HUVEC in addition to luciferase reporter gene assays in human embryonic kidney cells. XAV939 treatment leads to altered junctional dynamics and permeability as well as impaired endothelial migration. Mechanistically, XAV939 increased stability of the angiomotin-like proteins 1 and 2, which impedes the nuclear translocation of YAP1/TAZ and consequently suppresses TEAD-mediated transcription. Intriguingly, XAV939 disrupts adherens junctions by inducing RhoA-Rho dependent kinase (ROCK)-mediated F-actin bundling, whereas disruption of F-actin bundling through the ROCK inhibitor H1152 restores endothelial cell function. Unexpectedly, this was accompanied by an increase in nuclear TAZ and TEAD-mediated transcription, suggesting differential regulation of YAP1 and TAZ by the actin cytoskeleton in endothelial cells. In conclusion, our findings elucidate the complex relationship between the actin cytoskeleton, YAP1/TAZ signaling, and endothelial cell function and how tankyrase inhibition disturbs this well-balanced signaling. [ABSTRACT FROM AUTHOR]

CD38 is the main NADase in mammalian cells. It regulates the homeostasis of nicotinamide adenine dinucleotide (NAD+) and extracellular nucleotides. Its function plays an important role in infection and aging. However, its potential functions in tumor cells have not been fully elucidated. In the present study, we demonstrated that lactate, which is derived from tumor metabolism remodeling, upregulates the expression of CD38 through OXPHOS‐driven Hippo‐TAZ pathway. The highly expressed CD38 converts NAD + to adenosine through the CD203a/CD73 complex and adenosine binds and activates its receptor A2AR, inducing the expression of Snail and promoting the invasion and metastasis of lung cancer cells. This finding elucidates a new perspective on the interplay between NAD + metabolism and glycolysis in tumor development. [ABSTRACT FROM AUTHOR]

The article reveals the content of the Temporary Autonomous Zones’ conception (TAZ), proposed by the American anarchist thinker and poet Hakim Bey (real name – Peter Lamborn Wilson, 1945–2022) and rather poorly represented in Russian-language scientific publications. The political and intellectual contexts within which this concept was formed and formulated, as well as its ontological roots, theorized by Hakim Bey himself, are highlighted. A brief overview of the main provisions of this concept, a critical reaction to it from other anarchist authors (M. Bookchin), as well as counterarguments by post-anarchist theorists R. F. Day and S. Newman are presented. The relevance of this work is due to the fact that the trends of instability and non-linearity, fixed both in the modern post-non-classical world picture (reflected in philosophy) and in current global politics, though not identical, but in a certain way correlate with anarchist approaches to understanding reality in general and political reality in particular. The purpose of this articleis attempt to incorporate the concepts of ontological anarchy and autonomous zones, developed by Bey in the 80s of the 20th century, into the context of the latest theoretical approaches in ontology, namely those presented by Q. Meillassoux’s speculative materialism, L. R. Brynt’s object-oriented ontology (onticology) and B. Latour’s actor-network theory. This also determines the scientific novelty of this work, achieved by methods of historical and philosophical description and comparative analysis and also thanks to the involvement of a number of rare English-language sources devoted to the scientific consideration of the work of Hakim Bey. The results of the work include the detection of theoretical approaches to the development and articulation of an anarchist political ontology, which may be associated with further areas of scientific research. In addition, as a conclusion, those nuances of the concept of autonomous zones that seem to be the most relevant today are outlined.

The core Hippo pathway module consists of a tumour‐suppressive kinase cascade that inhibits the transcriptional coactivators Yes‐associated protein (YAP) and WW domain‐containing transcription regulator protein 1 (WWTR1; also known as TAZ). When the Hippo pathway is downregulated, as often occurs in breast cancer, YAP/TAZ activity is induced. To elaborate the roles of TAZ in triple‐negative breast cancer (TNBC), we depleted Taz in murine TNBC 4T1 cells, using either CRISPR/Cas9 or small hairpin RNA (shRNA). TAZ‐depleted cells and their controls, harbouring wild‐type levels of TAZ, were orthotopically injected into the mammary fat pads of syngeneic BALB/c female mice, and mice were monitored for tumour growth. TAZ depletion resulted in smaller tumours compared to the tumours generated by control cells, in line with the notion that TAZ functions as an oncogene in breast cancer. Tumours, as well as their corresponding in vitro cultured cells, were then subjected to gene expression profiling by RNA sequencing (RNA‐seq). Interestingly, pathway analysis of the RNA‐seq data indicated a TAZ‐dependent enrichment of ‘Inflammatory Response’, a pathway correlated with TAZ expression levels also in human breast cancer tumours. Specifically, the RNA‐seq analysis predicted a significant depletion of regulatory T cells (Tregs) in TAZ‐deficient tumours, which was experimentally validated by the staining of tumour sections and by quantitative cytometry by time of flight (CyTOF). Strikingly, the differences in tumour size were completely abolished in immune‐deficient mice, demonstrating that the immune‐modulatory capacity of TAZ is critical for its oncogenic activity in this setting. Cytokine array analysis of conditioned medium from cultured cells revealed that TAZ increased the abundance of a small group of cytokines, including plasminogen activator inhibitor 1 (Serpin E1; also known as PAI‐1), CCN family member 4 (CCN4; also known as WISP‐1) and interleukin‐23 (IL‐23), suggesting a potential mechanistic explanation for its in vivo immunomodulatory effect. Together, our results imply that TAZ functions in a non‐cell‐autonomous manner to modify the tumour immune microenvironment and dampen the anti‐tumour immune response, thereby facilitating tumour growth.

Pulmonary fibrosis (PF) is a severe, irreversible lung disease characterized by progressive scarring, with idiopathic pulmonary fibrosis (IPF) being the most prevalent form. IPF’s pathogenesis involves repetitive lung epithelial injury leading to fibroblast activation and excessive extracellular matrix (ECM) deposition. The prognosis for IPF is poor, with limited therapeutic options like nintedanib and pirfenidone offering only modest benefits. Emerging research highlights the dysregulation of the yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) signaling pathway as a critical factor in PF. YAP and TAZ, components of the Hippo pathway, play significant roles in cell proliferation, differentiation, and fibrosis by modulating gene expression through interactions with TEA domain (TEAD) transcription factors. The aberrant activation of YAP/TAZ in lung tissue promotes fibroblast activation and ECM accumulation. Targeting the YAP/TAZ pathway offers a promising therapeutic avenue. Preclinical studies have identified potential treatments, such as trigonelline, dopamine receptor D1 (DRD1) agonists, and statins, which inhibit YAP/TAZ activity and demonstrate antifibrotic effects. These findings underscore the importance of YAP/TAZ in PF pathogenesis and the potential of novel therapies aimed at this pathway, suggesting a new direction for improving IPF treatment outcomes. Further research is needed to validate these approaches and translate them into clinical practice.

Background: Lichen planus is a chronic inflammatory disorder. Transcriptional coactivator with PDZ‐binding motif (TAZ/WWTR1) is an important downstream effector of the Hippo pathway which regulates organ size and tissue homeostasis. But little is known about the role of TAZ in lichen planus so far. Objective: To explore the expression of TAZ in lichen planus and normal skin, and to discover the relationship between TAZ expression and the clinical characteristics of lichen planus patients. Methods: The method of immunohistochemistry was performed to quantify the expression of TAZ in 262 patients with lichen planus and 90 control tissues. Western blot and quantitative real‐time reverse transcriptase‐PCR (qRT‐PCR) analysis were performed to examine and compare TAZ expression in 4 cases of fresh lichen planus lesions and normal skin tissues. Results: TAZ was weakly expressed in the basal layers of the epidermis in normal skin tissues with a positive rate of 52.22% (47/90). But in lichen planus, TAZ was strongly expressed in almost the entire epidermis with a positive rate of 81.30% (213/262), and the difference between the two groups was statistically significant (p<0.05). Additionally, TAZ expression was significantly related to the location of the lichen planus, clinical phenotype, smoking, and alcohol preference (p<0.05). Western blot and qRT‐PCR showed that the expression of TAZ in protein and mRNA levels in four cases of lichen planus lesions was significantly higher than that in normal skin tissues. Conclusion: TAZ may play a regulatory role in the occurrence and development of lichen planus, which might provide a new perspective for studying pathogenesis and theoretical treatment targets. [ABSTRACT FROM AUTHOR]

Orthodontic tooth movement (OTM) involves mechanical-biochemical signal transduction, which results in tissue remodeling of the tooth-periodontium complex and the movement of orthodontic teeth. The dynamic regulation of osteogenesis and osteoclastogenesis serves as the biological basis for remodeling of the periodontium, and more importantly, the prerequisite for establishing periodontal homeostasis. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are key effectors of the Hippo signaling pathway, which actively respond to mechanical stimuli during tooth movement. Specifically, they participate in translating mechanical into biochemical signals, thereby regulating periodontal homeostasis, periodontal remodeling, and tooth development. YAP and TAZ have widely been considered as key factors to prevent dental dysplasia, accelerate orthodontic tooth movement, and shorten treatment time. In this review, we summarize the functions of YAP and TAZ in regulating tooth development and periodontal remodeling, with the aim to gain a better understanding of their mechanisms of action and provide insights into maintaining proper tooth development and establishing a healthy periodontal and alveolar bone environment. Our findings offer novel perspectives and directions for targeted clinical treatments. Moreover, considering the similarities and differences in the development, structure, and physiology between YAP and TAZ, these molecules may exhibit functional variations in specific regulatory processes. Hence, we pay special attention to their distinct roles in specific regulatory functions to gain a comprehensive and profound understanding of their contributions. [ABSTRACT FROM AUTHOR]

BACKGROUND: Piezo1, a mechanosensitive protein, is tightly connected to osteogenic differentiation, and it has been demonstrated that TAZ has a role in regulating osteogenic differentiation. It is unclear whether TAZ participates in the regulation of osteogenic differentiation of human bone marrow mesenchymal stem cells by Piezo1, so it is crucial to investigate its unique mechanism to prevent osteonecrosis of the femoral head. OBJECTIVE: To elucidate what function Piezo1 plays in osteogenic differentiation and TAZ expression in human bone marrow mesenchymal stem cells. METHODS: The siRNA targeting Piezo1 was constructed and transfected into 293T cells. The silencing efficiency was detected by RT-qPCR. The selected Piezo1- Home-2337 was packaged according to the silencing efficiency, and its optimal multiplicity of infection value was assayed by immunofluorescence staining. The packaged Piezo1 silencing recombinant lentivirus was transfected into human bone marrow mesenchymal stem cells, and its silencing effect was detected by RT-qPCR and western blot assay. Alizarin red staining, alkaline phosphatase activity analysis, immunofluorescence staining, RT-qPCR and western blot assay were utilized to analyze the effect of silencing Piezo1 on the osteogenic differentiation of human bone marrow mesenchymal stem cells. RESULTS AND CONCLUSION: (1) The mRNA and protein levels of Piezo1 in human bone marrow mesenchymal stem cells transfected by si-Piezo1 were decreased significantly, with a statistically significant difference compared with normal and negative control groups. (2) The alkaline phosphatase activity in the si-Piezo1 group was much lower and the calcium deposition in the si-Piezo1 group was significantly reduced compared with the negative control group. (3) The mRNA levels of osteogenesis-related genes including Runt-related transcription factor 2 (Runx2), osteopontin (OPN), distal-less homeobox 5 (DLX5), osteocalcin, β-catenin and Tafazzin (TAZ) in the si-Piezo1 group were significantly decreased compared with the negative control group. Afterward, the expression levels of TAZ and β-catenin protein in the si-Piezo1 group were down-regulated significantly compared with the negative control group, whereas the expression levels of p-TAZ and p-β-catenin protein in the si-Piezo1 group had the opposite condition. (4) The results of immunofluorescence staining showed that the expression of TAZ and β-catenin in human bone marrow mesenchymal stem cells in the si-Piezo1 group was less compared with the negative control group. (5) These findings indicate that Piezo1 can promote the osteogenic differentiation of human bone marrow mesenchymal stem cells. The osteogenic ability of human bone marrow mesenchymal stem cells is significantly reduced after silencing Piezo1, and the expression of TAZ is also reduced. [ABSTRACT FROM AUTHOR]

OBJECTIVE The growth arrest of epiphyseal plates is an inevitable complication of radiotherapy in most pediatric cancer patients, yet our understanding of the regulatory mechanisms governing the recovery response remains limited. This experiment sought to delve into the roles of yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) transcriptional co-activators, crucial drivers of the regenerative process, in this recovery response. METHODS In the study, thirty-six 8-week-old male rabbits underwent radiotherapy targeting the left distal femur and proximal tibia growth plates, while the right extremity served as an unirradiated control. The rabbits were divided into six groups based on post-irradiation time points (1, 7, 10, 14, 17, and 21 days). Histomorphological assessments through hematoxylin-eosin staining and immunohistochemical labeling of PTHrP, YAP1, and TAZ were conducted on the excised growth plates from both irradiated and unirradiated sides. RESULTS The initial week post-radiotherapy exhibited arresting effects, including increased apoptosis, reduced proliferative activity, and disruption of the columnar structure. Evidence of the recovery response, characterized by regenerative chondrocyte clones, became evident around day 10 and peaked on day 14. Subsequently, cellular and structural degeneration prevailed, with a transition to osteogenesis in the following days. The radiation notably decreased the nuclear immunopositivity ratio of the three molecules. While nuclear expression levels of YAP1 and TAZ initially declined within the 1st week, they subsequently rebounded sharply, though not reaching control levels. CONCLUSION These preliminary findings suggest that YAP1 and TAZ could play a pivotal role as regulators in the recovery response of growth plates following irradiation. [ABSTRACT FROM AUTHOR]

Aim: Ankylosing spondylitis (AS) is a chronic, progressive, and inflammatory autoimmune disease of unknown origin that affects the axial skeleton and sacroiliac joints, resulting in pain and loss of function. AS is characterized by the overdifferentiation of T helper 17 (Th17) cells, which contribute to the development of the disease. The Hippo signaling pathway is an important regulator of Th17 differentiation, but its role in patients with AS is unclear. We aimed to investigate the role of key molecules of the Hippo signaling pathway in inflammatory Th17 differentiation in patients with AS and to examine their correlation with disease stages. Methods: We examined the activity of the Hippo pathway in patients with AS and the regulation of Th17 differentiation during AS‐mediated inflammation. Blood samples were collected from 60 patients with AS at various stages and 30 healthy controls. Peripheral blood mononuclear cells (PBMCs) were isolated from peripheral blood by density gradient centrifugation. The Serum Interleukin‐17 (IL‐17) levels in patients with AS and healthy controls were quantified by ELISA. The key molecules of Hippo pathway were assessed by real‐time PCR for their mRNA expression, and protein levels were determined by Western blot analysis. Results: Elevated serum interleukin‐17 (IL‐17) levels were observed in patients with AS compared with healthy controls. The protein and mRNA levels of retinoic acid receptor‐related orphan receptor γt (RORγt), transcriptional coactivator with a PDZ‐binding motif (TAZ), and key upstream transcription factors in the Hippo signaling pathway were measured. The expression of RORγt and TAZ was increased in the blood of patients with AS, whereas the expression of other Hippo pathway proteins, such as MST1/2 and NDR1/2, was significantly decreased. Increased levels of IL‐17 and TAZ were significantly associated with disease activity. In addition, MST1, MST2, and NDR1 levels were negatively correlated with TAZ, RORγt, and IL‐17 levels. Conclusion: Our findings suggest that the Hippo pathway plays a significant role in the regulation of Th17 differentiation and disease activity in patients with AS. The upregulation of TAZ and downregulation of key Hippo pathway proteins, such as MST1/2 and NDR1/2, may contribute to AS pathogenesis. These proteins may serve as biomarkers and may lead to the development of novel therapeutic strategies for AS. [ABSTRACT FROM AUTHOR]

Introduction: The Hippo pathway and its transcriptional effectors yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are targets for cancer therapy. It is important to determine if the activation of one factor compensates for the inhibition of the other. Moreover, it is unknown if YAP/TAZ-directed perturbation affects cell–cell communication of non-malignant liver cells. Materials and Methods: To investigate liver-specific phenotypes caused by YAP and TAZ inactivation, we generated mice with hepatocyte (HC) and biliary epithelial cell (BEC)-specific deletions for both factors (YAPKO, TAZKO and double knock-out (DKO)). Immunohistochemistry, single-cell sequencing, and proteomics were used to analyze liver tissues and serum. Results: The loss of BECs, liver fibrosis, and necrosis characterized livers from YAPKO and DKO mice. This phenotype was weakened in DKO tissues compared to specimens from YAPKO animals. After depletion of YAP in HCs and BECs, YAP expression was induced in non-parenchymal cells (NPCs) in a cholestasis-independent manner. YAP positivity was detected in subgroups of Kupffer cells (KCs) and endothelial cells (ECs). The secretion of pro-inflammatory chemokines and cytokines such as C-X-C motif chemokine ligand 11 (CXCL11), fms-related receptor tyrosine kinase 3 ligand (FLT3L), and soluble intercellular adhesion molecule-1 (ICAM1) was increased in the serum of YAPKO animals. YAP activation in NPCs could contribute to inflammation via TEA domain transcription factor (TEAD)-dependent transcriptional regulation of secreted factors. Conclusion: YAP inactivation in HCs and BECs causes liver damage, and concomitant TAZ deletion does not enhance but reduces this phenotype. Additionally, we present a new mechanism by which YAP contributes to cell–cell communication originating from NPCs. [ABSTRACT FROM AUTHOR]

This article discusses the potential of inhibiting the protein BRD4 in tumor mechanosignaling. The physical properties of cancer cells play a crucial role in tumor development, and recent research is focusing on targeting the mechanical aspects of cancer for improved clinical outcomes. The article explains that BRD4 interacts with the YAP/TAZ complex to promote tumor progression, angiogenesis, metastasis, and resistance to therapy. Inhibiting BRD4 has shown promise in suppressing gene transcription and reducing tumor growth in various types of cancer. However, the full potential of BRD4 inhibition has not yet been realized due to the lack of predictive biomarkers and dose-limiting toxicities. The article suggests that dual inhibition of BRD4 and YAP/TAZ could be a rational therapeutic approach to improve outcomes. Further research is needed to understand the molecular mechanisms and identify biomarkers to overcome resistance to these treatments. [Extracted from the article]

The Hippo signaling pathway regulates developmental organ growth, regeneration, and cell fate decisions. Although the role of the Hippo pathway, and its transcriptional effectors YAP and TAZ, has been well documented in many cell types and species, only recently have the roles for this pathway come to light in vascular development and disease. Experiments in mice, zebrafish, and in vitro have uncovered roles for the Hippo pathway, YAP, and TAZ in vasculogenesis, angiogenesis, and lymphangiogenesis. In addition, the Hippo pathway has been implicated in vascular cancers and cardiovascular diseases, thus identifying it as a potential therapeutic target for the treatment of these conditions. However, despite recent advances, Hippo's role in the vasculature is still underappreciated compared with its role in epithelial tissues. In this review, we appraise our current understanding of the Hippo pathway in blood and lymphatic vessel development and highlight the current knowledge gaps and opportunities for further research. Major roles for the Hippo signaling pathway and its transcriptional effectors YAP and TAZ have recently emerged in vascular development. In this review, Kobayashi et al. discuss how the pathway controls the formation of different vessel types, the major mechanisms at play, and emerging roles for Hippo signaling in vascular diseases. [ABSTRACT FROM AUTHOR]

Simple Summary: The Hippo pathway is crucial for regulating cell growth, organ size, and tissue regeneration. When this pathway goes awry, it can lead to uncontrolled cell growth, tumor spread, and resistance to cancer treatments. This review covers recent progress in understanding how the Hippo pathway is involved in cancer and discusses potential therapies targeting this pathway. In addition, we address ongoing debates and provide perspectives on debated topics in this field. The Hippo pathway is conserved across species. Key mammalian Hippo pathway kinases, including MST1/2 and LATS1/2, inhibit cellular growth by inactivating the TEAD coactivators, YAP, and TAZ. Extensive research has illuminated the roles of Hippo signaling in cancer, development, and regeneration. Notably, dysregulation of Hippo pathway components not only contributes to tumor growth and metastasis, but also renders tumors resistant to therapies. This review delves into recent research on YAP/TAZ-TEAD-mediated gene regulation and biological processes in cancer. We focus on several key areas: newly identified molecular patterns of YAP/TAZ activation, emerging mechanisms that contribute to metastasis and cancer therapy resistance, unexpected roles in tumor suppression, and advances in therapeutic strategies targeting this pathway. Moreover, we provide an updated view of YAP/TAZ's biological functions, discuss ongoing controversies, and offer perspectives on specific debated topics in this rapidly evolving field. [ABSTRACT FROM AUTHOR]

The core Hippo pathway module consists of a tumour‐suppressive kinase cascade that inhibits the transcriptional coactivators Yes‐associated protein (YAP) and WW domain‐containing transcription regulator protein 1 (WWTR1; also known as TAZ). When the Hippo pathway is downregulated, as often occurs in breast cancer, YAP/TAZ activity is induced. To elaborate the roles of TAZ in triple‐negative breast cancer (TNBC), we depleted Taz in murine TNBC 4T1 cells, using either CRISPR/Cas9 or small hairpin RNA (shRNA). TAZ‐depleted cells and their controls, harbouring wild‐type levels of TAZ, were orthotopically injected into the mammary fat pads of syngeneic BALB/c female mice, and mice were monitored for tumour growth. TAZ depletion resulted in smaller tumours compared to the tumours generated by control cells, in line with the notion that TAZ functions as an oncogene in breast cancer. Tumours, as well as their corresponding in vitro cultured cells, were then subjected to gene expression profiling by RNA sequencing (RNA‐seq). Interestingly, pathway analysis of the RNA‐seq data indicated a TAZ‐dependent enrichment of 'Inflammatory Response', a pathway correlated with TAZ expression levels also in human breast cancer tumours. Specifically, the RNA‐seq analysis predicted a significant depletion of regulatory T cells (Tregs) in TAZ‐deficient tumours, which was experimentally validated by the staining of tumour sections and by quantitative cytometry by time of flight (CyTOF). Strikingly, the differences in tumour size were completely abolished in immune‐deficient mice, demonstrating that the immune‐modulatory capacity of TAZ is critical for its oncogenic activity in this setting. Cytokine array analysis of conditioned medium from cultured cells revealed that TAZ increased the abundance of a small group of cytokines, including plasminogen activator inhibitor 1 (Serpin E1; also known as PAI‐1), CCN family member 4 (CCN4; also known as WISP‐1) and interleukin‐23 (IL‐23), suggesting a potential mechanistic explanation for its in vivo immunomodulatory effect. Together, our results imply that TAZ functions in a non‐cell‐autonomous manner to modify the tumour immune microenvironment and dampen the anti‐tumour immune response, thereby facilitating tumour growth. [ABSTRACT FROM AUTHOR]

Previously we showed that the hippo pathway transcriptional effectors, YAP and TAZ, are essential for Schwann cells (SCs) to develop, maintain and regenerate myelin . Although TEAD1 has been implicated as a partner transcription factor, the mechanisms by which it mediates YAP/TAZ regulation of SC myelination are unclear. Here, using conditional and inducible knockout mice, we show that TEAD1 is crucial for SCs to develop and regenerate myelin. It promotes myelination by both positively and negatively regulating SC proliferation, enabling Krox20/Egr2 to upregulate myelin proteins, and upregulating the cholesterol biosynthetic enzymes FDPS and IDI1. We also show stage-dependent redundancy of TEAD1 and that non-myelinating SCs have a unique requirement for TEAD1 to enwrap nociceptive axons in Remak bundles. Our findings establish TEAD1 as a major partner of YAP/TAZ in developmental myelination and functional nerve regeneration and as a novel transcription factor regulating Remak bundle integrity.

Significance: Adaptor proteins control the spatiotemporal dynamics of cellular signaling. Dysregulation of adaptor protein function can cause aberrant cell signaling and promote cancer. The arrestin family of adaptor proteins are known to regulate signaling by the superfamily of G protein-coupled receptors (GPCRs). The GPCRs are highly druggable and implicated in cancer progression. However, the molecular mechanisms responsible for arrestin dysregulation and the impact on GPCR function in cancer have yet to be fully elucidated. Recent Advances: A new family of mammalian arrestins, termed the α-arrestins, was recently discovered. The α-arrestin, arrestin domain-containing protein 3 (ARRDC3), in particular, has been identified as a tumor suppressor and is reported to control cellular signaling of GPCRs in cancer. Critical Issues: Compared with the extensively studied mammalian β-arrestins, there is limited information regarding the regulatory mechanisms that control α-arrestin activation and function. Here, we discuss the molecular mechanisms that regulate ARRDC3, which include post-translational modifications such as phosphorylation and ubiquitination. We also provide evidence that ARRDC3 can interact with a wide array of proteins that control diverse biological functions. Future Directions: ARRDC3 interacts with numerous proteins and is likely to display diverse functions in cancer, metabolic disease, and other syndromes. Thus, understanding the regulatory mechanisms of ARRDC3 activity in various cellular contexts is critically important. Recent studies suggest that α-arrestins may be regulated through post-translational modification, which is known to impact adaptor protein function. However, additional studies are needed to determine how these regulatory mechanisms affect ARRDC3 tumor suppressor function. Antioxid. Redox Signal. 36, 1066-1079.