Transcriptional Coactivator Yes-associated Protein Research Articles

Studying the Geroprotective Properties of YAP/TAZ Signaling Inhibitors on Drosophila melanogaster Model

The transcriptional coactivators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are the main downstream effectors of the evolutionarily conserved Hippo signaling pathway. YAP/TAZ are implicated in the transcriptional regulation of target genes that are involved in a wide range of key biological processes affecting tissue homeostasis and play dual roles in the aging process, depending on the cellular and tissue context. The aim of the present study was to investigate whether pharmacological inhibitors of Yap/Taz increase the lifespan of Drosophila melanogaster. Real-time qRT-PCR was performed to measure the changes in the expression of Yki (Yorkie, the Drosophila homolog of YAP/TAZ) target genes. We have revealed a lifespan-increasing effect of YAP/TAZ inhibitors that was mostly associated with decreased expression levels of the wg and E2f1 genes. However, further analysis is required to understand the link between the YAP/TAZ pathway and aging.

Non-hippo kinases: indispensable roles in YAP/TAZ signaling and implications in cancer therapy.

The transcriptional co-activators Yes-associated protein (YAP) and PDZ-binding domain (TAZ) are the known downstream effectors of the Hippo kinase cascade. YAP/TAZ have been shown to play important roles in cellular growth and differentiation, tissue development and carcinogenesis. Recent studies have found that, in addition to the Hippo kinase cascade, multiple non-Hippo kinases also regulate the YAP/TAZ cellular signaling and produce important effects on cellular functions, particularly on tumorigenesis and progression. In this article, we will review the multifaceted regulation of the YAP/TAZ signaling by the non-Hippo kinases and discuss the potential application of the non-Hippo kinase-regulated YAP/TAZ signaling for cancer therapy.

Lipophilic Statins Inhibit YAP Nuclear Localization, Coactivator Activity, and Migration in Response to Ligation of HLA Class I Molecules in Endothelial Cells: Role of YAP Multisite Phosphorylation.

Solid-organ transplant recipients exhibiting HLA donor-specific Abs are at risk for graft loss due to chronic Ab-mediated rejection. HLA Abs bind HLA molecules expressed on the surface of endothelial cells (ECs) and induce intracellular signaling pathways, including the activation of the transcriptional coactivator yes-associated protein (YAP). In this study, we examined the impact of lipid-lowering drugs of the statin family on YAP localization, multisite phosphorylation, and transcriptional activity in human ECs. Exposure of sparse cultures of ECs to cerivastatin or simvastatin induced striking relocalization of YAP from the nucleus to the cytoplasm and inhibited the expression of the YAP/TEA domain DNA-binding transcription factor-regulated genes connective tissue growth factor and cysteine-rich angiogenic inducer 61. In dense cultures of ECs, statins prevented YAP nuclear import and expression of connective tissue growth factor and cysteine-rich angiogenic inducer 61 stimulated by the mAb W6/32 that binds HLA class I. Exposure of ECs to either cerivastatin or simvastatin completely blocked the migration of ECs stimulated by ligation of HLA class I. Exogenously supplied mevalonic acid or geranylgeraniol reversed the inhibitory effects of statins on YAP localization either in low-density ECs or high-density ECs challenged with W6/32. Mechanistically, cerivastatin increased the phosphorylation of YAP at Ser127, blunted the assembly of actin stress fiber, and inhibited YAP phosphorylation at Tyr357 in ECs. Using mutant YAP, we substantiated that YAP phosphorylation at Tyr357 is critical for YAP activation. Collectively, our results indicate that statins restrain YAP activity in EC models, thus providing a plausible mechanism underlying their beneficial effects in solid-organ transplant recipients.

The role of Hippo pathway in ferroptosis.

The role of Hippo pathway in ferroptosis The Hippo pathway is mainly composed of mammalian serine/threonine (Ste20)like kinases 1/2 (MST1/2), large tumor suppressor 1/2 (LATS1/2), and transcriptional coactivator Yes-associated protein (YAP), and is closely related to cell growth, survival, proliferation, and migration; tissue and organ size control; and tumorigenesis and development. Ferroptosis is a regulated form of cell death characterized by the accumulation of iron-dependent reactive oxygen species (ROS) and the depletion of plasma membrane polyunsaturated fatty acids (PUFAs), which is caused by the imbalance of oxidation and the antioxidant system. This article elaborates the role of Hippo pathway in ferroptosis, providing ideas for the regulation of cell fate and the treatment of tumors.

The Hippo-YAP/TAZ Signaling Pathway in Intestinal Self-Renewal and Regeneration After Injury.

The Hippo pathway and its downstream effectors, the transcriptional coactivators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), control stem cell fate and cell proliferation and differentiation and are essential for tissue self-renewal and regeneration. YAP/TAZ are the core components of the Hippo pathway and they coregulate transcription when localized in the nucleus. The intestinal epithelium undergoes well-regulated self-renewal and regeneration programs to maintain the structural and functional integrity of the epithelial barrier. This prevents luminal pathogen attack, and facilitates daily nutrient absorption and immune balance. Inflammatory bowel disease (IBD) is characterized by chronic relapsing inflammation of the entire digestive tract. Impaired mucosal healing is a prominent biological feature of IBD. Intestinal self-renewal is primarily dependent on functional intestinal stem cells (ISCs), especially Lgr5+ crypt base columnar (CBC) cells and transient-amplifying (TA) cells in the crypt base. However, intestinal wound healing is a complicated process that is often associated with epithelial cells, and mesenchymal and immune cells in the mucosal microenvironment. Upon intestinal injury, nonproliferative cells rapidly migrate towards the wound bed to reseal the damaged epithelium, which is followed by cell proliferation and differentiation. YAP is generally localized in the nucleus of Lgr5+ CBC cells, where it transcriptionally regulates the expression of the ISC marker Lgr5 and plays an important role in intestinal self-renewal. YAP/TAZ are the primary mechanical sensors of the cellular microenvironment. Their functions include expanding progenitor and stem cell populations, reprogramming differentiated cells into a primitive state, and mediating the regenerative function of reserve stem cells. Thus, YAP/TAZ play extremely crucial roles in epithelial repair after damage. This review provides an overview of the Hippo–YAP/TAZ signaling pathway and the processes of intestinal self-renewal and regeneration. In particular, we summarize the roles of YAP/TAZ in the phases of intestinal self-renewal and regeneration to suggest a potential strategy for IBD treatment.

Role of YAP in early ectodermal specification and a Huntington's Disease model of human neurulation.

The Hippo pathway, a highly conserved signaling cascade that functions as an integrator of molecular signals and biophysical states, ultimately impinges upon the transcription coactivator Yes-associated protein 1 (YAP). Hippo-YAP signaling has been shown to play key roles both at the early embryonic stages of implantation and gastrulation, and later during neurogenesis. To explore YAP's potential role in neurulation, we used self-organizing neuruloids grown from human embryonic stem cells on micropatterned substrates. We identified YAP activation as a key lineage determinant, first between neuronal ectoderm and nonneuronal ectoderm, and later between epidermis and neural crest, indicating that YAP activity can enhance the effect of BMP4 stimulation and therefore affect ectodermal specification at this developmental stage. Because aberrant Hippo-YAP signaling has been implicated in the pathology of Huntington's Disease (HD), we used isogenic mutant neuruloids to explore the relationship between signaling and the disease. We found that HD neuruloids demonstrate ectopic activation of gene targets of YAP and that pharmacological reduction of YAP's transcriptional activity can partially rescue the HD phenotype.

Calmodulin activates the Hippo signaling pathway by promoting LATS1 kinase–mediated inhibitory phosphorylation of the transcriptional coactivator YAP

The Hippo signaling pathway regulates tissue growth and cell fate, and its dysregulation can induce tumorigenesis. When Hippo is activated by cell–cell contact, extracellular signals, or cell polarity among others, the large tumor suppressor 1 (LATS1) kinase catalyzes inhibitory phosphorylation of the transcriptional coactivator Yes-associated protein (YAP) to maintain YAP in the cytoplasm or promote its degradation. Separately, calmodulin is a Ca2+-dependent protein that modulates the activity of target proteins and regulates several signaling cascades; however, its potential role in the Hippo pathway has not been identified. Here, using diverse experimental approaches, including in vitro binding analyses, kinase assays, RT–PCR, and confocal microscopy, we reveal that calmodulin promotes Hippo signaling. We show that purified YAP and LATS1 bind directly to calmodulin and form a Ca2+-dependent ternary complex in vitro. Importantly, Ca2+/calmodulin directly stimulated the activity of LATS1 kinase. In cultured mammalian cells, we demonstrated that endogenous YAP and LATS1 coimmunoprecipitate with endogenous calmodulin. In cells with activated Hippo signaling, we show that calmodulin antagonism significantly (i) decreases YAP phosphorylation, (ii) increases expression of two Hippo target genes (connective tissue growth factor [CTGF] and cysteine-rich angiogenic inducer 61 [CYR61]) that regulate cell proliferation and tumor progression, and (iii) enhances the interaction of YAP with its major transcription factor, thereby facilitating transcription of target genes. Collectively, our data demonstrate that calmodulin activates the Hippo kinase cascade and inhibits YAP activity via a direct interaction with LATS1 and YAP, thereby uncovering previously unidentified crosstalk between the Ca2+/calmodulin and Hippo signaling pathways.

Hippo signalling in the liver: role in development, regeneration and disease.

The Hippo signalling pathway has emerged as a major player in many aspects of liver biology, such as development, cell fate determination, homeostatic function and regeneration from injury. The regulation of Hippo signalling is complex, with activation of the pathway by diverse upstream inputs including signals from cellular adhesion, mechanotransduction and crosstalk with other signalling pathways. Pathological activation of the downstream transcriptional co-activators yes-associated protein 1 (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ, encoded by WWTR1), which are negatively regulated by Hippo signalling, has been implicated in multiple aspects of chronic liver disease, such as the development of liver fibrosis and tumorigenesis. Thus, development of pharmacological inhibitors of YAP-TAZ signalling has been an area of great interest. In this Review, we summarize the diverse roles of Hippo signalling in liver biology and highlight areas where outstanding questions remain to be investigated. Greater understanding of the mechanisms of Hippo signalling in liver function should help facilitate the development of novel therapies for the treatment of liver disease.

YAP1 induces marrow derived suppressor cell recruitment in Chlamydia trachomatis infection

Chlamydia trachomatis (C. trachomatis) is the most commonly diagnosed bacterial sexually transmitted infection (STI) worldwide. Marrow derived suppressor cells (MDSCs) are a heterogeneous population of immature monocytes and granulocytes, which are effective inhibitors for T cell activation. This study explores the role of MDSCs in the immune escape mechanism of C. trachomatis. We established a vaginal infection model of a BALB/c-Chlamydia trachomatis mouse pneumonia strain (MoPn), and compared the percentages of MDSCs, CD4+T, and CD8+T cells in the spleen and cervix of mice before and after infection. The expression levels of arginase-1 (Arg-1) and inducible nitric oxide synthase (iNOS) in MDSCs, and the expression level of transcriptional co-activator yes-associated protein 1 (YAP1) in the cervix were also compared. The results show that the proportion of MDSCs increases, while the proportion of CD4+T and CD8+T cells decreases after C. trachomatis-infection. The expression of Arg-1 and iNOS in MDSCs and YAP1 in host cells is up-regulated. C. trachomatis growth is inhibited after the inhibition of YAP1 in host cells. The proportion of MDSCs decreases after in vivo pharmacological inhibition of YAP1 in the C. trachomatis-infected mouse model. These results demonstrate, for the first time, the participation of MDSC in the immune escape of C. trachomatis under the action of YAP1.

Impaired Sphingosine-1-Phosphate Synthesis Induces Preeclampsia by Deactivating Trophoblastic YAP (Yes-Associated Protein) Through S1PR2 (Sphingosine-1-Phosphate Receptor-2)-Induced Actin Polymerizations.

Incomplete spiral artery remodeling, caused by impaired extravillous trophoblast invasion, is a fundamental pathogenic process associated with malplacentation and the development of preeclampsia. Nevertheless, the mechanisms controlling this regulation of trophoblast invasion are largely unknown. We report that sphingosine-1-phosphate synthesis and expression is abundant in healthy trophoblast, whereas in pregnancies complicated by preeclampsia the placentae are associated with reduced sphingosine-1-phosphate and lower SPHK1 (sphingosine kinase 1) expression and activity. In vivo inhibition of sphingosine kinase 1 activity during placentation in pregnant mice led to decreased placental sphingosine-1-phosphate production and defective placentation, resulting in a preeclampsia phenotype. Moreover, sphingosine-1-phosphate increased HTR8/SVneo (immortalized human trophoblst cells) cell invasion in a Hippo-signaling-dependent transcriptional coactivator YAP (Yes-associated protein) dependent manner, which is activated by S1PR2 (sphingosine-1-phosphate receptor-2) and downstream RhoA (Ras homolog gene family, member A)/ROCK (Rho-associated protein kinase) induced actin polymerization. Mutation-based YAP-5SA (S61A, S109A, S127A, S164A, S381A) demonstrated that sphingosine-1-phosphate activation of YAP could be either dependent or independent of Hippo signaling. Together, these findings suggest a novel pathogenic pathway of preeclampsia via disrupted sphingosine-1-phosphate metabolism and signaling-induced, interrupted actin dynamics and YAP deactivation; this may lead to potential novel intervention targets for the prevention and management of preeclampsia.

CHRAC1 promotes human lung cancer growth through regulating YAP transcriptional activity.

ATP-dependent chromatin remodeling complexes regulate chromatin structure and play important roles in gene expression, differentiation, development and cancer progression. Dysregulation in the subunits of the complexes often has been found in different cancers, but how they influence cancer initiation and progression is not fully understood. Here, we show that Chromatin Accessibility Complex Subunit 1 (CHRAC1), the accessory subunit of chromatin remodeling complex, is highly expressed in lung cancer tissues, which correlates with poor prognosis in lung cancer patients. CHRAC1 overexpression promotes lung cancer cell proliferation and migration in vitro and tumor growth in genetically engineered KrasG12D.LSL lung adenocarcinoma mouse model. Consistent with this, CHRAC1 silencing inhibits cell proliferation and migration in lung cancer cells and suppresses tumor growth in xenograft mouse model. Further, CHRAC1 binds to the transcription coactivator Yes-associated protein (YAP), enhances the transcription of downstream target oncogenes in Hippo pathway and thus promotes the tumor growth. Together, our study defines a critical role of CHRAC1 in promoting YAP transcriptional activity and lung cancer tumorigenesis, which makes it a potential target for lung cancer.

Discovery of a cryptic site at the interface 2 of TEAD – Towards a new family of YAP/TAZ-TEAD inhibitors

The Hippo pathway is involved in organ size control and tissue homeostasis by regulating cell growth, proliferation and apoptosis. It controls the phosphorylation of the transcription co-activator YAP (Yes associated protein) and TAZ (Transcriptional coactivator with PDZ-binding motif) in order to control their nuclear import and their interaction with TEAD (Transcriptional Enhanced Associated Domain). YAP, TAZ and TEADs are dysregulated in several cancers making YAP/TAZ-TEAD interaction a new emerging anti-cancer target. We report the synthesis of a set of trisubstituted pyrazoles which bind to hTEAD2 at the interface 2 revealing for the first time a cryptic pocket created by the movement of the phenol ring of Y382. Compound 6 disrupts YAP/TAZ-TEAD interaction in HEK293T cells and inhibits TEAD target genes and cell proliferation in MDA-MB-231 cells. Compound 6 is therefore the first inhibitor of YAP/TAZ-TEAD targeting interface 2. This molecule could serve with other pan-TEAD inhibitors such as interface 3 ligands, for the delineation of the relative importance of VGLL vs YAP/TAZ in a given cellular model.

Emerging roles for the YAP/TAZ transcriptional regulators in brain tumour pathology and targeting options

The transcriptional co-activators Yes-associated protein 1/transcriptional co-activator with PDZ-binding motif (YAP/TAZ) have emerged as significant regulators of a wide variety of cellular and organ functions with impact in early embryonic development, especially during the expansion of the neural progenitor cell pool. YAP/TAZ signalling regulates organ size development, tissue homeostasis, wound healing and angiogenesis by participating in a complex network of various pathways. However, recent evidence suggests an association of these physiologic regulatory effects of YAP/TAZ with pro-oncogenic activities. Herein, we discuss the physiological functions of YAP/TAZ as well as the extensive network of signalling pathways that control their expression and activity, leading to brain tumour development and progression. Furthermore, we describe current targeting approaches and drug options including direct YAP/TAZ and YAP-TEA domain transcription factor (TEAD) interaction inhibitors, G-protein coupled receptors (GPCR) signalling modulators and kinase inhibitors, which may be used to successfully attack YAP/TAZ-dependent tumours.

YAP drives cell competition by activating choline metabolism

Cell competition is a phenomenon that eliminates unfit cells from cell society, a function vital for maintaining cellular and organismal homeostasis. We previously showed that Madin-Darby canine kidney (MDCK) epithelial cells expressing the active form of the transcriptional coactivator Yes-associated protein (YAP) are apically extruded when surrounded by normal MDCK cells. Although we demonstrated that the arachidonic acid (AA) cascade is involved in YAP-dependent apical extrusion, the metabolic events leading to this outcome remained unclear. Here, we present the results of metabolomic analysis that identified phosphatidylcholine (PC) biosynthesis as the most significant player in this process. Removal of the PC biosynthetic components choline and methionine from culture medium inhibited YAP-dependent apical extrusion. Inhibition of either choline uptake or metabolic cycles involving choline or methionine also decreased YAP-dependent apical extrusion. At the molecular level, active YAP induced expression of the genes encoding glycerophosphocholine phosphodiesterase 1 (GPCPD1) and lecithin–cholesterol acyltransferase (LCAT), which are involved in choline metabolism. Our results indicate that YAP-dependent cell competition depends on YAP-mediated activation of the choline metabolic cycle.

PPP1CA/YAP/GS/Gln/mTORC1 pathway activates retinal Müller cells during diabetic retinopathy

Diabetic retinopathy (DR) is a vision-loss complication caused by diabetes with high prevalence. During DR, the retinal microvascular injury and neurodegeneration derived from chronic hyperglycemia have attracted global attention to retinal Müller cells (RMCs), the major macroglia in the retina contributes to neuroprotection. Protein Phosphatase 1 Catalytic Subunit Alpha (PPP1CA) dephosphorylates the transcriptional coactivator Yes-associated protein (YAP) to promote the transcription of glutamine synthetase (GS). GS catalyzes the transformation of neurotoxic glutamate (Glu) into nontoxic glutamine (Gln) to activate the mammalian target of rapamycin complex 1 (mTORC1), which promotes the activation of RMCs. In this study, in vitro MIO-M1 cell and in vivo mouse high-fat diet and streptozotocin (STZ)-induced diabetic model to explore the role of the PPP1CA/YAP/GS/Gln/mTORC1 pathway on the activation of MRCs during DR. Results showed that PPP1CA promoted the dephosphorylation and nuclear translocation of YAP in high glucose (HG)-exposed MIO-M1 cells. YAP transcribed GS in HG-exposed MIO-M1 cells in a TEAD1-dependent and PPP1CA-dependent way. GS promoted the biosynthesis of Gln in HG-exposed MIO-M1 cells. Gln activated mTORC1 instead of mTORC2 in HG-exposed MIO-M1 cells. The proliferation and activation of HG-exposed MIO-M1 cells were PPP1CA/YAP/GS/Gln/mTORC1-dependent. Finally, RMC proliferation and activation during DR were inhibited by the PPP1CA/YAP/GS/Gln/mTORC1 blockade. The findings supplied a potential idea to protect RMCs and alleviate the development of DR.

Conformational flexibility determines the Nf2/merlin tumor suppressor functions

The Neurofibromatosis type 2 gene encodes the Nf2/merlin tumor suppressor protein that is responsible for the regulation of cell proliferation. Once activated, Nf2/merlin modulates adhesive signaling pathways and thereby inhibits cell growth. Nf2/merlin controls oncogenic gene expression by modulating the Hippo pathway. By responding to several physical and biochemical stimuli, Hippo signaling determines contact inhibition of proliferation as well as organ size. The large tumor suppressor (LATS) serine/threonine-protein kinase is the key enzyme in the highly conserved kinase cascade that negatively regulates the activity and localization of the transcriptional coactivators Yes-associated protein (YAP) and its paralogue transcriptional coactivator with PDZ-binding motif (TAZ). Nf2/merlin belongs to the band 4.1, ezrin, radixin, moesin (FERM) gene family that links the actin cytoskeleton to adherens junctions, remodels adherens junctions during epithelial morphogenesis and maintains organized apical surfaces on the plasma cell membrane. Nf2/merlin and ERM proteins have a globular N-terminal cloverleaf head domain, the FERM domain, that binds to the plasma membrane, a central α-helical domain, and a tail domain that binds to its head domain. Here we present the high-resolution crystal structure of Nf2/merlin bound to LATS1 which shows that LATS1 binding to Nf2/merlin displaces the Nf2/merlin tail domain and causes an allosteric shift in the Nf2/merlin α-helix that extends from its FERM domain. This is consistent with the fact that full-length Nf2/merlin binds LATS1 ~10-fold weaker compared to LATS1 binding to the Nf2/merlin-PIP2 complex. Our data increase our understanding of Nf2/merlin biology by providing mechanistic insights into the Hippo pathway that are relevant to several diseases in particular oncogenic features that are associated with cancers.

Yes-Associated Protein (Yap) Is Up-Regulated in Heart Failure and Promotes Cardiac Fibroblast Proliferation

Left ventricular (LV) heart failure (HF) is a significant and increasing cause of death worldwide. HF is characterized by myocardial remodeling and excessive fibrosis. Transcriptional co-activator Yes-associated protein (Yap), the downstream effector of HIPPO signaling pathway, is an essential factor in cardiomyocyte survival; however, its status in human LV HF is not entirely elucidated. Here, we report that Yap is elevated in LV tissue of patients with HF, and is associated with down-regulation of its upstream inhibitor HIPPO component large tumor suppressor 1 (LATS1) activation as well as upregulation of the fibrosis marker connective tissue growth factor (CTGF). Applying the established profibrotic combined stress of TGFβ and hypoxia to human ventricular cardiac fibroblasts in vitro increased Yap protein levels, down-regulated LATS1 activation, increased cell proliferation and collagen I production, and decreased ribosomal protein S6 and S6 kinase phosphorylation, a hallmark of mTOR activation, without any significant effect on mTOR and raptor protein expression or phosphorylation of mTOR or 4E-binding protein 1 (4EBP1), a downstream effector of mTOR pathway. As previously reported in various cell types, TGFβ/hypoxia also enhanced cardiac fibroblast Akt and ERK1/2 phosphorylation, which was similar to our observation in LV tissues from HF patients. Further, depletion of Yap reduced TGFβ/hypoxia-induced cardiac fibroblast proliferation and Akt phosphorylation at Ser 473 and Thr308, without any significant effect on TGFβ/hypoxia-induced ERK1/2 activation or reduction in S6 and S6 kinase activities. Taken together, these data demonstrate that Yap is a mediator that promotes human cardiac fibroblast proliferation and suggest its possible contribution to remodeling of the LV, opening the door to further studies to decipher the cell-specific roles of Yap signaling in human HF.

YAP-dependent proliferation by a small molecule targeting annexin A2.

The transcriptional coactivator Yes-associated protein 1 (YAP) orchestrates a proproliferative transcriptional program that controls the fate of somatic stem cells and the regenerative responses of certain tissues. As such, agents that activate YAP may hold therapeutic potential in disease states exacerbated by insufficient proliferative repair. Here we report the discovery of a small molecule, termed PY-60, which robustly activates YAP transcriptional activity in vitro and promotes YAP-dependent expansion of epidermal keratinocytes in mouse following topical drug administration. Chemical proteomics revealed the relevant target of PY-60 to be annexin A2 (ANXA2), a protein that directly associates with YAP at the cell membrane in response to increased cell density. PY-60 treatment liberates ANXA2 from the membrane, ultimately promoting a phosphatase-bound, nonphosphorylated and transcriptionally active form of YAP. This work reveals ANXA2 as a previously undescribed, druggable component of the Hippo pathway and suggests a mechanistic rationale to promote regenerative repair in disease.

Hippo/TEAD4 signaling pathway as a potential target for the treatment of breast cancer.

Breast cancer is the most common type of cancer among women worldwide. The Hippo signaling pathway is strongly associated with cell proliferation, migration, invasion, metastasis and resistance to breast cancer treatment. The upstream factors involved in the Hippo signaling pathway, including mammalian Ste20 kinases 1/2, large tumor suppressor kinases 1/2 and transcription coactivator Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ), have been extensively studied as they are considered therapeutic targets for breast cancer. Recently, it has been suggested that the transcriptional enhancer factor domain (TEAD) family of transcription factors, particularly TEAD4, plays an important role in breast cancer. TEADs interact with YAP/TAZ to act as transcription factors. Notably, recent studies have demonstrated that TEAD4 may also function in a YAP/TAZ-independent manner and serve as a prognostic marker for breast cancer. The present review summarizes the current research on the effect of the aberrant activation of the Hippo signaling pathway on breast cancer progression. Furthermore, the latest advances on the role of the TEAD family in breast cancer are highlighted, and the role of TEAD4 as a potential target for therapeutic intervention in breast cancer is discussed.

YAP in pancreatic cancer: oncogenic role and therapeutic strategy.

Pancreatic cancer, especially pancreatic ductal adenocarcinoma (PDAC), remains a fatal disease with few efficacious treatments. The Hippo signaling pathway, an evolutionarily conserved signaling module, plays critical roles in tissue homeostasis, organ size control and tumorigenesis. The transcriptional coactivator yes-associated protein (YAP), a major downstream effector of the Hippo pathway, is associated with various human cancers including PDAC. Considering its importance in cancer, YAP is emerging as a promising therapeutic target. In this review, we summarize the current understanding of the oncogenic role and regulatory mechanism of YAP in PDAC, and the potential therapeutic strategies targeting YAP.