Hippo Signaling Pathway Components Research Articles

Targeting the Hippo- Yes-Associated Protein/Transcriptional Coactivator with PDZ-Binding Motif Signaling Pathway in Primary Liver Cancer Therapy

Liver cancer imposes a pervasive global health challenge, ranking among the most prevalent cancers worldwide. Its prevalence and mortality rates are on a concerning upward trajectory and exacerbated by the dearth of efficacious treatment options. The Hippo signaling pathway, originally discovered in Drosophila, comprises the following four core components: MST1/2, WW45, MOB1A/B, and LATS1/2. This pathway regulates the cellular localization of the transcriptional coactivator Yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ) through a series of enzymatic reactions. The Hippo-YAP/TAZ pathway maintains a balance between cell proliferation and apoptosis, regulates tissue and organ sizes, and stabilizes the internal environment. Abnormalities of any genes within the Hippo signaling pathway, such as deletion or mutation, disturb the delicate balance between cell proliferation and apoptosis, creating a favorable condition for tumor initiation and progression. Mutations or epigenetic alterations in the Hippo signaling pathway components can lead to its inactivation. Consequently, YAP/TAZ becomes overexpressed and activated, promoting excessive cell proliferation and inhibiting apoptosis. This dysregulation is closely associated with the development of liver cancer. This review discusses the pivotal role of the Hippo signaling pathway in the pathogenesis and progression of liver cancer. By elucidating its mechanisms, we aim to offer new insights into potential therapeutic targets for effectively combating liver cancer.

Hippo pathway effectors YAP, TAZ and TEAD are associated with EMT master regulators ZEB, Snail and with aggressive phenotype in phyllodes breast tumors

BackgroundPhyllodes tumors (PTs) of the breast are uncommon fibroepithelial neoplasms that tend to recur locally and may have metastatic potential. Their pathogenesis is poorly understood. Hippo signaling pathway plays an essential role in organ size control, tumor suppression, tissue regeneration and stem cell self-renewal. Hippo signaling dysfunction has been implicated in cancer. Recent evidence suggests that there is cross-talk between the Hippo signaling key proteins YAP/TAZ and the epithelial-mesenchymal transition (EMT) master regulators Snail and ZEB. In this study we aimed to investigate the expression of Hippo signaling pathway components and EMT regulators in PTs, in relation to tumor grade. MethodsExpression of Hippo signaling effector proteins YAP, TAZ and their DNA binding partner TEAD was evaluated by immunohistochemistry in paraffin-embedded tissue specimens from 86 human phyllodes breast tumors (45 benign, 21 borderline, 20 malignant), in comparison with tumor grade and with the expression of EMT-related transcription factors ZEB and Snail. ResultsNuclear immunopositivity for YAP, TAZ and TEAD was detected in both stromal and epithelial cells in PTs and was significantly higher in high grade tumors. Interestingly, there was a significant correlation between the expression of YAP, TAZ, TEAD and the expression of ZEB and SNAIL. ConclusionsOur results originally implicate Hippo signaling pathway in PTs pathogenesis and suggest that an interaction between Hippo signaling key components and EMT regulators may promote the malignant features of PTs.

Abstract 7282: Comparing TEAD palmitoylation inhibitors with differential TEAD selectivity in combination efficacy with targeted therapies and in renal safety

Abstract Genetic alterations of the Hippo signaling pathway components resulting in YAP/TAZ activation have been reported in a variety of human malignancies. YAP/TAZ activation and functional requirement have also been linked to resistance to targeted therapies by providing the essential survival signal in drug-tolerant persister/dormant cells. As the main drivers for YAP/TAZ recruitment to chromatin, TEAD transcription factors are the major effectors of the Hippo-YAP/TAZ pathway involved in the regulation of cell proliferation, survival, and cell migration. There are four members in the TEAD family: TEAD1, TEAD2, TEAD3, and TEAD4. All four members have a conserved cysteine residue that gets auto-palmitoylated and a highly conserved central pocket in which the palmitate is buried. TEAD auto-palmitoylation is required for TEAD interaction with coactivator YAP/TAZ and transcriptional activity. We have discovered and developed highly potent and selective TEAD auto-palmitoylation inhibitors that interact directly with TEAD by occupying the central palmitate pocket, disrupt YAP/TAZ-TEAD protein interaction, suppress TEAD transcriptional activity, and selectively block NF2-deficient mesothelioma proliferation in vitro and inhibit NF2 mutant tumor growth in vivo. One of these compounds, VT3989, is being evaluated in an ongoing phase 1 clinical trial, where partial responses in mesothelioma patients have been demonstrated, showing for the first time that the Hippo pathway is druggable and that the Hippo pathway is now a validated target for cancer therapy. It remained a question, however, which TEAD members are more important and whether it would be safer and as efficacious to inhibit one TEAD member than multiple TEAD members. Thus, we utilized our TEAD inhibitors with differential TEAD selectivity to determine the importance of TEAD1 selectivity in anti-tumor efficacy and in renal safety. We evaluated the anti-tumor efficacy of several potent TEAD1-selective and pan-TEAD inhibitors in in vivo combination studies using EGFR mutant/KRAS mutant xenograft models. We found that TEAD1-selective TEAD palmitoylation inhibitors are less efficacious than pan-TEAD/multiple-TEAD inhibitors in combination studies with targeted therapies (as such EGFRi and KRASi). In 14-day/28-day rat studies, TEAD1-selective TEAD inhibitors also exhibited proteinuric nephropathy similar to that observed with pan-/multiple-TEAD inhibitors. Therefore, based on our findings, we can conclude that TEAD1-selective TEAD palmitoylation inhibitors can have similar on-target effect on kidneys as TEAD inhibitors with broader TEAD selectivity while having reduced anti-tumor efficacy and durability of response in combination with targeted therapies. Citation Format: Tracy T. Tang, Leonard Post. Comparing TEAD palmitoylation inhibitors with differential TEAD selectivity in combination efficacy with targeted therapies and in renal safety [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7282.

The compensatory increase of Gli-similar 3 inhibited neuronal apoptosis through regulating Mps one binder kinase activator 1b (MOB1b): a possible strategy for the functional recovery after spinal cord injury.

Spinal cord injury (SCI) is a devastating disease characterized by neuronal apoptosis. Gli-similar 3 (GLIS3), a transcriptional factor, was involved in cell apoptosis and associated with the transcription of downstream target genes related to neuronal function. However, the function of GLIS3 in SCI remains unknown. Therefore, we used the mouse model of SCI to explore the role of GLIS3 in SCI. The results showed that GLIS3 expression was significantly increased in spinal cord tissues of SCI mice, and GLIS3 overexpression promoted the functional recovery, reserved histological changes, and inhibited neuronal apoptosis after SCI. Through online tools, the potential target genes of GLIS3 were analyzed and we found that Mps one binder kinase activator 1b (Mob1b) had a strong association with SCI among these genes. MOB1b is a core component of Hippo signaling pathway, which was reported to inhibit cell apoptosis. MOB1b expression was significantly increased in mice at 7 days post-SCI and GLIS3 overexpression further increased its expression. Dual-luciferase reporter assay revealed that GLIS3 bound to the promoter of Mob1b and promoted its transcription. In conclusion, our findings reveal that the compensatory increase of GLIS3 promotes functional recovery after SCI through inhibiting neuronal apoptosis by transcriptionally regulating MOB1b. Our study provides a novel target for functional recovery after SCI.

The critical role of the Hippo signaling pathway in kidney diseases.

The Hippo signaling pathway is involved in cell growth, proliferation, and apoptosis, and it plays a key role in regulating organ size, tissue regeneration, and tumor development. The Hippo signaling pathway also participates in the occurrence and development of various human diseases. Recently, many studies have shown that the Hippo pathway is closely related to renal diseases, including renal cancer, cystic kidney disease, diabetic nephropathy, and renal fibrosis, and it promotes the transformation of acute kidney disease to chronic kidney disease (CKD). The present paper summarizes and analyzes the research status of the Hippo signaling pathway in different kidney diseases, and it also summarizes the expression of Hippo signaling pathway components in pathological tissues of kidney diseases. In addition, the present paper discusses the positive therapeutic significance of traditional Chinese medicine (TCM) in regulating the Hippo signaling pathway for treating kidney diseases. This article introduces new targets and ideas for drug development, clinical diagnosis, and treatment of kidney diseases.

Differential regulation of Hippo signaling pathway components between 8-cell and blastocyst stages of bovine preimplantation embryogenesis.

The Hippo signaling pathway is an important regulator of lineage segregation (trophectoderm and inner cell mass) during blastocyst formation in the mouse embryos. However, the role and regulation of Hippo signaling pathway components during bovine embryonic development is not completely understood. This study was thus designed to interpret the roles of Hippo cell signaling pathway components using two different yet specific chemical inhibitors (Cerivastatin and XMU-MP-1). A significant decrease in the blastocyst rates were observed on treatment with Cerivastatin and XMU-MP-1 inhibitors for the treatment groups, in comparison to the control groups. At the 8-cell stage, a significant decrease was observed in the gene expression and nuclear protein localization of YAP1 (Yes Associated Protein 1) and pYAP1 components of Hippo signaling pathway. However, no such effect of Cerivastatin treatment was observed on the localization of TAZ at this cell stage. On the contrary, during bovine blastocyst formation a significant decrease in the gene expression and nuclear localization of both YAP1 and TAZ suggest differences in the regulation of these components at 8-cell and blastocyst stages of embryonic development. Furthermore, XMU-MP-1 mediated chemical inhibition of Mst1 at the blastocyst stage also suggests differences in the regulation of Yap1 and Taz components of Hippo signaling pathway. Overall, this study indicates novel differences in the regulation of Hippo signaling transcript levels and protein localization between the 8-cell and blastocyst stages of bovine preimplantation embryonic development.

Zinc Oxide Nanoparticles Promote YAP/TAZ Nuclear Localization in Alveolar Epithelial Type II Cells

We investigated roles of Hippo signaling pathway components in alveolar type II cells (AECII) after zinc oxide nanoparticle (ZnONP) exposure. ZnONPs physicochemistry was characterized using field emission-scanning electron microscopy (FE-SEM) and energy-dispersive X-ray (EDX) microanalysis. ZnONP deposition in human respiratory tract was estimated using multiple-path particle dosimetry (MPPD) model. MLE-12 AECII were cultured and exposed to 0, 1, and 5 μg/mL of ZnONPs for 24 h. Western blots were used to investigate signaling pathways associated with Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ), cell adherens junctions, differentiation, and senescence. ZnONPs morphology was irregular, with Zn and O identified. Approximately 72% of inhaled ZnONPs were deposited in lungs, with 26% being deposited in alveolar regions. ZnONP exposure increased nuclear YAP expression and decreased cytoplasmic YAP expression by AECII. Adherens junction proteins, E-cadherin, α-catenin, and β-catenin, on AECII decreased after ZnONP exposure. ZnONP exposure of AECII increased alveolar type I (AECI) transition protein, LGALS3, and the AECI protein, T1α, while decreasing AECII SPC expression. ZnONP exposure induced Sirt1 and p53 senescence proteins by AECII. Our findings showed that inhalable ZnONPs can deposit in alveoli, which promotes YAP nuclear localization in AECII, resulting in decrease tight junctions, cell differentiation, and cell senescence.

A Comparative Analysis of Hippo Signaling Pathway Components during Murine and Bovine Early Mammalian Embryogenesis.

The time required for successful blastocyst formation varies among multiple species. The formation of a blastocyst is governed by numerous molecular cell signaling pathways, such as the Hippo signaling pathway. The Hippo signaling pathway is initiated by increased cell–cell contact and via apical polarity proteins (AMOT, PARD6, and NF2) during the period of preimplantation embryogenesis. Cell–cell contact and cell polarity activate (phosphorylates) the core cascade components of the pathway (mammalian sterile twenty like 1 and 2 (MST1/2) and large tumor suppressor 1 and 2 (LATS1/2)), which in turn phosphorylate the downstream effectors of the pathway (YAP1/TAZ). The Hippo pathway remains inactive with YAP1 (Yes Associated protein 1) present inside the nucleus in the trophectoderm (TE) cells (polar blastomeres) of the mouse blastocyst. In the inner cell mass (ICM) cells (apolar blastomeres), the pathway is activated with p-YAP1 present in the cytoplasm. On the contrary, during bovine embryogenesis, p-YAP1 is exclusively present in the nucleus in both TE and ICM cells. Contrary to mouse embryos, transcription co activator with PDZ-binding motif (TAZ) (also known as WWTR1) is also predominantly present in the cytoplasm in all the blastomeres during bovine embryogenesis. This review outlines the major differences in the localization and function of Hippo signaling pathway components of murine and bovine preimplantation embryos, suggesting significant differences in the regulation of this pathway in between the two species. The variance observed in the Hippo signaling pathway between murine and bovine embryos confirms that both of these early embryonic models are quite distinct. Moreover, based on the similarity of the Hippo signaling pathway between bovine and human early embryo development, bovine embryos could be an alternate model for understanding the regulation of the Hippo signaling pathway in human embryos.

Catechol enhances chemo‑ and radio‑sensitivity by targeting AMPK/Hippo signaling in pancreatic cancer cells.

Overcoming chemo- and radio-resistance is a major challenge in pancreatic cancer treatment. Therefore, there is an urgent need to discover novel therapeutic approaches to avoid chemo- and radio-resistance in pancreatic cancer. Catechol is a phytochemical found in some fruits and vegetables. A few studies have reported on the potential anticancer effects of pure catechol. The present study aimed to explore the chemo- and radio-sensitizing effects of catechol in Panc-1 human pancreatic cancer cells. The effects of catechol on Panc-1 cell proliferation, clonogenic survival, invasion, and migration were assessed using MTT, cell migration, and Transwell invasion assays. The chemo- and radio-sensitizing effects of catechol on Panc-1 cells were evaluated via MTT assay and flow cytometry. Western blotting was conducted to analyze the expression of proteins involved in several mechanisms induced by catechol in Panc-1 cells, including growth inhibition, apoptosis, suppression of epithelial-mesenchymal transition (EMT), and chemo- and radio-sensitizing activities. The results indicated that catechol inhibited proliferation, promoted apoptosis, and suppressed cell migration, invasion, and EMT in Panc-1 cells in a dose-dependent manner. Catechol treatment also induced the phosphorylation of AMP-activated protein kinase (AMPK) with a concomitant reduction in the expression of Hippo signaling pathway components, including Yes-associated protein, cysteine-rich angiogenic inducer 61, and connective tissue growth factor. In addition, catechol enhanced the chemosensitivity of Panc-1 cells to gemcitabine, a commonly used chemotherapy in pancreatic cancer treatment. A combination of catechol and radiation enhanced apoptosis and increased the expression of two radiation-induced DNA damage markers, p-ATM and p-Chk2. Collectively, the present results demonstrated that catechol, a naturally occurring compound, could suppress the proliferation of pancreatic cancer cells, reduce the expression of EMT-related proteins, and enhance the chemo- and radio-sensitivity of Panc-1 cells by targeting AMPK/Hippo signaling.

Effects of Quinacrine on Expression of Hippo signaling Pathway Components (LATS1, LATS2, and YAP) in Human Breast Cancer Stem Cells.

Objective:The Hippo signaling pathway has important role in the pathogenesis of some tumors. Breast cancer is the most prevalent cancer among females in the world. In recent years, various articles referred to inhibiting effect of quinacrine, a derivative of 9-aminoacridine, on the growth of several types of cancer cells. In this study, we evaluated the effect of quinacrine on expression of LATS1, LATS2, and YAP genes of the Hippo signaling pathway and YAP level in human breast cancer stem cells (MDA-MB 231 cell line). This cell line of breast cancer expresses the triple negative characteristics. Methods:MDA-MB 231 cells was treated with 0.5 µM of quinacrine for 3 days. The dose was selected using MTT assays. The expression of genes was quantified by Real-time PCR. The protein expression was performed by Western blotting. Significance of observations were checked by means of Mann-Whitney test using p<0.05 as the level of significance. Results:The present study demonstrated that expression of YAP gene in MDA-MB 231 cell line significantly down regulated by quinacrine. Quinacrine significantly decreased the amount of YAP protein. Moreover, quinacrine did not have meaningful effect on LATS1 and LATS2 genes expression. Conclusion: YAP gene is an oncogene and inhibition of its expression by quinacrine could effect on breast cancer cell progression.

STUB1 suppresseses tumorigenesis and chemoresistance through antagonizing YAP1 signaling.

Yes‐associated protein (YAP) is a component of the canonical Hippo signaling pathway that is known to play essential roles in modulating organ size, development, and tumorigenesis. Activation or upregulation of YAP1, which contributes to cancer cell survival and chemoresistance, has been verified in different types of human cancers. However, the molecular mechanism of YAP1 upregulation in cancer is still unclear. Here we report that the E3 ubiquitin ligase STUB1 ubiquitinates and destabilizes YAP1, thereby inhibiting cancer cell survival. Low levels of STUB1 expression were correlated with increased protein levels of YAP1 in human gastric cancer cell lines and patient samples. Moreover, we revealed that STUB1 ubiquitinates YAP1 at the K280 site by K48‐linked polyubiquitination, which in turn increases YAP1 turnover and promotes cellular chemosensitivity. Overall, our study establishes YAP1 ubiquitination and degradation mediated by the E3 ligase STUB1 as an important regulatory mechanism in gastric cancer, and provides a rationale for potential therapeutic interventions.

MTA2 promotes HCC progression through repressing FRMD6, a key upstream component of hippo signaling pathway

Discerning oncogenic drivers from passengers remains a major effort in understanding of the essence of the initiation and development of hepatocellular carcinoma (HCC), the most common primary liver malignancy and the third leading cause of cancer mortality worldwide. Here we report that MTA2, Metastasis Associated 1 Family Member 2, is significantly up-regulated in HCC. We show that high level of MTA2 expression is strongly correlated with advanced pathological stages and poor overall survival of the patients. Genome-wide identification of the transcriptional targets of MTA2 by ChIP-seq indicates that MTA2 represses a cohort of genes including FRMD6 that are critically involved in the growth and mobility of HCC. We demonstrate that the MTA2 promotes the proliferation and metastasis of HCC in vitro and in vivo through suppressing Hippo signaling pathway. Together, these results reveal a key role for the MTA2-FRDM6-Hippo axis in human hepatocarcinogenesis.

Expression of Hippo signaling pathway components in Hu sheep male reproductive tract and spermatozoa

Hippo signaling pathway is essential for tissue development and homeostasis, while its specific role in male reproductive tract development is still unclear. The objective of this study is to elucidate the localization and expressions of key Hippo pathway components (MST1/2, LATS1/2 and YAP1) in male reproductive tract (testis, epididymis, and ductus deferens) of prepubertal (3-month-old) and postpubertal (9-month-old) Hu sheep, as well as in the cauda epididymal and ejaculated spermatozoa. Results showed that the Hippo pathway proteins were diversely localized in male reproductive tract portions, and most of their expression levels increased during sheep testicular maturation. In addition, these Hippo components were mainly localized and highly expressed in ejaculated spermatozoa compared with cauda epididymal spermatozoa. In ejaculated spermatozoa, LATS1 was localized in the acrosomal head region, and LATS2 and YAP1 were expressed in the midpiece part. Taken together, the presence of Hippo signaling cascade in the pubertal development of male reproductive tract and spermatogenesis of Hu sheep, provides new insights on the function of these components in the process of male sexual maturation, capacitation and fertilization.

MiR-302/367/LATS2/YAP pathway is essential for prostate tumor-propagating cells and promotes the development of castration resistance.

Clinical intervention for patients with advanced prostate cancer (PCa) remains challenging due to the inevitable recurrence of castration-resistant prostate cancer (CRPC) after androgen deprivation therapy (ADT). Cancer stem cells (CSCs) with serial tumor-propagating capacity are considered to be the driving force for PCa progression and recurrence. In this study, we report that the miR-302/367 cluster, a previously identified potent pluripotency regulator, is upregulated in prostate tumors. Specifically, the forced expression of the miR-302/367 cluster accelerates the in vitro and in vivo growth of PCa cells and their resistance to androgen ablation, whereas the knockdown of the miR-302/367 cluster using anti-sense RNA suppresses the incidence of formation, growth rate and endpoint weight of PCa cell tumors. Mechanistically, we find that LATS2, a key component of the tumor-suppressive Hippo signaling pathway, acts as a direct target of the miR-302/367 cluster in PCa cells. The downregulation of LATS2 by the miR-302/367 cluster reduces the phosphorylation and enhances the nuclear translocation of the YAP oncoprotein. Conversely, the restoration of LATS2 expression abrogates the tumor-promoting effects of forced miR-302/367 cluster expression. Collectively, the potent pluripotency regulator-triggered miR-302/367/LATS2/YAP pathway is essential for prostate tumor-propagating cells and promotes castration resistance. Thus, targeting this signaling axis may represent a promising therapeutic strategy for CRPC.

Research progresses on the molecular structure of the Hippo signaling pathway components.

The Hippo signaling pathway has been identified to be involved in development and tissue homeostasis during the past decade, and is evolutionarily conserved from Drosophila to mammals. It transduces the signal through a series of protein-protein interaction and kinase cascades, to control the cell number and organ size by inhibiting cell proliferation and promoting apoptosis. Dysregulation of the Hippo signaling pathway is associated with tumorigenesis and cancers, so it is a crucial target for cancer therapy and regeneration medicine. Most of the Hippo signaling pathway components have been identified, and the cellular function and molecular mechanism have been revealed by structural and functional researches. In this review, we summarize the molecular structure of Hippo signaling pathway components and related targeting inhibitors from a structural view. We hope to improve the understandings of the regulation mechanism of the Hippo signaling transduction, and facilitate further functional studies and potential therapeutic interventions.

Highlights of This Issue

Manipulation of the apoptosis pathway is an appealing strategy for cancer treatment using BH3 mimetics such as ABT-263, although predictive biomarkers are required to identify patients who may benefit from their use. To investigate this problem, Suryani and colleagues studied the in vivo efficacy of ABT-263 against 31 pediatric acute lymphoblastic leukemia xenografts. High MCL1 expression and function correlated with in vivo ABT-263 resistance, and in vitro assays predicted in vivo ABT-263 responses. These approaches could be included in the design of prospective clinical trials to determine if they can identify patients who may respond to treatment with this class of therapeutic agents.Gastric carcinoma (GC) is the second leading cause of cancer deaths in the world, with many deaths occurring in East Asia. To identify DNA methylation biomarkers for prediction of GC metastasis, scientists, and oncologists from China, the United States, Japan, and Korea have profiled differential methylation patterns in GCs and perform an in-depth characterization of methylation changes in 73 candidate genes. The authors have established a methylation biomarker-set composed of three genes GFRA1, SRF, and ZNF382 that could be used to synergistically predict GC metastasis and patients' overall survival from multiple patient cohorts in China, Japan, and Korea.TAZ, the core component of Hippo signaling pathway, attracts increasing attention as a critical player in tumorigenesis. Using an integrated translational approach, the authors explored the role of TAZ in non-small cell lung cancer (NSCLC). Noguchi and colleagues showed that higher TAZ expression was associated with shorter patient survival, and TAZ promoted lung cancer cell proliferation in vitro and tumor development in vivo. Moreover, TAZ regulated the expression of ErbB ligands and the EGFR signaling pathway was activated in NSCLC tissues with high TAZ expression. This study offers potential therapeutic strategies, either directly against TAZ or indirectly via EGFR pathway.Activation of Wnt-signaling is a common event in colorectal carcinoma (CRC), but its role in CRC metastasis is still under extensive study. In the present study, Zhang and colleagues revealed subcellular redistribution of NAT10 (N-acetyltransferase 10) in CRCs, which correlated well with nuclear translocation of β-catenin and reflected invasive potential of CRC. They demonstrated that inhibition of GSK-3β induced NAT10 redistribution through increasing its stability and nuclear export, which consequently enhanced cytoskeletal remodeling and promoted migration, invasion, and metastasis of cancer cells. These findings suggest NAT10 could be a useful prognostic marker and potential therapeutic target in CRC.

MST1, a Key Player, in Enhancing Fast Skeletal Muscle Atrophy

Skeletal muscle undergoes rapid atrophy upon denervation and the process of denervation-induced skeletal muscle atrophy is complicated. MST1 (mammalian sterile 20-like kinase 1) is identified as a central component of Hippo signaling pathway. In the present study, we identified that MST1 kinase was expressed widely in skeletal muscles and found that it was dramatically up-regulated in fast- but not slow-dominant skeletal muscles immediately upon denervation. The results of our histological and biochemical studies demonstrated that deletion of MST1 significantly attenuated denervation-induced skeletal muscle content loss and decreased expression level of Atrogin-1 and LC-3 genes in mice. Further studies indicated that MST1, but not MST2, remarkably increased FOXO3a phosphorylation level at Ser207 and promoted its nuclear translocation in atrophic fast-dominant muscles. Thus, we, in our knowledge for the first time, demonstrated that MST1 kinase plays an important role in regulation of denervation-induced skeletal muscle apotrophy, namely, the upregulated MST1 kinase promoted progression of neurogenic atrophy in fast-dominant skeletal muscles through activation of FOXO3a transcription factors.

Hippo signaling pathway in mammals：a new therapeutic target for tumors

Hippo signaling pathway was first discovered in Drosophila as regulator of cell proliferation and apoptosis during development. It has been widely reported that Hippo signaling pathway plays an essential role in embryonic differentiation, pattern formation and adult cell homeostasis. Furthermore, Hippo signaling has close correlation with Wnt and Notch signaling pathways, and has an important effect on tumor initiation and progression. Recent studies have shown that the Drosophila Hippo signaling pathway is highly conserved over evolutionary time, the mammalian Hippo signaling pathway has been implicated in regulating cell contact inhibition, organsize and tumorigenesis. This review firstly focuses on the composition, regulatory mechanism and physiological functions of mammalian Hippo signaling pathway, and then lists the relationship with other signaling pathways and protein factors, and tumors in mammals. Finally, the therapeutic approaches to targeting Hippo signaling pathway components or regulators have also been summarized, which might be beneficial to tumor therapeutic intervention.

SATB Homeobox Proteins Regulate Trophoblast Stem Cell Renewal and Differentiation

The morphogenesis of the hemochorial placenta is dependent upon the precise expansion and differentiation of trophoblast stem (TS) cells. SATB homeobox 1 (SATB1) and SATB2 are related proteins that have been implicated as regulators of some stem cell populations. SATB1 is highly expressed in TS cells, which prompted an investigation of SATB1 and the related SATB2 as regulators of TS cells. SATB1 and SATB2 were highly expressed in rat TS cells maintained in the stem state and rapidly declined following induction of differentiation. SATB proteins were also present within the rat placenta during early stages of its morphogenesis and disappeared as gestation advanced. Silencing Satb1 or Satb2 expression decreased TS cell self-renewal and increased differentiation, whereas ectopic expression of SATB proteins promoted TS cell expansion and blunted differentiation. Eomes, a key transcriptional regulator of TS cells, was identified as a target for SATB proteins. SATB knockdown decreased Eomes transcript levels and promoter activity, whereas SATB ectopic expression increased Eomes transcript levels and promoter activity. Electrophoretic mobility shift assay as well as chromatin immunoprecipitation analyses demonstrated that SATB proteins physically associate with a regulatory site within the Eomes promoter. We conclude that SATB proteins promote TS cell renewal and inhibit differentiation. These actions are mediated in part by regulating the expression of the TS cell stem-associated transcription factor, EOMES.

E-cadherin mediates contact inhibition of proliferation through Hippo signaling-pathway components

Contact inhibition of cell growth is essential for embryonic development and maintenance of tissue architecture in adult organisms, and the growth of tumors is characterized by a loss of contact inhibition of proliferation. The recently identified Hippo signaling pathway has been implicated in contact inhibition of proliferation as well as organ size control. The modulation of the phosphorylation and nuclear localization of Yes-associated protein (YAP) by the highly conserved kinase cascade of the Hippo signaling pathway has been intensively studied. However, cell-surface receptors regulating the Hippo signaling pathway in mammals are not well understood. In this study, we show that Hippo signaling pathway components are required for E-cadherin-dependent contact inhibition of proliferation. Knockdown of the Hippo signaling components or overexpression of YAP inhibits the decrease in cell proliferation caused by E-cadherin homophilic binding at the cell surface, independent of other cell-cell interactions. We also demonstrate that the E-cadherin/catenin complex functions as an upstream regulator of the Hippo signaling pathway in mammalian cells. Expression of E-cadherin in MDA-MB-231 cells restores the density-dependent regulation of YAP nuclear exclusion. Knockdown of β-catenin in densely cultured MCF10A cells, which mainly depletes E-cadherin-bound β-catenin, induces a decrease in the phosphorylation of S127 residue of YAP and its nuclear accumulation. Moreover, E-cadherin homophilic binding independent of other cell interactions is sufficient to control the subcellular localization of YAP. Therefore, Our results indicate that, in addition to its role in cell-cell adhesion, E-cadherin-mediated cell-cell contact directly regulates the Hippo signaling pathway to control cell proliferation.