MST1/2 exerts a pivotal role in inducing neuroinflammation and Coxsackievirus-A10 replication by interacting with innate immunity.

Coxsackievirus-A10 (CV-A10), responsible for the hand, foot and mouth disease (HFMD) pandemic, could cause serious central nervous system (CNS) complications. The underlying molecular basis of CV-A10 and host interactions inducing neuropathogenesis is still unclear. The Hippo signaling pathway, historically known for a dominator of organ development and homeostasis, has recently been implicated as an immune regulator. However, its role in host defense against CV-A10 has not been investigated. Herein, it was found that CV-A10 proliferated in HMC3 cells and promoted the release of inflammatory cytokines. Moreover, pattern recognition receptors (PRRs)-mediated pathways, including TLR3-TRIF-TRAF3-TBK1-NF-κB axis, RIG-I/MDA5-MAVS-TRAF3-TBK1-NF-κB axis and TLR7-MyD88-IRAK1/IRAK4-TRAF6-TAK1-NF-κB axis, were examined to be elevated under CV-A10 infection. Meanwhile, it was further uncovered that Hippo signaling pathway was inhibited in HMC3 cells with CV-A10 infection. Previous studies have been reported that there exist complex relations between innate immune and Hippo signaling pathway. Then, plasmids of knockdown and overexpression of MST1/2 were transfected into HMC3 cells. Our results showed that MST1/2 suppressed the levels of inflammatory cytokines via interacting with TBK1 and IRAK1, and also enhanced virus production via restricting IRF3 and IFN-ß expressions. Overall, these data obviously pointed out that CV-A10 accelerated the formation of neuroinflammation by the effect of the Hippo pathway on the PRRs-mediated pathway, which delineates a negative immunoregulatory role for MST1/2 in CV-A10 infection and the potential for this pathway to be pharmacologically targeted to treat CV-A10.

MST1/2 regulates fibro/adipogenic progenitor fate decisions in skeletal muscle regeneration.

Defective skeletal muscle regeneration is often accompanied by fibrosis. Fibroblast/adipose progenitors (FAPs) are important in these processes, however, the regulation of FAP fate decisions is unclear. Here, using inducible conditional knockout mice, we show that blocking mammalian Ste20-like kinases 1/2 (MST1/2) of FAPs prevented apoptosis and reduced interleukin-6 secretion in vivo and in vitro, which impaired myoblast proliferation and differentiation, as well as impaired muscle regeneration. Deletion of Mst1/2 increased co-localization of Yes-associated protein (YAP) with Smad2/3 in nuclei and promoted differentiation of FAPs toward myofibroblasts, resulting in excessive collagen deposition and skeletal muscle fibrosis. Meanwhile, inhibition of MST1/2 increased YAP/Transcriptional co-activator with PDZ-binding motif activation, which promoted activation of the WNT/ß-catenin pathway and impaired the differentiation of FAPs toward adipocytes. These results reveal a new mechanism for MST1/2 action in disrupted skeletal muscle regeneration and fibrosis via regulation of FAP apoptosis and differentiation. MST1/2 is a potential therapeutic target for the treatment of some myopathies.

The significance of Hippo pathway protein expression in oral squamous cell carcinoma.

Introduction: The Hippo pathway consists of mammalian sterile 20-like kinase 1/2 (MST1/2), large tumor suppressor 1/2 (LATS1/2), and yes-associated protein (YAP)1. Herein, we present the first report on the significance of major Hippo pathway protein expression in oral squamous cell carcinoma (OSCC). Methods: The analyses included oral epithelial dysplasia (OED, n = 7), carcinoma in situ (CIS, n = 14), and oral squamous cell carcinoma (OSCC, n = 109). Results: Cytoplasmic expression of MST1, LATS1, and LATS2 was low in OED, CIS, and OSCC. The cytoplasmic expression of MST2 was high in OED (5/7 cases), CIS (9/14 cases), and poorly differentiated OSCC (8/8 cases) but was low/lost in a proportion of differentiated OSCC (60/101 cases). The expression of YAP1 was associated with differentiation; low YAP expression was significantly more frequent in well-differentiated OSCC (35/71 cases), compared to moderately and poorly differentiated OSCC (11/38 cases). An infiltrative invasion pattern was associated with a high expression of MST2 and high expression of YAP1. The high expression of YAP1 was associated with features of epithelial-to-mesenchymal transition (EMT), such as the loss of E-cadherin and high expression of vimentin, laminin 5, and Slug. High expression of protein arginine methyltransferase (PRMT) 1 or 5, which positively regulates YAP activity, was associated with the high expression of YAP1 (p < 0.0001). Conclusion: Among the major Hippo pathway proteins, MST2 displayed a distinctive expression pattern in a significant proportion of differentiated OSCC, suggesting a possible differential role for MST2 depending on the course of OSCC progression. A high YAP1 expression may indicate aggressive OSCC with EMT via PRMTs at the invasive front.

Inactivation of MST1/2 Controls Macrophage Polarization to Affect Macrophage-Related Disease via YAP and Non-YAP Mechanisms.

Macrophage polarization is a critical process that regulates in inflammation, pathogen defense, and tissue repair. Here we demonstrate that MST1/2, a core kinase of Hippo pathway and a recently identified regulator of inflammation, plays a significant role in promoting M2 polarization. We provide evidence that inhibition of MST1/2, achieved through either gene-knockout or pharmacological treatment, leads to increased M1 polarization in a YAP-dependent manner, resulting in the development of M1-associated inflammatory disorders. Moreover, MST1/2 inhibition also leads to a substantial reduction in M2 polarization, but this occurs through the STAT6 and MEK/ERK signaling. The STAT6 is independent of YAP, but MEK/ERK is dependent of YAP. Consistent with these observations, both MST1/2-conditional knockout mice and wild-type mice treated with XMU-MP-1, a chemical inhibitor of MST1/2, exhibited reduced M2-related renal fibrosis, while simultaneously displaying enhanced LPS-mediated inflammation and improved clearance of MCR3-modified gram-negative bacteria. These findings uncover a novel role of MST1/2 in regulating macrophage polarization and establish it as a potential therapeutic target for the treatment of macrophage-related fibrotic diseases.

Shenhuang plaster enhances intestinal anastomotic healing in rabbits through activation of the TGF-ß and Hippo/YAP signaling pathways.

Although many efforts have been made to improve management strategies and diagnostic methods in the past several decades, the prevention of anastomotic complications, such as anastomotic leaks and strictures, remain a major clinical challenge. Therefore, new molecular pathways need to be identified that regulate anastomotic healing, and to design new treatments for patients after anastomosis to reduce the occurrence of complications. Rabbits were treated with a MST1/2 inhibitor XMU-XP-1, a Chinese medicine formula Shenhuang plaster (SHP) or a control vehicle immediately after surgery. The anastomotic burst pressure, collagen deposition, and hydroxyproline concentration were evaluated at 3 and 7 days after the surgery, and qRT-PCR and western-blot analyses were used to characterize mRNA and protein expression levels. Both XMU-XP-1 and SHP significantly increased anastomotic burst pressure, collagen deposition, and the concentration of hydroxyproline in intestinal anastomotic tissue at postoperative day 7 (POD 7). Importantly, SHP could induce TGF-ß1 expression, which activated its downstream target Smad-2 to activate the TGF-ß1 signaling pathway. Moreover, SHP reduced the phosphorylation level of YAP and increased its active form, and treatment with verteporfin, a YAP-TEAD complex inhibitor, significantly suppressed the effects induced by SHP during anastomotic tissue healing. This study demonstrated that activation of the Hippo-YAP pathway enhances anastomotic healing, and that SHP enhances both the TGF-ß1/Smad and YAP signaling pathways to promote rabbit anastomotic healing after surgery. These results suggest that SHP could be used to treat patients who underwent anastomosis to prevent the occurrence of anastomotic complications.

Smurf1 polyubiquitinates on K285/K282 of the kinases Mst1/2 to attenuate their tumor-suppressor functions.

Sterile 20-like kinases Mst1 and Mst2 (Mst1/2) and large tumor suppressor 1/2 are core kinases to mediate Hippo signaling in maintaining tissue homeostasis. We have previously demonstrated that Smad ubiquitin (Ub) regulatory factor 1 (Smurf1), a HECT-type E3 ligase, ubiquitinates and in turn destabilizes large tumor suppressor 1/2 to induce the transcriptional output of Hippo signaling. Here, we unexpectedly find that Smurf1 interacts with and polyubiquitinates Mst1/2 by virtue of K27- and K29-linked Ub chains, resulting in the proteasomal degradation of Mst1/2 and attenuation of their tumor-suppressor functions. Among the potential Ub acceptor sites on Mst1/2, K285/K282 are conserved and essential for Smurf1-induced polyubiquitination and degradation of Mst1/2 as well as transcriptional output of Hippo signaling. As a result, K285R/K282R mutation of Mst1/2 not only negates the transcriptional output of Hippo signaling but enhances the tumor-suppressor functions of Mst1/2. Together, we demonstrate that Smurf1-mediated polyubiquitination on K285/K282 of Mst1/2 destabilizes Mst1/2 to attenuate their tumor-suppressor functions. Thus, the present study identifies Smurf1-mediated ubiquitination of Mst1/2 as a hitherto uncharacterized mechanism fine-tuning the Hippo signaling pathway and may provide additional targets for therapeutic intervention of diseases associated with this important pathway.

Low MST1/2 and negative LATS1/2 expressions are associated with poor prognosis of colorectal cancers.

Mammalian STe20-like protein kinase 1/2 (MST1/2) and large tumor suppressor homolog 1/2 (LATS1/2) are the core components of the tumor-suppressive Hippo pathway. Dysregulation of this pathway is associated with the progression and metastasis of various cancers. However, MST1/2 and LATS1/2 expressions have not been systematically evaluated in colorectal cancers. We evaluated the clinicopathologic correlation and prognostic significance of MST1/2 and LATS1/2 immunohistochemical expressions in 327 colorectal cancer patients. Low MST1/2 expression, identified in 235 (71.9 %) cases, was significantly associated with poor differentiation (P = 0.018) and large size (P < 0.001) of the tumor. Negative LATS1/2 expression, identified in 226 (69.1 %) cases, was significantly correlated with low MST1/2 expression (P = 0.044). Low MST1/2 and negative LATS1/2 expressions were significantly associated with poor overall survivals (P = 0.015 and P = 0.038, respectively). Furthermore, the combined MST1/2lowLATS1/2negative expression group showed significantly worse overall survival than other groups (P = 0.003), and considered as an independent poor prognostic factor for colorectal cancer patients (hazard ratio = 1.720; 95 % confidence interval, 1.143-2.588; P = 0.009). Low MST1/2 and negative LATS1/2 expressions may serve as prognostic indicators in patients with colorectal cancer.

The hippo kinases MST1/2 in cardiovascular and metabolic diseases: A promising therapeutic target option for pharmacotherapy.

Cardiovascular diseases (CVDs) and metabolic disorders are major components of noncommunicable diseases, causing an enormous health and economic burden worldwide. There are common risk factors and developmental mechanisms among them, indicating the far-reaching significance in exploring the corresponding therapeutic targets. MST1/2 kinases are well-established proapoptotic effectors that also bidirectionally regulate autophagic activity. Recent studies have demonstrated that MST1/2 influence the outcome of cardiovascular and metabolic diseases by regulating immune inflammation. In addition, drug development against them is in full swing. In this review, we mainly describe the roles and mechanisms of MST1/2 in apoptosis and autophagy in cardiovascular and metabolic events as well as emphasis on the existing evidence for their involvement in immune inflammation. Moreover, we summarize the latest progress of pharmacotherapy targeting MST1/2 and propose a new mode of drug combination therapy, which may be beneficial to seek more effective strategies to prevent and treat CVDs and metabolic disorders.

Expression of the Hippo Pathway Core Components in Endometrial Cancer and Its Association with Clinicopathologic Features.

BACKGROUND: The Hippo signaling pathway has a key role in tumorigenesis. This study aimed to evaluate the relationship between the expression of core components of the Hippo signaling pathway and its association with clinicopathological features in endometrial cancer. MATERIALS AND METHODS: We retrospectively collected endometrioid endometrial cancer specimens from 60 patients between January 2002 and December 2009 at Gyeongsang National University Hospital. Relevant clinicopathological data were obtained through electronic medical records of patients. The expression patterns of six core components (YAP, p-YAP, LATS1/2, MST1/2, KIBRA, and Merlin) were identified by immunohistochemistry on tissue microarray sections. RESULTS: The positive expression ratio was 75.0% for YAP, 73.3% for p-YAP, 26.7% for MST1/2, 16.7% for KIBRA, 15.0% for Merlin, and 15.0% for LATS1/2. YAP expression was negatively correlated with MST 1/2 kinases (p = 0.045) and positively correlated with p-YAP (p = 0.012). Merlin, and MST 1/2 kinases (p = 0.043) showed a positive correlation. A subgroup of patients aged below 60 years (p = 0.004) and with myometrial invasion depth of less than 1/2 (p = 0.041) showed a positive association with YAP expression. p-YAP expression was negatively associated with a subset of patients with primary tumour size ≥4 cm (p = 0.03). Logistic regression analysis showed a significant association between age and YAP expression. The odds ratio of p-YAP expression was significantly lower in the group with tumour size ≥4 cm. CONCLUSION: Two prognostic factors, age and tumour size, were significantly associated with the expression of YAP and p-YAP in endometrial cancer. Further research should focus on their expression as a marker for prediction of clinicopathological implications in endometrial cancer.

In-silico studies to analyse the possible interactions of CircPPP1R12A translated peptide with Mst proteins.

The Mammalian sterile 20 kinase (Mst) pathway controls organ development by regulating cell proliferation through apoptosis and has a noncanonical role in cancer. Overexpression of the peptide translated from circular RNA, circPPP1R12A, corelated with the activation of YAP, an oncogene whose expression is triggered upon dysregulation of Mst signalling. The exact mode of molecular interaction(s) leading to inactivation of the Mst pathway by this peptide is hitherto unknown. Mst1 and Mst2 are two prime proteins that require dimerization with their scaffold protein, Sav1 at the early step of Mst signalling. We have investigated the interaction of Mst1/2 proteins with this peptide using molecular docking and molecular dynamics simulation studies. The amino acids involved in binding of the peptide were identified and a comparison between the binding interfaces of Mst1/2 - peptide with Mst1/2 - Sav1 complexes indicated that the binding of the peptide to these Mst proteins may prevent the interactions of these proteins with Sav1. Studying the possible binding modes of Sav1 to the Mst proteins already complexed with the peptide further confirmed that the binding of the peptide may hinder their activation. The in-silico study indicated for the first time the possible molecular mechanism of how the peptide can promote cancer by interfering with the Mst pathway.

Mst1/2 Is Necessary for Satellite Cell Differentiation to Promote Muscle Regeneration.

The diminished ability for muscle to regenerate is associated with aging, diabetes, and cancers. Muscle regeneration depends on the activation and differentiation of satellite cells (SCs). Inactivation of Mst1/2 promotes cell proliferation by activating Yap, and that has been reported as a potential therapeutic target for improving many organ regeneration. However, the function of Mst1/2 in SCs fate decision and that effect on muscle regeneration remain unknown. By using inducible conditional knockout Mst1/2 in the SCs of mice and an inhibitor of Mst1/2, we found that inhibition of Mst1/2 in SCs significantly decrease Yap phosphorylation, thus causing Yap to accumulate in the nucleus and impairing SC differentiation; Mst1/2 were slightly elevated by irisin stimulation during SC differentiation; but inhibiting Mst1/2 in SCs significantly impaired irisin-induced muscle regeneration. These results indicate that Mst1/2 is necessary for SC differentiation and inhibiting Mst1/2 as a therapeutic target has potential risks for muscle regeneration.

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.

Metformin suppresses interleukin-22 induced hepatocellular carcinoma by upregulating Hippo signaling pathway.

BACKGROUND AND AIMS: Epidemiological studies have shown direct associations between type 2 diabetes and the risk of cancers. Accumulating evidence indicates that metformin is profoundly implicated in preventing tumor development. However, the exact mechanism underlying the antitumor effects of metformin in hepatocellular carcinoma (HCC) is still not clear. METHODS: In this study, we investigated the effects of metformin on a mouse HCC model and interleukin-22 (IL-22)-associated carcinogenesis in vitro. RESULTS: We found that metformin significantly suppressed the incidence and tumor burden of HCC in the diethyl-nitrosamine-induced HCC mouse model. As expected, the expression of IL-22, an important factor involved in HCC progression, was markedly reduced by metformin. Treatment of HCC cells with metformin inhibited IL-22 induced cell proliferation, migration, and invasion, and promoted cell apoptosis. Furthermore, ectopic expression of IL-22 makes HCC more aggressive, whereas metformin largely compromised it in vitro and in vivo. Mechanistically, the whole transcriptome analysis and functional analysis revealed that Hippo signaling pathway was involved in the antitumor ability of metformin. Consistent with this, metformin directly inhibited LATS1/2 and activated Mst1/2, phosphorylated YAP1 in vitro. After blocking the Hippo pathway by XMU-MP-1, the inhibitor of MST1/2, the inhibitory effects by metformin were dramatically attenuated as shown by in vitro study. CONCLUSIONS: Collectively, our findings illuminate a new regulatory mechanism, metformin activates Hippo signaling pathway to regulate IL-22 mediated HCC progression and provide new insights into its tumor-suppressive roles.

Hippo Signaling Pathway in Pancreas Development.

The Hippo signaling pathway is a vital regulator of pancreatic development and homeostasis, directing cell fate decisions, morphogenesis, and adult pancreatic cellular plasticity. Through loss-of-function research, Hippo signaling has been found to play key roles in maintaining the proper balance between progenitor cell renewal, proliferation, and differentiation in pancreatic organogenesis. Other studies suggest that overactivation of YAP, a downstream effector of the pathway, promotes ductal cell development and suppresses endocrine cell fate specification via repression of Ngn3. After birth, disruptions in Hippo signaling have been found to lead to de-differentiation of acinar cells and pancreatitis-like phenotype. Further, Hippo signaling directs pancreatic morphogenesis by ensuring proper cell polarization and branching. Despite these findings, the mechanisms through which Hippo governs cell differentiation and pancreatic architecture are yet to be fully understood. Here, we review recent studies of Hippo functions in pancreatic development, including its crosstalk with NOTCH, WNT/ß-catenin, and PI3K/Akt/mTOR signaling pathways.

Mst1/2 Kinases Inhibitor, XMU-MP-1, Attenuates Angiotensin II-Induced Ascending Aortic Expansion in Hypercholesterolemic Mice.

Background: Ascending and abdominal aortic aneurysms (AAs) are asymptomatic, permanent dilations of the aorta with surgical intervention as the currently available therapy. Hippo-Yap signaling cascade plays a critical role in stem cell self-renewal, tissue regeneration and organ size control. By using XMU-MP-1, a pharmacological inhibitor of the key component of Hippo-Yap signaling, MST1/2, we examined the functional contribution of Hippo-Yap in the development of AAs in Angiotensin II (AngII)-infused hypercholesterolemic mice. Methods and Results: MST, p-MST, p-YAP, p-MOB and TAZ proteins in AngII-infused ascending and abdominal aortas were assessed by immunohistochemical and western blot analyses. To examine the effect of MST1/2 inhibition on AAs, western diet-fed low density lipoprotein (LDL) receptor -/- mice infused with AngII were administered with either vehicle or XMU-MP-1 for 5 weeks. Hippo-YAP signaling proteins were significantly elevated in AngII infused ascending and abdominal aortas. XMU-MP-1 administration resulted in the attenuation of AngII-induced ascending AAs without influencing abdominal AAs and aortic atherosclerosis. Inhibition of Hippo-YAP signaling also resulted in the suppression of AngII-induced matrix metalloproteinase 2 (MMP2) activity, macrophage accumulation, aortic medial hypertrophy and elastin breaks in the ascending aorta. Conclusions: The present study demonstrates a pivotal role for the Hippo-YAP signaling pathway in AngII-induced ascending AA development.

Hippo Signaling Pathway in Gliomas.

The Hippo signaling pathway is a highly conserved pathway involved in tissue development and regeneration that controls organ size through the regulation of cell proliferation and apoptosis. The core Hippo pathway is composed of a block of kinases, MST1/2 (Mammalian STE20-like protein kinase 1/2) and LATS1/2 (Large tumor suppressor 1/2), which inhibits nuclear translocation of YAP/TAZ (Yes-Associated Protein 1/Transcriptional co-activator with PDZ-binding motif) and its downstream association with the TEAD (TEA domain) family of transcription factors. This pathway was recently shown to be involved in tumorigenesis and metastasis in several cancers such as lung, breast, or colorectal cancers but is still poorly investigated in brain tumors. Gliomas are the most common and the most lethal primary brain tumors representing about 80% of malignant central nervous system neoplasms. Despite intensive clinical protocol, the prognosis for patients remains very poor due to systematic relapse and treatment failure. Growing evidence demonstrating the role of Hippo signaling in cancer biology and the lack of efficient treatments for malignant gliomas support the idea that this pathway could represent a potential target paving the way for alternative therapeutics. Based on recent advances in the Hippo pathway deciphering, the main goal of this review is to highlight the role of this pathway in gliomas by a state-of-the-art synthesis.

Deubiquitinase JOSD2 stabilizes YAP/TAZ to promote cholangiocarcinoma progression.

Cholangiocarcinoma (CCA) has emerged as an intractable cancer with scanty therapeutic regimens. The aberrant activation of Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are reported to be common in CCA patients. However, the underpinning mechanism remains poorly understood. Deubiquitinase (DUB) is regarded as a main orchestrator in maintaining protein homeostasis. Here, we identified Josephin domain-containing protein 2 (JOSD2) as an essential DUB of YAP/TAZ that sustained the protein level through cleavage of polyubiquitin chains in a deubiquitinase activity-dependent manner. The depletion of JOSD2 promoted YAP/TAZ proteasomal degradation and significantly impeded CCA proliferation in vitro and in vivo. Further analysis has highlighted the positive correlation between JOSD2 and YAP abundance in CCA patient samples. Collectively, this study uncovers the regulatory effects of JOSD2 on YAP/TAZ protein stabilities and profiles its contribution in CCA malignant progression, which may provide a potential intervention target for YAP/TAZ-related CCA patients.

Nogo-B is a key mediator of hepatic ischemia and reperfusion injury.

Nogo-B is an endoplasmic reticulum-residential protein with distinctive functions in different diseases. However, it remains unclear the role of Nogo-B in liver sterile inflammatory injury. This study aims to elucidate the functions and mechanisms in liver ischemia and reperfusion injury (IRI). The Nogo-B expression and liver function were analyzed in biopsy/serum specimens from 36 patients undergoing ischemia-related hepatectomy and in a mouse model of liver IRI. Human specimens were harvested prior to ischemia and post-reperfusion. The Nogo-B knockout (Nogo-BKO) and myeloid-specific Nogo-B knockout (Nogo-BMKO) mice were used to analyze the function and mechanism of Nogo-B in a mouse model of liver IRI. In human specimens, the Nogo-B expression was positively correlated with higher levels of serum transaminase (sALT) and severe histopathological injury at one day post-hepatectomy. Moreover, Nogo-B is mainly expressed on macrophages in normal and ischemic liver tissues from human and mice. Unlike in controls, the Nogo-BKO or Nogo-BMKO livers was protected against IRI, with reduced reactive oxygen species (ROS) production and liver inflammation in ischemic livers. In parallel in vitro studies, Nogo-B deficiency reduced M1 macrophage polarization and inhibited proinflammatory cytokines (TNF-α, IL-6, MCP-1 and iNOS) in response to LPS or HMGB-1 stimulation. Mechanistic studies showed that Nogo-B bound to MST1/2, increased MST1/2, LAST1, and YAP phosphorylation, leading to reduced YAP activity. Interestingly, disruption of macrophage YAP abolished Nogo-B deficiency-mediated cytoprotective effects in vitro and in vivo. Thus, YAP is crucial for the regulation of macrophage Nogo-B-triggered liver inflammation. Nogo-B promotes macrophage-related innate inflammation and contributes to IR-induced liver injury by activating the MST-mediated Hippo/YAP pathway, which provides a potential therapeutic target for clinical management in liver IRI.

XMU-MP-1 induces growth arrest in a model human mini-organ and antagonises cell cycle-dependent paclitaxel cytotoxicity.

BACKGROUND: XMU-MP-1 is an inhibitor of the Hippo pathway kinases MST1/2 and has been shown to promote the downstream activation of the pro-proliferative, pro-regenerative and anti-apoptotic transcriptional regulator YAP1. We tested whether XMU-MP-1 can activate YAP1 in a model human mini-organ, namely the hair follicle, to determine whether it can be pharmacologically exploited to promote regeneration in the hair follicle as a novel strategy to treat pathological hair loss disorders. RESULTS: XMU-MP-1 treatment inhibited MOB1 phosphorylation but did not increase active YAP1 in the hair follicle. Rather than promote proliferation, XMU-MP-1 serendipitously decreased the number of Ki-67+, EdU+ and phospho histone H3+ hair matrix keratinocytes and antagonised the cytotoxic effects of paclitaxel. CONCLUSIONS: XMU-MP-1 perturbs epithelial cell cycle progression in a model human mini-organ. This may arise as an off-target effect, especially when XMU-MP-1 has been described to strongly inhibit 21 additional kinases beyond MST1/2. Therefore, whilst these effects may be dependent on tissue context, researchers should exercise caution when interpreting the effects of XMU-MP-1, especially in tissues with actively proliferating cell populations.