scholarly journals Disease implication of hyper-Hippo signalling

Open Biology ◽  
2016 ◽  
Vol 6 (10) ◽  
pp. 160119 ◽  
Author(s):  
Shu-Ping Wang ◽  
Lan-Hsin Wang
Keyword(s):  
Cellular Proliferation ◽  
Current Knowledge ◽  
Hippo Pathway ◽  
Living Cells ◽  
Regulatory Mechanisms ◽  
Arrhythmogenic Cardiomyopathy ◽  
Tumour Suppressor Function ◽  
The Hippo Pathway ◽  
Lateral Sclerosis ◽  
Hippo Signalling

The Hippo signalling pathway regulates cellular proliferation, apoptosis and differentiation, thus exerting profound effects on cellular homeostasis. Inhibition of Hippo signalling has been frequently implicated in human cancers, indicating a well-known tumour suppressor function of the Hippo pathway. However, it is less certain whether and how hyperactivation of the Hippo pathway affects biological outcome in living cells. This review describes current knowledge of the regulatory mechanisms of the Hippo pathway, mainly focusing on hyperactivation of the Hippo signalling nexus. The disease implications of hyperactivated Hippo signalling have also been discussed, including arrhythmogenic cardiomyopathy, Sveinsson's chorioretinal atrophy, Alzheimer's disease, amyotrophic lateral sclerosis and diabetes. By highlighting the significance of disease-relevant Hippo signalling activation, this review can offer exciting prospects to address the onset and potential reversal of Hippo-related disorders.

scholarly journals The Hippo Pathway Is Activated and Is a Causal Mechanism for Adipogenesis in Arrhythmogenic Cardiomyopathy

2014 ◽  
Vol 114 (3) ◽  
pp. 454-468 ◽  
Author(s):  
Suet Nee Chen ◽  
Priyatansh Gurha ◽  
Raffaella Lombardi ◽  
Alessandra Ruggiero ◽  
James T. Willerson ◽  
...  
Keyword(s):  
Hippo Pathway ◽  
Causal Mechanism ◽  
Arrhythmogenic Cardiomyopathy ◽  
The Hippo Pathway

scholarly journals NPHP4, a cilia-associated protein, negatively regulates the Hippo pathway

2011 ◽  
Vol 193 (4) ◽  
pp. 633-642 ◽  
Author(s):  
Sandra Habbig ◽  
Malte P. Bartram ◽  
Roman U. Müller ◽  
Ricarda Schwarz ◽  
Nikolaos Andriopoulos ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cellular Proliferation ◽  
Nuclear Translocation ◽  
Hippo Pathway ◽  
Negative Regulator ◽  
Hippo Signaling ◽  
Transcriptional Coactivator ◽  
Hippo Signaling Pathway ◽  
The Hippo Pathway ◽  
Potent Negative Regulator

The conserved Hippo signaling pathway regulates organ size in Drosophila melanogaster and mammals and has an essential role in tumor suppression and the control of cell proliferation. Recent studies identified activators of Hippo signaling, but antagonists of the pathway have remained largely elusive. In this paper, we show that NPHP4, a known cilia-associated protein that is mutated in the severe degenerative renal disease nephronophthisis, acts as a potent negative regulator of mammalian Hippo signaling. NPHP4 directly interacted with the kinase Lats1 and inhibited Lats1-mediated phosphorylation of the Yes-associated protein (YAP) and TAZ (transcriptional coactivator with PDZ-binding domain), leading to derepression of these protooncogenic transcriptional regulators. Moreover, NPHP4 induced release from 14-3-3 binding and nuclear translocation of YAP and TAZ, promoting TEA domain (TEAD)/TAZ/YAP-dependent transcriptional activity. Consistent with these data, knockdown of NPHP4 negatively affected cellular proliferation and TEAD/TAZ activity, essentially phenocopying loss of TAZ function. These data identify NPHP4 as a negative regulator of the Hippo pathway and suggest that NPHP4 regulates cell proliferation through its effects on Hippo signaling.

1183Beta-Adrenoceptor activation increases cardiac galectin-3 levels via the hippo signaling pathway

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
X.-J Du ◽  
W B Zhao ◽  
Q Lu ◽  
M N Nguyen ◽  
M Ziemann ◽  
...  
Keyword(s):  
Hippo Pathway ◽  
Fold Increase ◽  
Signalling Pathway ◽  
Mutant Form ◽  
Wild Type ◽  
Galectin 3 ◽  
Β Blockers ◽  
The Hippo Pathway ◽  
Hippo Signalling

Abstract Background Galectin-3 (Gal-3) is a clinical biomarker for risk of cardiovascular disease and a disease mediator forming a therapeutic target. However, the mechanism(s) that regulate cardiac expression of Gal-3 remains unknown. Activation of the sympatho-β-adrenergic system is a hallmark of heart disease, but the relationship of βAR activation and cardiac content of Gal-3 remains unknown. Purpose To determine the role of βAR activation in regulating cardiac Gal-3 level and the responsible mechanism focusing on the Hippo signalling pathway. Methods Wild-type and Gal-3 gene deleted (Gal3-KO) mice were used. To test the role of the Hippo pathway, we used transgenic (TG) mouse strains with cardiac overexpression of mammalian-20-like sterile kinase 1 (Mst1, mammalian orthology of Drosophila Hippo kinase) either in wild-type form (TG-Mst1) or dominative-negative kinase dead mutant form (TG-dnMst1). Effects of β-antagonist (isoprenaline, ISO) and antagonists were determined. We measured phosphorylation (Ser127) of YAP as a transcription co-regulator acting as the main signal output of the Hippo pathway. Results In wild-type mice, treatment with ISO led to a time- and dose-dependent increase in cardiac expression of Gal-3 (Fig. A) accompanied by elevated circulating Gal-3 levels (Fig. B). ISO treatment stimulated cardiac expression of Mst1 and YAP hyper-phosphorylation (i.e. inactivation, Fig. C), indicating activation of the Hippo signalling. These effects of ISO were inhibited by β-blockers (propranolol, Prop; carvedilol, Carv; Fig. D,E). Relative to non-TG controls, ISO-induced expression of Gal-3 was inhibited by 75% in TG-dnMst1 mice (inactivated Mst1), but exaggerated by 7-fold in TG-Mst1 mice (activated Mst1). Mst1-TG mice had a 45-fold increase in Gal-3 content, YAP hyper-phosphorylation and enhanced pro-fibrotic signaling. In Mst1-TG mice, whilst blood Gal-3 level was unchanged, treatment with ISO (6 mg, 2 days) evoked a marked increase in cardiac and blood Gal-3 levels. Using rat cardiomyoblasts, we showed that ISO-mediated Mst1 expression and YAP phosphorylation were PKA-dependent and that siRNA-mediated YAP knockdown led to Gal-3 upregulation. The role of Gal-3 in mediating ISO-induced cardiomyopathy was examined by treating wild-type and Gal3-KO mice with ISO (30 mg/kg, 7 days). ISO-treated wild-type mice had 8-fold increase in cardiac Gal-3, ventricular dysfunction, fibrosis, hypertrophy and activated inflammatory or fibrotic signalling. All these changes, except hypertrophy, were abolished by Gal3-KO. beta-AR regulates galectin-3 Conclusion βAR stimulation increases cardiac expression of Gal-3 through activation of the Hippo signalling pathway. This is accompanied by elevated circulating Gal-3 level. βAR antagonists inhibited βAR-Mst1 (Hippo) signalling and cardiac Gal-3 expression, actions likely contributing to the overall efficacy of β-blockers. Acknowledgement/Funding NHMRC of Australia; Nature Science Fund of China

Abstract A26: Classification of glioblastoma tumorsphere depending on the regulatory mechanisms of the Hippo pathway

2020 ◽  
Author(s):  
Yoojung Oh ◽  
Eui Hyun Kim ◽  
Dongkyu Lee ◽  
Junseong Park ◽  
Ju Hyung Moon ◽  
...  
Keyword(s):  
Hippo Pathway ◽  
Regulatory Mechanisms ◽  
The Hippo Pathway

scholarly journals Hippo signaling in the kidney: the good and the bad

2016 ◽  
Vol 311 (2) ◽  
pp. F241-F248 ◽  
Author(s):  
Jenny S. Wong ◽  
Kristin Meliambro ◽  
Justina Ray ◽  
Kirk N. Campbell
Keyword(s):  
Embryonic Development ◽  
Current Knowledge ◽  
Hippo Pathway ◽  
Hippo Signaling ◽  
Filtration Barrier ◽  
Signaling Axis ◽  
Kinase Cascade ◽  
Barrier Regulation ◽  
Renal Tubular ◽  
The Hippo Pathway

The Hippo signaling pathway is an evolutionarily conserved kinase cascade, playing multiple roles in embryonic development that controls organ size, cell proliferation, and apoptosis. At the center of this network lie the Hippo kinase target and downstream pathway effector Yes-associated protein (YAP) and its paralog TAZ. In its phosphorylated form, cytoplasmic YAP is sequestered in an inactive state. When it is dephosphorylated, YAP, a potent oncogene, is activated and relocates to the nucleus to interact with a number of transcription factors and signaling regulators that promote cell growth, differentiation, and survival. The identification of YAP activation in human cancers has made it an attractive target for chemotherapeutic drug development. Little is known to date about the function of the Hippo pathway in the kidney, but that is rapidly changing. Recent studies have shed light on the role of Hippo-YAP signaling in glomerular and lower urinary tract embryonic development, maintenance of podocyte homeostasis, the integrity of the glomerular filtration barrier, regulation of renal tubular cyst growth, renal epithelial injury in diabetes, and renal fibrogenesis. This review summarizes the current knowledge of the Hippo-YAP signaling axis in the kidney under normal and disease conditions.

scholarly journals Crumbs and the apical spectrin cytoskeleton regulate r8 cell fate in the Drosophila eye

PLoS Genetics ◽  
2021 ◽  
Vol 17 (6) ◽  
pp. e1009146
Author(s):  
Jonathan M. Pojer ◽  
Abdul Jabbar Saiful Hilmi ◽  
Shu Kondo ◽  
Kieran F. Harvey
Keyword(s):  
Cell Fate ◽  
Hippo Pathway ◽  
Green Light ◽  
Photoreceptor Cells ◽  
Organ Growth ◽  
Important Regulator ◽  
Spectrin Cytoskeleton ◽  
Fate Decision ◽  
The Hippo Pathway ◽  
Hippo Signalling

The Hippo pathway is an important regulator of organ growth and cell fate. In the R8 photoreceptor cells of the Drosophila melanogaster eye, the Hippo pathway controls the fate choice between one of two subtypes that express either the blue light-sensitive Rhodopsin 5 (Hippo inactive R8 subtype) or the green light-sensitive Rhodopsin 6 (Hippo active R8 subtype). The degree to which the mechanism of Hippo signal transduction and the proteins that mediate it are conserved in organ growth and R8 cell fate choice is currently unclear. Here, we identify Crumbs and the apical spectrin cytoskeleton as regulators of R8 cell fate. By contrast, other proteins that influence Hippo-dependent organ growth, such as the basolateral spectrin cytoskeleton and Ajuba, are dispensable for the R8 cell fate choice. Surprisingly, Crumbs promotes the Rhodopsin 5 cell fate, which is driven by Yorkie, rather than the Rhodopsin 6 cell fate, which is driven by Warts and the Hippo pathway, which contrasts with its impact on Hippo activity in organ growth. Furthermore, neither the apical spectrin cytoskeleton nor Crumbs appear to regulate the Hippo pathway through mechanisms that have been observed in growing organs. Together, these results show that only a subset of Hippo pathway proteins regulate the R8 binary cell fate decision and that aspects of Hippo signalling differ between growing organs and post-mitotic R8 cells.

The Hippo pathway regulates human megakaryocytic differentiation

2017 ◽  
Vol 117 (01) ◽  
pp. 116-126 ◽  
Author(s):  
Chanchao Lorthongpanich ◽  
Nittaya Jiamvoraphong ◽  
Kantpitchar Supraditaporn ◽  
Phatchanat Klaihmon ◽  
Yaowalak U-pratya ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Hippo Pathway ◽  
Functional Changes ◽  
Supplementary Material ◽  
The Hippo Pathway ◽  
Insight Into ◽  
Component Gene ◽  
Hippo Signalling ◽  
Platelet Formation

SummaryThe Hippo pathway is involved in several biological processes in both flies and mammals. Recent studies have shown that the Hippo pathway regulates Drosophila’s haematopoiesis; however, understanding of its role in mammalian haematopoiesis is still limited. In flies, deletion of the Hippo component gene, Warts, affects crystal cell differentiation. We explored the role of the Hippo pathway in human haemato-poiesis focusing on megakaryopoiesis. To investigate the role of LATS1/2 (a mammalian homolog of Warts) in human megakaryo -blastic cell differentiation and platelet formation, megakaryoblastic cell (MEG-01) line was used as a model to gain insight into mechan-ism of the Hippo pathway in mammalian megakaryopoiesis. Effect of LATS1/2 on megakaryoblastic cell differentiation and platelet production were determined by functional changes. We found that depletion of LATS1/2 resulted in an increase of CD41+ megakaryocytes with impaired platelet biogenesis. Our study shows that the Hippo signalling pathway plays a crucial role in human megakaryoblastic cell differentiation and thrombopoiesis.Supplementary Material to this article is available online at www.thrombosis-online.com.

scholarly journals STK25 directly activates LATS1/2 independent of MST/MAP4Ks

2018 ◽  
Author(s):  
Sanghee Lim ◽  
Nicole Hermance ◽  
Tenny Mudianto ◽  
Hatim M. Mustaly ◽  
Ian Paolo Morelos Mauricio ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Cellular Proliferation ◽  
Wide Spectrum ◽  
Hippo Pathway ◽  
Common Mechanism ◽  
Activation Loop ◽  
Hippo Signaling ◽  
New Paradigm ◽  
Functional Inactivation ◽  
The Hippo Pathway

AbstractThe Hippo pathway maintains tissue homeostasis by negatively regulating the oncogenic transcriptional co-activators YAP and TAZ. Though functional inactivation of the Hippo pathway is common in tumors, mutations in core pathway components are rare. Thus, understanding how tumor cells inactivate Hippo signaling remains a key unresolved question. Here, we identify the kinase STK25 as a novel activator of Hippo signaling. We demonstrate that loss of STK25 promotes YAP/TAZ activation and enhanced cellular proliferation, even under normally growth-suppressive conditions. We reveal that STK25 activates LATS via a previously unobserved mechanism, in which STK25 directly phosphorylates the LATS activation loop. This represents a new paradigm in Hippo activation and distinguishes STK25 from all other identified kinase activators of LATS. STK25 is significantly focally deleted across a wide spectrum of human cancers, suggesting STK25 loss may represent a common mechanism by which tumor cells functionally impair the Hippo tumor suppressor pathway.

Hippo and TGF-β interplay in the lung field

2015 ◽  
Vol 309 (8) ◽  
pp. L756-L767 ◽  
Author(s):  
Akira Saito ◽  
Takahide Nagase
Keyword(s):  
Lung Development ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Current Knowledge ◽  
Hippo Pathway ◽  
Binding Motif ◽  
Lung Field ◽  
Biological Processes ◽  
Mesenchymal Transition ◽  
The Hippo Pathway

The Hippo pathway is comprised of a kinase cascade that involves mammalian Ste20-like serine/threonine kinases (MST1/2) and large tumor suppressor kinases (LATS1/2) and leads to inactivation of transcriptional coactivator with PDZ-binding motif (TAZ) and yes-associated protein (YAP). Protein stability and subcellular localization of TAZ/YAP determine its ability to regulate a diverse array of biological processes, including proliferation, apoptosis, differentiation, stem/progenitor cell properties, organ size control, and tumorigenesis. These actions are enabled by interactions with various transcription factors or through cross talk with other signaling pathways. Interestingly, mechanical stress has been shown to be an upstream regulator of TAZ/YAP activity, and this finding provides a novel clue for understanding how mechanical forces influence a broad spectrum of biological processes, which involve cytoskeletal structure, cell adhesion, and extracellular matrix (ECM) organization. Transforming growth factor-β (TGF-β) pathway is a critical component of lung development and the progression of lung diseases including emphysema, fibrosis, and cancer. In addition, TGF-β is a key regulator of ECM remodeling and cell differentiation processes such as epithelial-mesenchymal transition. In this review, we summarize the current knowledge of the Hippo pathway regarding lung development and diseases, with an emphasis on its interplay with TGF-β signaling.

scholarly journals Reciprocal Regulation of Hippo and WBP2 Signalling—Implications in Cancer Therapy

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3130
Author(s):  
Yvonne Xinyi Lim ◽  
Hexian Lin ◽  
Sock Hong Seah ◽  
Yoon Pin Lim
Keyword(s):  
Cancer Therapy ◽  
Feedback Loop ◽  
Molecular Mechanisms ◽  
Hippo Pathway ◽  
Biological Mechanisms ◽  
Reciprocal Regulation ◽  
Cancer Initiation ◽  
The Hippo Pathway ◽  
Global Health Problem ◽  
Hippo Signalling

Cancer is a global health problem. The delineation of molecular mechanisms pertinent to cancer initiation and development has spurred cancer therapy in the form of precision medicine. The Hippo signalling pathway is a tumour suppressor pathway implicated in a multitude of cancers. Elucidation of the Hippo pathway has revealed an increasing number of regulators that are implicated, some being potential therapeutic targets for cancer interventions. WW domain-binding protein 2 (WBP2) is an oncogenic transcriptional co-factor that interacts, amongst others, with two other transcriptional co-activators, YAP and TAZ, in the Hippo pathway. WBP2 was recently discovered to modulate the upstream Hippo signalling components by associating with LATS2 and WWC3. Exacerbating the complexity of the WBP2/Hippo network, WBP2 itself is reciprocally regulated by Hippo-mediated microRNA biogenesis, contributing to a positive feedback loop that further drives carcinogenesis. Here, we summarise the biological mechanisms of WBP2/Hippo reciprocal regulation and propose therapeutic strategies to overcome Hippo defects in cancers through targeting WBP2.

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