scholarly journals Regulation of posterior body and epidermal morphogenesis in zebrafish by localized Yap1 and Wwtr1

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
David Kimelman ◽  
Natalie L Smith ◽  
Jason Kuan Han Lai ◽  
Didier YR Stainier
Keyword(s):  
Molecular Mechanisms ◽  
Morphological Changes ◽  
Hippo Pathway ◽  
Cell Movement ◽  
The Body ◽  
Complex Processes ◽  
Vertebrate Embryo ◽  
Epithelial Sheet ◽  
Epidermal Morphogenesis ◽  
The Hippo Pathway

The vertebrate embryo undergoes a series of dramatic morphological changes as the body extends to form the complete anterior-posterior axis during the somite-forming stages. The molecular mechanisms regulating these complex processes are still largely unknown. We show that the Hippo pathway transcriptional coactivators Yap1 and Wwtr1 are specifically localized to the presumptive epidermis and notochord, and play a critical and unexpected role in posterior body extension by regulating Fibronectin assembly underneath the presumptive epidermis and surrounding the notochord. We further find that Yap1 and Wwtr1, also via Fibronectin, have an essential role in the epidermal morphogenesis necessary to form the initial dorsal and ventral fins, a process previously thought to involve bending of an epithelial sheet, but which we now show involves concerted active cell movement. Our results reveal how the Hippo pathway transcriptional program, localized to two specific tissues, acts to control essential morphological events in the vertebrate embryo.

scholarly journals A tale of two cell-fates: role of the Hippo signaling pathway and transcription factors in early lineage formation in mouse preimplantation embryos

2020 ◽  
Vol 26 (9) ◽  
pp. 653-664
Author(s):  
Challis Karasek ◽  
Mohamed Ashry ◽  
Chad S Driscoll ◽  
Jason G Knott
Keyword(s):  
Signaling Pathway ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Hippo Pathway ◽  
Cell Mass ◽  
Preimplantation Embryos ◽  
Hippo Signaling ◽  
Cell Fate Decisions ◽  
Hippo Signaling Pathway ◽  
The Hippo Pathway

Abstract In mammals, the first cell-fate decision occurs during preimplantation embryo development when the inner cell mass (ICM) and trophectoderm (TE) lineages are established. The ICM develops into the embryo proper, while the TE lineage forms the placenta. The underlying molecular mechanisms that govern lineage formation involve cell-to-cell interactions, cell polarization, cell signaling and transcriptional regulation. In this review, we will discuss the current understanding regarding the cellular and molecular events that regulate lineage formation in mouse preimplantation embryos with an emphasis on cell polarity and the Hippo signaling pathway. Moreover, we will provide an overview on some of the molecular tools that are used to manipulate the Hippo pathway and study cell-fate decisions in early embryos. Lastly, we will provide exciting future perspectives on transcriptional regulatory mechanisms that modulate the activity of the Hippo pathway in preimplantation embryos to ensure robust lineage segregation.

scholarly journals Downregulation of MYPT1 increases tumor resistance in ovarian cancer by targeting the Hippo pathway and increasing the stemness

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Sandra Muñoz-Galván ◽  
Blanca Felipe-Abrio ◽  
Eva M. Verdugo-Sivianes ◽  
Marco Perez ◽  
Manuel P. Jiménez-García ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Hippo Pathway ◽  
Ovarian Tumors ◽  
Tumor Resistance ◽  
Functional Link ◽  
The Hippo Pathway

Abstract Background Ovarian cancer is one of the most common and malignant cancers, partly due to its late diagnosis and high recurrence. Chemotherapy resistance has been linked to poor prognosis and is believed to be linked to the cancer stem cell (CSC) pool. Therefore, elucidating the molecular mechanisms mediating therapy resistance is essential to finding new targets for therapy-resistant tumors. Methods shRNA depletion of MYPT1 in ovarian cancer cell lines, miRNA overexpression, RT-qPCR analysis, patient tumor samples, cell line- and tumorsphere-derived xenografts, in vitro and in vivo treatments, analysis of data from ovarian tumors in public transcriptomic patient databases and in-house patient cohorts. Results We show that MYPT1 (PPP1R12A), encoding myosin phosphatase target subunit 1, is downregulated in ovarian tumors, leading to reduced survival and increased tumorigenesis, as well as resistance to platinum-based therapy. Similarly, overexpression of miR-30b targeting MYPT1 results in enhanced CSC-like properties in ovarian tumor cells and is connected to the activation of the Hippo pathway. Inhibition of the Hippo pathway transcriptional co-activator YAP suppresses the resistance to platinum-based therapy induced by either low MYPT1 expression or miR-30b overexpression, both in vitro and in vivo. Conclusions Our work provides a functional link between the resistance to chemotherapy in ovarian tumors and the increase in the CSC pool that results from the activation of the Hippo pathway target genes upon MYPT1 downregulation. Combination therapy with cisplatin and YAP inhibitors suppresses MYPT1-induced resistance, demonstrating the possibility of using this treatment in patients with low MYPT1 expression, who are likely to be resistant to platinum-based therapy.

scholarly journals The Hippo Pathway: Biology and Pathophysiology

2019 ◽  
Vol 88 (1) ◽  
pp. 577-604 ◽  
Author(s):  
Shenghong Ma ◽  
Zhipeng Meng ◽  
Rui Chen ◽  
Kun-Liang Guan
Keyword(s):  
Molecular Mechanisms ◽  
Hippo Pathway ◽  
Size Control ◽  
Tissue Growth ◽  
Cell Contact ◽  
Energy Status ◽  
Downstream Effectors ◽  
Kinase Cascade ◽  
Fate Decision ◽  
The Hippo Pathway

The Hippo pathway was initially discovered in Drosophila melanogaster as a key regulator of tissue growth. It is an evolutionarily conserved signaling cascade regulating numerous biological processes, including cell growth and fate decision, organ size control, and regeneration. The core of the Hippo pathway in mammals consists of a kinase cascade, MST1/2 and LATS1/2, as well as downstream effectors, transcriptional coactivators YAP and TAZ. These core components of the Hippo pathway control transcriptional programs involved in cell proliferation, survival, mobility, stemness, and differentiation. The Hippo pathway is tightly regulated by both intrinsic and extrinsic signals, such as mechanical force, cell–cell contact, polarity, energy status, stress, and many diffusible hormonal factors, the majority of which act through G protein–coupled receptors. Here, we review the current understanding of molecular mechanisms by which signals regulate the Hippo pathway with an emphasis on mechanotransduction and the effects of this pathway on basic biology and human diseases.

scholarly journals The Hippo Pathway in Cardiac Regeneration and Homeostasis: New Perspectives for Cell-Free Therapy in the Injured Heart

Biomolecules ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 1024
Author(s):  
Mingjie Zheng ◽  
Joan Jacob ◽  
Shao-Hsi Hung ◽  
Jun Wang
Keyword(s):  
Chromatin Remodeling ◽  
Molecular Mechanisms ◽  
Hippo Pathway ◽  
Cell Communication ◽  
Cardiac Regeneration ◽  
Heart Regeneration ◽  
Regenerative Capacity ◽  
The World ◽  
Causes Of Mortality ◽  
The Hippo Pathway

Intractable cardiovascular diseases are leading causes of mortality around the world. Adult mammalian hearts have poor regenerative capacity and are not capable of self-repair after injury. Recent studies of cell-free therapeutics such as those designed to stimulate endogenous cardiac regeneration have uncovered new feasible therapeutic avenues for cardiac repair. The Hippo pathway, a fundamental pathway with pivotal roles in cell proliferation, survival and differentiation, has tremendous potential for therapeutic manipulation in cardiac regeneration. In this review, we summarize the most recent studies that have revealed the function of the Hippo pathway in heart regeneration and homeostasis. In particular, we discuss the molecular mechanisms of how the Hippo pathway maintains cardiac homeostasis by directing cardiomyocyte chromatin remodeling and regulating the cell-cell communication between cardiomyocytes and non-cardiomyocytes in the heart.

209 Rho signaling-directed regulation of YAP/TAZ in parthenogenetic stem cells

2020 ◽  
Vol 32 (2) ◽  
pp. 233
Author(s):  
G. Pennarossa ◽  
S. Arcuri ◽  
F. Gandolfi ◽  
T. Brevini
Keyword(s):  
Stem Cells ◽  
Molecular Mechanisms ◽  
Rho Gtpase ◽  
Hippo Pathway ◽  
Genetic Material ◽  
Embryonic Stem ◽  
Cell Types ◽  
Embryonic Cell ◽  
And Migration ◽  
The Hippo Pathway

Mammalian oocyte maturation is characterised by asymmetric meiotic division that is regulated by specific cytoskeleton organisation. Similarly, during early embryonic divisions, one of the most important steps is the establishment of polarity that allows cells to adopt distinct developmental fates. All of these events are driven by dynamic changes in actin filaments. It has been demonstrated recently that the Rho signalling pathway plays a key role in the organisation and rearrangement of actin-containing structures, regulating cell polarity and migration. In addition, beside its effect on cell cytoskeleton, Rho directly interacts with the Hippo pathway, influencing both embryonic cell proliferation and differentiation. Because both Rho and Hippo are expressed by the oocyte and maternally inherited (Zhang et al. 2014 Cell Cycle 13, 3390-3403, https://doi.org/10.4161/15384101.2014.952967; Menchero et al. 2017 Dev. Dyn. 246, 245-261, https://doi.org/10.1002/dvdy.24471), we investigated their regulation in parthenogenetic embryonic stem cells (ParthESC) that possess exclusively maternal genetic material, and compared the results with biparental ESCs. Previous results obtained by whole-transcriptome analysis revealed the presence of several differentially expressed genes involved in the Rho pathway and showed no differences for most of the Hippo signalling genes. To better elucidate the molecular mechanisms involved, in the present study, we dissected the expression pattern of the Rho and Hippo regulatory genes in human biparental ESCs and ParthESC. Experiments were performed on 4 biparental ESC and 4 ParthESC lines using cells between passages 5 to 25. The results showed significantly increased transcription of the Rho GTPase family genes (RHOA, RHOB, and RHOC) in ParthESC compared with biparental ESCs. Consistent with this, 12 of 17 Rho activators were significantly upregulated, whereas 8 of 11 Rho inhibitors were significantly decreased in ParthESC. Furthermore, monoparental cells displayed significantly higher expression levels of YAP and TAZ, whereas the upstream genes involved in the Hippo pathway (LATS1/2, MOB1, MST1/2, NF2) were comparable in the two cell types. Interestingly, a significantly higher total YAP protein content was detected in ParthESC, whereas the quantity of the phosphorylated form was comparable in the two cell types. This accounts for the observed upregulation of Rho genes, which stimulate the assembly of contractile actin stress fibres, inhibiting LATS1/2 phosphorylation and preventing subsequent phosphorylation of YAP/TAZ (Yu and Guan 2013 Genes Dev. 27, 355-371; https://doi.org/10.1101/gad.210773.112). Altogether, our results suggest that the Rho pathway may regulate YAP/TAZ behaviour via a LATS/MST/NF2-independent process in ParthESC, similarly to a previous report in oocytes (Posfai and Rossant 2016 Cell Res. 26, 393-394; https://doi.org/10.1038/cr.2016). Although further clarifications are needed, we hypothesise that the regulatory mechanisms detected in ParthESC may be related to their strictly maternal origin, with a possible impact on their plasticity and potency. This study was supported by Carraresi Foundation. Authors are members of the COST Actions CA16119.

scholarly journals SAV1 promotes Hippo kinase activation through antagonizing the PP2A phosphatase STRIPAK

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Sung Jun Bae ◽  
Lisheng Ni ◽  
Adam Osinski ◽  
Diana R Tomchick ◽  
Chad A Brautigam ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Hippo Pathway ◽  
Tissue Growth ◽  
Activation Loop ◽  
Hippo Signaling ◽  
Ww Domains ◽  
Kinase Activation ◽  
Genetic Ablation ◽  
Kinase Cascade ◽  
The Hippo Pathway

The Hippo pathway controls tissue growth and homeostasis through a central MST-LATS kinase cascade. The scaffold protein SAV1 promotes the activation of this kinase cascade, but the molecular mechanisms remain unknown. Here, we discover SAV1-mediated inhibition of the PP2A complex STRIPAKSLMAP as a key mechanism of MST1/2 activation. SLMAP binding to autophosphorylated MST2 linker recruits STRIPAK and promotes PP2A-mediated dephosphorylation of MST2 at the activation loop. Our structural and biochemical studies reveal that SAV1 and MST2 heterodimerize through their SARAH domains. Two SAV1–MST2 heterodimers further dimerize through SAV1 WW domains to form a heterotetramer, in which MST2 undergoes trans-autophosphorylation. SAV1 directly binds to STRIPAK and inhibits its phosphatase activity, protecting MST2 activation-loop phosphorylation. Genetic ablation of SLMAP in human cells leads to spontaneous activation of the Hippo pathway and alleviates the need for SAV1 in Hippo signaling. Thus, SAV1 promotes Hippo activation through counteracting the STRIPAKSLMAP PP2A phosphatase complex.

scholarly journals The Hippo pathway oncoprotein YAP promotes melanoma cell invasion and spontaneous metastasis

2019 ◽  
Author(s):  
Xiaomeng Zhang ◽  
Lie Yang ◽  
Pacman Szeto ◽  
Youfang Zhang ◽  
Kaushalya Amarasinghe ◽  
...  
Keyword(s):  
Cell Fate ◽  
Melanoma Cell ◽  
Cell Invasion ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Expression Profiles ◽  
Hippo Pathway ◽  
Melanoma Metastasis ◽  
The Hippo Pathway

ABSTRACTMelanoma is a deadly form of skin cancer that accounts for a disproportionally large proportion of cancer-related deaths in younger people. Compared to most other skin cancers, a feature of melanoma is its high metastatic capacity, although molecular mechanisms that confer this are not well understood. The Hippo pathway is a key regulator of organ growth and cell fate that is deregulated in many cancers. To analyse the Hippo pathway in cutaneous melanoma, we generated a transcriptional signature of pathway activity in melanoma cells. Hippo-mediated transcriptional activity varied in melanoma cell lines but failed to cluster with known genetic drivers of melanomagenesis such as BRAF and NRAS mutation status. Instead, it correlated strongly with published gene expression profiles linked to melanoma cell invasiveness. Consistent with this, the central Hippo oncogene, YAP, was both necessary and sufficient for melanoma cell invasion in vitro. In in vivo murine studies, YAP promoted spontaneous melanoma metastasis, whilst the growth of YAP-expressing primary tumours was impeded. Finally, we identified the YAP target genes AXL, THBS1 and CYR61 as key mediators of YAP-induced melanoma cell invasion. These data suggest that the Hippo pathway is a critical regulator of melanoma metastasis.

scholarly journals The Hippo pathway transcriptional co-activator YAP is involved in head regeneration and bud development in Hydra

2021 ◽  
Author(s):  
Manu Krishnan Unni ◽  
Puli Chandramouli Reddy ◽  
Sanjeev Galande
Keyword(s):  
Target Genes ◽  
Hippo Pathway ◽  
Early Response ◽  
Immunofluorescence Assay ◽  
The Body ◽  
Hippo Signaling ◽  
Fate Specification ◽  
The Hippo Pathway ◽  
Body Column ◽  
Head Regeneration

The Hippo signaling pathway has been shown to be involved in the regulation of cellular identity, cell/tissue size maintenance and mechanotransduction. The Hippo pathway consists of a kinase cascade which determines the nucleo-cytoplasmic localization of YAP in the cell. YAP is the effector protein in the Hippo pathway which acts as a transcriptional cofactor for TEAD. Phosphorylation of YAP upon activation of the Hippo pathway prevents it from entering the nucleus and hence abrogates its function in transcription of target genes. In Cnidaria, the information on the regulatory roles of the Hippo pathway is virtually lacking. Here, we report for the first time the existence of a complete set of Hippo pathway core components in Hydra. By studying their phylogeny and domain organization, we report evolutionary conservation of the components of the Hippo pathway. Protein modelling suggested conservation of YAP-TEAD interaction in Hydra. We also characterized the expression pattern of the homologs of yap, hippo, mob and sav in Hydra using whole mount RNA in situ hybridization and report their possible role in stem cell maintenance. Immunofluorescence assay revealed that Hvul_YAP expressing cells occur in clusters in the body column and are excluded in the terminally differentiated regions. The YAP expressing cells are recruited early during head regeneration and budding implicating the Hippo pathway in early response to injury or establishment of oral fate. These cells exhibit a non-clustered existence at the site of regeneration and budding, indicating the involvement of a new population of YAP expressing cells during oral fate specification. Collectively, we posit that the Hippo pathway is an important signaling system in Hydra, its components are ubiquitously expressed in the Hydra body column, and may play crucial role in Hydra oral fate specification.

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.

scholarly journals Identification of Components of the Hippo Pathway in Hydra and Potential Role of YAP in Cell Division and Differentiation

2021 ◽  
Vol 12 ◽  
Author(s):  
Manu Unni ◽  
Puli Chandramouli Reddy ◽  
Mrinmoy Pal ◽  
Irit Sagi ◽  
Sanjeev Galande
Keyword(s):  
Target Genes ◽  
Hippo Pathway ◽  
Critical Role ◽  
Immunofluorescence Assay ◽  
The Body ◽  
Hippo Signaling ◽  
Proliferating Cells ◽  
The Hippo Pathway ◽  
Body Column

The Hippo signaling pathway has been shown to be involved in regulating cellular identity, cell/tissue size maintenance and mechanotransduction. The Hippo pathway consists of a kinase cascade which determines the nucleo-cytoplasmic localization of YAP in the cell. YAP is the effector protein in the Hippo pathway, which acts as a transcriptional cofactor for TEAD. Phosphorylation of YAP upon activation of the Hippo pathway prevents it from entering the nucleus and abrogates its function in the transcription of the target genes. In Cnidaria, the information on the regulatory roles of the Hippo pathway is virtually lacking. Here, we report the existence of a complete set of Hippo pathway core components in Hydra for the first time. By studying their phylogeny and domain organization, we report evolutionary conservation of the components of the Hippo pathway. Protein modelling suggested the conservation of YAP-TEAD interaction in Hydra. Further, we characterized the expression pattern of the homologs of yap, hippo, mob and sav in Hydra using whole-mount RNA in situ hybridization and report their possible role in stem cell maintenance. Immunofluorescence assay revealed that Hvul_YAP expressing cells occur in clusters in the body column and are excluded in the terminally differentiated regions. Actively proliferating cells marked by Ki67 exhibit YAP colocalization in their nuclei. Strikingly, a subset of these colocalized cells is actively recruited to the newly developing bud. Disruption of the YAP-TEAD interaction increased the budding rate indicating a critical role of YAP in regulating cell proliferation in Hydra. Collectively, we posit that the Hippo pathway is an essential signaling system in Hydra; its components are ubiquitously expressed in the Hydra body column and play a crucial role in Hydra tissue homeostasis.

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