scholarly journals Yorkie controls tube length and apical barrier integrity during airway development

2019 ◽  
Vol 218 (8) ◽  
pp. 2762-2781 ◽  
Author(s):  
Kassiani Skouloudaki ◽  
Ioannis Christodoulou ◽  
Dilan Khalili ◽  
Vasilios Tsarouhas ◽  
Christos Samakovlis ◽  
...  
Keyword(s):  
Hippo Pathway ◽  
Apical Cell ◽  
Tube Length ◽  
Transcriptional Coactivator ◽  
Apical Cell Membrane ◽  
Aminolevulinate Synthase ◽  
Cell Matrix ◽  
Membrane Growth ◽  
The Hippo Pathway ◽  
Shape Changes

Epithelial organ size and shape depend on cell shape changes, cell–matrix communication, and apical membrane growth. The Drosophila melanogaster embryonic tracheal network is an excellent model to study these processes. Here, we show that the transcriptional coactivator of the Hippo pathway, Yorkie (YAP/TAZ in vertebrates), plays distinct roles in the developing Drosophila airways. Yorkie exerts a cytoplasmic function by binding Drosophila Twinstar, the orthologue of the vertebrate actin-severing protein Cofilin, to regulate F-actin levels and apical cell membrane size, which are required for proper tracheal tube elongation. Second, Yorkie controls water tightness of tracheal tubes by transcriptional regulation of the δ-aminolevulinate synthase gene (Alas). We conclude that Yorkie has a dual role in tracheal development to ensure proper tracheal growth and functionality.

scholarly journals Yorkie controls tube length and apical barrier integrity in the developing Drosophila airways

2019 ◽  
Author(s):  
Dimitrios K. Papadopoulos ◽  
Pavel Tomancak ◽  
Vasilios Tsarouhas ◽  
Christos Samakovlis ◽  
Elisabeth Knust ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
Hippo Pathway ◽  
Apical Cell ◽  
Tube Length ◽  
Apical Cell Membrane ◽  
Aminolevulinate Synthase ◽  
Cell Matrix ◽  
Membrane Growth ◽  
The Hippo Pathway

AbstractEpithelial organ size and shape depend on cell shape changes, cell-matrix communication and apical membrane growth. The Drosophila embryonic tracheal network is an excellent model to study these processes. Here, we show that the transcriptional co-activator of the Hippo pathway, Yorkie (YAP in vertebrates), plays distinct roles in the developing Drosophila airways. Yorkie exerts a cytoplasmic function by binding Drosophila Twinstar, the orthologue of the vertebrate actin-severing protein Cofilin, to regulate F-actin levels and apical cell membrane size, which are required for proper tracheal tube elongation. Second, Yorkie controls water-tightness of tracheal tubes by transcriptional regulation of the enzyme δ-aminolevulinate synthase (Alas). We conclude that Yorkie has a dual role in tracheal development to ensure proper tracheal growth and functionality.Short SummaryThis work identified an alternative role of the transcriptional co-activator Yorkie (Yki) in controlling water impermeability and tube size of the developing Drosophila airways. Tracheal impermeability is triggered by Yki-mediated transcriptional regulation of δ-aminolevulinate synthase, Alas, whereas tube elongation is controlled by binding of Yki to the actin severing factor Twinstar.

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.

scholarly journals Hippo and rassf1a Pathways: A Growing Affair

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Francesca Fausti ◽  
Silvia Di Agostino ◽  
Andrea Sacconi ◽  
Sabrina Strano ◽  
Giovanni Blandino
Keyword(s):  
Developmental Biology ◽  
Tissue Regeneration ◽  
Target Genes ◽  
Hippo Pathway ◽  
Hippo Signaling ◽  
Transcriptional Coactivator ◽  
Pathway Activity ◽  
Kinase Cascade ◽  
The Hippo Pathway ◽  
The Impact

First discovered in Drosophila, the Hippo pathway regulates the size and shape of organ development. Its discovery and study have helped to address longstanding questions in developmental biology. Central to this pathway is a kinase cascade leading from the tumor suppressor Hippo (Mst1 and Mst2 in mammals) to the Yki protein (YAP and TAZ in mammals), a transcriptional coactivator of target genes involved in cell proliferation, survival, and apoptosis. A dysfunction of the Hippo pathway activity is frequently detected in human cancers. Recent studies have highlighted that the Hippo pathway may play an important role in tissue homoeostasis through the regulation of stem cells, cell differentiation, and tissue regeneration. Recently, the impact of RASSF proteins on Hippo signaling potentiating its proapoptotic activity has been addressed, thus, providing further evidence for Hippo's key role in mammalian tumorigenesis as well as other important diseases.

scholarly journals Cyclopeptide RA-V Inhibits Organ Enlargement and Tumorigenesis Induced by YAP Activation

Cancers ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 449 ◽  
Author(s):  
Xinyan Ji ◽  
Lihua Song ◽  
Li Sheng ◽  
Anhui Gao ◽  
Yang Zhao ◽  
...  
Keyword(s):  
Target Genes ◽  
Hippo Pathway ◽  
Specific Inhibitor ◽  
Drug Candidate ◽  
Binding Motif ◽  
Mrna Levels ◽  
Transcriptional Coactivator ◽  
Genetic Inactivation ◽  
Liver Enlargement ◽  
The Hippo Pathway

The Hippo pathway restricts organ size during development and its inactivation plays a crucial role in cancer. Yes-associated protein (YAP) and its paralog transcriptional coactivator with PSD-95/Dlg/ZO-1 (PDZ)-binding motif (TAZ) are transcription co-activators and effectors of the Hippo pathway mediating aberrant enlargement of organs and tumor growth upon Hippo pathway inactivation. It has been demonstrated that genetic inactivation of YAP could be an effective approach to inhibit tumorigenesis. In order to identify pharmacological inhibitors of YAP, we screened a library of 52,683 compounds using a YAP-specific reporter assay. In this screen we identified cyclopeptide RA-V (deoxybouvardin) as a specific inhibitor of YAP and TAZ but not other reporters. Unexpectedly, later experiments demonstrated that RA-V represses the protein but not mRNA levels of YAP target genes. Nevertheless, RA-V strongly blocks liver enlargement induced by Mst1/2 knockout. Furthermore, RA-V not only inhibits liver tumorigenesis induced by YAP activation, but also induces regression of established tumors. We found that RA-V inhibits dedifferentiation and proliferation, while inducing apoptosis of hepatocytes. Furthermore, RA-V also induces apoptosis and inhibits proliferation of macrophages in the microenvironment, which are essential for YAP-induced tumorigenesis. RA-V is thus a drug candidate for cancers involving YAP/TAZ activation.

scholarly journals Angiomotins link F-actin architecture to Hippo pathway signaling

2014 ◽  
Vol 25 (10) ◽  
pp. 1676-1685 ◽  
Author(s):  
Sebastian Mana-Capelli ◽  
Murugan Paramasivam ◽  
Shubham Dutta ◽  
Dannel McCollum
Keyword(s):  
Actin Cytoskeleton ◽  
Hippo Pathway ◽  
Control Cell ◽  
Substrate Stiffness ◽  
Actin Binding ◽  
Transcriptional Coactivator ◽  
Stem Cell Maintenance ◽  
Actin Binding Domain ◽  
The Hippo Pathway ◽  
G Protein Coupled

The Hippo pathway regulates the transcriptional coactivator YAP to control cell proliferation, organ size, and stem cell maintenance. Multiple factors, such as substrate stiffness, cell density, and G protein–coupled receptor signaling, regulate YAP through their effects on the F-actin cytoskeleton, although the mechanism is not known. Here we show that angiomotin proteins (AMOT130, AMOTL1, and AMOTL2) connect F-actin architecture to YAP regulation. First, we show that angiomotins are required to relocalize YAP to the cytoplasm in response to various manipulations that perturb the actin cytoskeleton. Second, angiomotins associate with F-actin through a conserved F-actin–binding domain, and mutants defective for F-actin binding show enhanced ability to retain YAP in the cytoplasm. Third, F-actin and YAP compete for binding to AMOT130, explaining how F-actin inhibits AMOT130-mediated cytoplasmic retention of YAP. Furthermore, we find that LATS can synergize with F-actin perturbations by phosphorylating free AMOT130 to keep it from associating with F-actin. Together these results uncover a mechanism for how F-actin levels modulate YAP localization, allowing cells to make developmental and proliferative decisions based on diverse inputs that regulate actin architecture.

GPR39 Overexpression in OSCC Promotes YAP-Sustained Malignant Progression

2020 ◽  
Vol 99 (8) ◽  
pp. 949-958
Author(s):  
Y. Jiang ◽  
T. Li ◽  
Y. Wu ◽  
H. Xu ◽  
C. Xie ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Hippo Pathway ◽  
Activity Level ◽  
Malignant Progression ◽  
Transcriptional Coactivator ◽  
Poor Survival ◽  
The Hippo Pathway ◽  
G Protein Coupled ◽  
Dependent Signaling Pathway ◽  
Upstream Regulators

The clinical outcome of oral squamous cell carcinoma (OSCC) has not improved in recent years, mainly due to the limited effective targeted therapy that has been applied. Recently, a transcriptional coactivator, YAP, has been shown to have a key regulatory role in malignant progression in multiple cancers, including OSCC. But pharmacologically targeting YAP or the Hippo pathway, which is the main signaling pathway regulating YAP, has been proven to be challenging. Therefore, uncovering YAP upstream regulators in cancer would identify novel therapeutic targets for treatment of YAP-sustained cancers. Here, we showed that YAP was overactivated in OSCC and that high YAP activity in patients with OSCC was associated with malignant progression and poor survival. We uncovered that GPR39 (a G protein–coupled receptor) was overexpressed in OSCC, that the expression level of GPR39 was correlated with the activity level of YAP, and that the high GPR39 expression was associated with malignant progression and poor survival in patients with OSCC. Moreover, we found that GPR39 regulated YAP through a Gαq/11-RhoA–dependent signaling pathway. Importantly, inhibition of GPR39 resulted in YAP-sustained OSCC growth inhibition. Our findings suggest that GPR39 is a potential therapeutic target for OSCC treatment with itself as a biomarker.

scholarly journals Angiomotin family proteins are novel activators of the LATS2 kinase tumor suppressor

2011 ◽  
Vol 22 (19) ◽  
pp. 3725-3733 ◽  
Author(s):  
Murugan Paramasivam ◽  
Ali Sarkeshik ◽  
John R. Yates ◽  
Maria J. G. Fernandes ◽  
Dannel McCollum
Keyword(s):  
Tight Junction ◽  
Tight Junctions ◽  
Cell Density ◽  
Hippo Pathway ◽  
The Other ◽  
Transcriptional Coactivator ◽  
Inhibition Of Growth ◽  
Conserved Domain ◽  
Junction Protein ◽  
The Hippo Pathway

LATS2 kinase functions as part of the Hippo pathway to promote contact inhibition of growth and tumor suppression by phosphorylating and inhibiting the transcriptional coactivator YAP. LATS2 is activated by the MST2 kinase. How LATS2 is activated by MST2 in response to changes in cell density is unknown. Here we identify the angiomotin-family tight junction protein AMOTL2 as a novel activator of LATS2. Like AMOTL2, the other angiomotin-family proteins AMOT and AMOTL1 also activate LATS2 through a novel conserved domain that binds and activates LATS2. AMOTL2 binds MST2, LATS2, and YAP, suggesting that AMOTL2 might serve as a scaffold protein. We show that LATS2, AMOTL2, and YAP all localize to tight junctions, raising the possibility that clustering of Hippo pathway components at tight junctions might function to trigger LATS2 activation and growth inhibition in response to increased cell density.

Increased YAP1 expression is significantly associated with breast cancer progression, metastasis and poor survival

2021 ◽  
Author(s):  
Javeria Qadir ◽  
Syeda Kiran Riaz ◽  
Kiran Taj ◽  
Natasha Sattar ◽  
Namood-e Sahar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Cancer Progression ◽  
Hippo Pathway ◽  
Transcriptional Coactivator ◽  
Breast Cancer Patients ◽  
Poor Survival ◽  
Protein Levels ◽  
The Hippo Pathway

YAP1 plays a key role as a transcriptional coactivator in the Hippo pathway. Based on conflicting reports regarding YAP1 function in cancer, this study discerned its role in breast carcinogenesis. First, a systematic review of salient breast cancer studies targeting YAP1 dysregulation was performed. Additionally, freshly excised tumor specimens of approximately 200 breast cancer patients were processed for quantification of YAP1 expression at mRNA and protein levels using quantitative PCR and immunohistochemistry, respectively. YAP1 expression was nine folds higher in tumors versus controls and significantly associated with metastasis (p < 0.05) and poor survival in Pakistani breast cancer patients. These findings establish the role of YAP1 overexpression in tumorigenesis and metastasis. Hence, YAP1 inhibition may be considered a possible therapeutic strategy.

scholarly journals Hippo Pathway: An Emerging Regulator of Craniofacial and Dental Development

2017 ◽  
Vol 96 (11) ◽  
pp. 1229-1237 ◽  
Author(s):  
J. Wang ◽  
J.F. Martin
Keyword(s):  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Tooth Development ◽  
Hippo Pathway ◽  
Binding Motif ◽  
Hippo Signaling ◽  
Transcriptional Coactivator ◽  
Hippo Signaling Pathway ◽  
Evolutionarily Conserved ◽  
The Hippo Pathway

The evolutionarily conserved Hippo signaling pathway is a vital regulator of organ size that fine-tunes cell proliferation, apoptosis, and differentiation. A number of important studies have revealed critical roles of Hippo signaling and its effectors Yap (Yes-associated protein) and Taz (transcriptional coactivator with PDZ binding motif) in tissue development, homeostasis, and regeneration, as well as in tumorigenesis. In addition, recent studies have shown evidence of crosstalk between the Hippo pathway and other key signaling pathways, such as Wnt signaling, that not only regulates developmental processes but also contributes to disease pathogenesis. In this review, we summarize the major discoveries in the field of Hippo signaling and what has been learned about its regulation and crosstalk with other signaling pathways, with a particular focus on recent findings involving the Hippo-Yap pathway in craniofacial and tooth development. New and exciting studies of the Hippo pathway are anticipated that will significantly improve our understanding of the molecular mechanisms of human craniofacial and tooth development and disease and will ultimately lead to the development of new therapies.

scholarly journals Angiomotins stimulate LATS kinase autophosphorylation and act as scaffolds that promote Hippo signaling

2018 ◽  
Vol 293 (47) ◽  
pp. 18230-18241 ◽  
Author(s):  
Sebastian Mana-Capelli ◽  
Dannel McCollum
Keyword(s):  
Kinase Activity ◽  
Hippo Pathway ◽  
Kinase Domain ◽  
Activation Loop ◽  
Hippo Signaling ◽  
Transcriptional Coactivator ◽  
Mechanical Environment ◽  
Unknown Mechanism ◽  
The Hippo Pathway ◽  
Kinase A

The Hippo pathway controls cell proliferation, differentiation, and survival by regulating the Yes-associated protein (YAP) transcriptional coactivator in response to various stimuli, including the mechanical environment. The major YAP regulators are the LATS1/2 kinases, which phosphorylate and inhibit YAP. LATS1/2 are activated by phosphorylation on a hydrophobic motif (HM) outside of the kinase domain by MST1/2 and other kinases. Phosphorylation of the HM motif then triggers autophosphorylation of the kinase in the activation loop to fully activate the kinase, a process facilitated by MOB1. The angiomotin family of proteins (AMOT, AMOTL1, and AMOTL2) bind LATS1/2 and promote its kinase activity and YAP phosphorylation through an unknown mechanism. Here we show that angiomotins increase Hippo signaling through multiple mechanisms. We found that, by binding LATS1/2, SAV1, and YAP, angiomotins function as a scaffold that connects LATS1/2 to both its activator SAV1–MST1 and its target YAP. Deletion of all three angiomotins reduced the association of LATS1 with SAV1–MST1 and decreased MST1/2-mediated LATS1/2-HM phosphorylation. Angiomotin deletion also reduced LATS1/2's ability to associate with and phosphorylate YAP. In addition, we found that angiomotins have an unexpected function along with MOB1 to promote autophosphorylation of LATS1/2 on the activation loop motif independent of HM phosphorylation. These results indicate that angiomotins enhance Hippo signaling by stimulating LATS1/2 autophosphorylation and by connecting LATS1/2 with both its activator SAV1–MST1/2 and its substrate YAP.

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