YAP independently regulates cell size and population growth dynamics via non-cell autonomous mediators

2018 ◽  
Author(s):  
Douaa Mugahid ◽  
Marian Kalocsay ◽  
Scott Gruver ◽  
Leonid Peshkin ◽  
Marc W. Kirschner
Keyword(s):  
Cell Size ◽  
Mammalian Cells ◽  
Hippo Pathway ◽  
Growth Dynamics ◽  
Cell Number ◽  
Tissue Growth ◽  
Environment Control ◽  
Important Pathway ◽  
The Hippo Pathway

SummaryThe Hippo pathway, in which changes at the cell surface and in the extracellular environment control the activity of a downstream transcription factor, known as YAP in mammalian cells and Yorkie in Drosophila, has recently taken center-stage as perhaps the most important pathway in metazoans for controlling organ size. In intact tissues YAP activity is inhibited and the organ does not overgrow. When the organ is damaged, YAP is active and necessary for growth and regeneration to occur. The exact process by which YAP drives organ and tissue growth is not fully understood, although it is known to affect both cell size and cell number. Since cell size and proliferation are highly interdependent in many cultured cell studies, we investigated the role of YAP in the simultaneous regulation of both cell size and number. Our experiments reveal that YAP controls both cell size and cell proliferation by independent circuits, and that it affects each process non-cell autonomously via extracellular mediators. We identify that CYR61, a known secreted YAP target, is the major regulator of the non-cell autonomous increase in cell number, but does not affect cell size. The molecular identity of the non-cell autonomously acting mediator of cell size is yet to be identified.

scholarly journals YAP regulates cell size and growth dynamics via non-cell autonomous mediators

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Douaa Mugahid ◽  
Marian Kalocsay ◽  
Xili Liu ◽  
Jonathan Scott Gruver ◽  
Leonid Peshkin ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Size ◽  
Cultured Cells ◽  
Hippo Pathway ◽  
Growth Dynamics ◽  
Cell Number ◽  
Hek293 Cells ◽  
Tissue Size ◽  
The Stability ◽  
The Hippo Pathway

The Hippo pathway regulates organ size, regeneration, and cell growth by controlling the stability of the transcription factor, YAP (Yorkie in Drosophila). When there is tissue damage, YAP is activated allowing the restoration of homeostatic tissue size. The exact signals by which YAP is activated are still not fully understood, but its activation is known to affect both cell size and cell number. Here we used cultured cells to examine the coordinated regulation of cell size and number under the control of YAP. Our experiments in isogenic HEK293 cells reveal that YAP can affect cell size and number by independent circuits. Some of these effects are cell autonomous, such as proliferation, while others are mediated by secreted signals. In particular CYR61, a known secreted YAP target, is a non-cell autonomous mediator of cell survival, while another unidentified secreted factor controls cell size.

scholarly journals Impaired Hippo signaling promotes Rho1–JNK-dependent growth

2015 ◽  
Vol 112 (4) ◽  
pp. 1065-1070 ◽  
Author(s):  
Xianjue Ma ◽  
Yujun Chen ◽  
Wenyan Xu ◽  
Nana Wu ◽  
Maoquan Li ◽  
...  
Keyword(s):  
Rho Gtpases ◽  
Hippo Pathway ◽  
Tissue Growth ◽  
Hippo Signaling ◽  
Jnk Pathway ◽  
Jnk Signaling ◽  
Dependent Growth ◽  
Jnk Activation ◽  
The Hippo Pathway

The Hippo and c-Jun N-terminal kinase (JNK) pathway both regulate growth and contribute to tumorigenesis when dysregulated. Whereas the Hippo pathway acts via the transcription coactivator Yki/YAP to regulate target gene expression, JNK signaling, triggered by various modulators including Rho GTPases, activates the transcription factors Jun and Fos. Here, we show that impaired Hippo signaling induces JNK activation through Rho1. Blocking Rho1–JNK signaling suppresses Yki-induced overgrowth in the wing disk, whereas ectopic Rho1 expression promotes tissue growth when apoptosis is prohibited. Furthermore, Yki directly regulates Rho1 transcription via the transcription factor Sd. Thus, our results have identified a novel molecular link between the Hippo and JNK pathways and implicated the essential role of the JNK pathway in Hippo signaling-related tumorigenesis.

Growth of tissues and organs

2021 ◽  
pp. 921-940
Keyword(s):  
Disease Progression ◽  
Cell Size ◽  
Gene Function ◽  
Molecular Mechanisms ◽  
Cell Number ◽  
Tissue Growth ◽  
Adenomatous Polyposis ◽  
Environmental Carcinogens ◽  
Mechanisms Of Formation

‘Growth of tissues and organs’ is an overview of the general principles of tissue growth due to changes in cell size (normal and pathological atrophy, hypertrophy including pathological conditions) or cell number (hyperplasia). Neoplasia, the formation of neoplasms (i.e. cancerous tumours), is considered, including naming conventions for neoplasms, their morphology, and molecular mechanisms of formation and growth, including gains in gene function (proto-oncogenes, such as p53 and adenomatous polyposis coli) and environmental carcinogens, and the role of metastasis in disease progression. Finally, their treatment by chemotherapy and radiobiology is discussed.

scholarly journals The palmitoyltransferase Approximated promotes growth via the Hippo pathway by palmitoylation of Fat

2016 ◽  
Vol 216 (1) ◽  
pp. 265-277 ◽  
Author(s):  
Hitoshi Matakatsu ◽  
Seth S. Blair ◽  
Richard G. Fehon
Keyword(s):  
Posttranslational Modification ◽  
Hippo Pathway ◽  
Growth Control ◽  
Tissue Growth ◽  
Negative Regulator ◽  
Pathway Activity ◽  
Protein Association ◽  
Junctional Region ◽  
Growth Loss ◽  
The Hippo Pathway

The large protocadherin Fat functions to promote Hippo pathway activity in restricting tissue growth. Loss of Fat leads to accumulation of the atypical myosin Dachs at the apical junctional region, which in turn promotes growth by inhibiting Warts. We previously identified Approximated (App), a DHHC domain palmitoyltransferase, as a negative regulator of Fat signaling in growth control. We show here that App promotes growth by palmitoylating the intracellular domain of Fat, and that palmitoylation negatively regulates Fat function. Independently, App also recruits Dachs to the apical junctional region through protein–protein association, thereby stimulating Dachs’s activity in promoting growth. Further, we show that palmitoylation by App functions antagonistically to phosphorylation by Discs-overgrown, which activates Fat. Together, these findings suggest a model in which App promotes Dachs activity by simultaneously repressing Fat via posttranslational modification and recruiting Dachs to the apical junctional region, thereby promoting tissue growth.

P04.20 The role of YAP in Glioblastoma cell lines

2021 ◽  
Vol 23 (Supplement_2) ◽  
pp. ii22-ii23
Author(s):  
G Casati ◽  
L Giunti ◽  
A Iorio ◽  
A Marturano ◽  
I Sardi
Keyword(s):  
Cell Viability ◽  
Cell Lines ◽  
Western Blotting ◽  
Cytotoxic Effect ◽  
Target Genes ◽  
Hippo Pathway ◽  
Combined Treatment ◽  
Set Up ◽  
The Hippo Pathway

Abstract BACKGROUND Glioblastoma (GBM) is a primary human malignant brain tumor, the most common in adults. Several studies have highlighted the Hippo-pathway as a cancer signalling network. The Hippo pathway is an evolutionarily conserved signal cascade, which is involved in the control of organ growth. Dysregulations among this pathway have been found in lung, ovarian, liver and colorectal cancer. The key downstream effector of the Hippo-pathway is the Yes-associated protein (YAP); in the nucleus, its function as transcription co-activator is to interact with transcription factors, resulting in the expression of target genes involved in pro-proliferating and anti-apoptotic programs. MATERIAL AND METHODS Using western blotting analysis, we determined the nuclear expression of YAP on three GBM cell lines (U87MG, T98G and A172). To investigate which inhibitors against the Hippo-pathway were the most efficient, we performed a cytotoxic assay: we treated all the three cell lines with different inhibitors such as Verteporfin (VP), Cytochalasin D (CIT), Latrunculin A (LAT), Dobutamine (DOB) and Y27632. Afterwards, we performed a treatment using Doxorubicin (DOX) combined with the inhibitors, evaluating its cytotoxic effect on our cell lines, through cell viability experiments. More western blotting experiments were performed to investigate the oncogenic role of YAP at nucleus level. Furthermore, preliminary experiments have been conducted in order to investigate the apoptosis, senescence and autophagy modulation due to the Hippo-pathway. RESULTS We showed our cell lines express nuclear YAP. We assessed the efficiency of the main inhibitors against Hippo-pathway, proving that VP, LAT A and CIT show a strong cytostatic effect, linked to time increase; plus we saw a cytotoxic effect on T98G. The association of DOX with selected inhibitors is able to reduce cell viability and nuclear YAP expression rate in all three GBM lines. Finally, preliminary experiments were set up to assess how and if the mechanisms of apoptosis, autophagy and senescence were affected by the Hippo-pathway. The combination of DOX with inhibitors promotes resistance to apoptosis. CONCLUSION Our results show that nuclear YAP is present in all tumor lines, thus confirming that this molecular pathway is functioning in GBM lines. Nuclear YAP is more highly expressed after DOX administration. Moreover, the combined treatment (DOX with Hippo-pathway inhibitors) reduces both cell proliferation and viability, and increases the rate of apoptosis. Preliminary experiments on senescence and autophagy were used to determine the best Hippo-pathway inhibitor. These data demonstrate that the Hippo-pathway plays a crucial role in GBM proliferation and resistance to apoptosis. Inhibiting this pathway and in particular the transcription factor YAP, in association with DOX, might be an excellent therapeutic target.

scholarly journals Want to promote tissue growth? There’s an App for that!

2016 ◽  
Vol 216 (1) ◽  
pp. 1-1 ◽  
Author(s):  
Ben Short
Keyword(s):  
Hippo Pathway ◽  
Tissue Growth ◽  
The Hippo Pathway

Study describes how a palmitoyltransferase regulates the Hippo pathway in flies.

scholarly journals The Hippo Pathway: Immunity and Cancer

Cancers ◽  
2018 ◽  
Vol 10 (4) ◽  
pp. 94 ◽  
Author(s):  
Zaid Taha ◽  
Helena Janse van Rensburg ◽  
Xiaolong Yang
Keyword(s):  
Immune Response ◽  
Immune Cells ◽  
Mammalian Cells ◽  
Immune Cell ◽  
Hippo Pathway ◽  
Tissue Homeostasis ◽  
Hippo Signaling ◽  
Core Components ◽  
The Hippo Pathway ◽  
Future Work

Since its discovery, the Hippo pathway has emerged as a central signaling network in mammalian cells. Canonical signaling through the Hippo pathway core components (MST1/2, LATS1/2, YAP and TAZ) is important for development and tissue homeostasis while aberrant signaling through the Hippo pathway has been implicated in multiple pathologies, including cancer. Recent studies have uncovered new roles for the Hippo pathway in immunology. In this review, we summarize the mechanisms by which Hippo signaling in pathogen-infected or neoplastic cells affects the activities of immune cells that respond to these threats. We further discuss how Hippo signaling functions as part of an immune response. Finally, we review how immune cell-intrinsic Hippo signaling modulates the development/function of leukocytes and propose directions for future work.

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

scholarly journals Novel linear motif filtering protocol reveals the role of the LC8 dynein light chain in the Hippo pathway

2017 ◽  
Vol 13 (12) ◽  
pp. e1005885 ◽  
Author(s):  
Gábor Erdős ◽  
Tamás Szaniszló ◽  
Mátyás Pajkos ◽  
Borbála Hajdu-Soltész ◽  
Bence Kiss ◽  
...  
Keyword(s):  
Light Chain ◽  
Hippo Pathway ◽  
Dynein Light Chain ◽  
Linear Motif ◽  
The Hippo Pathway

scholarly journals Differential regulation of the Hippo pathway by adherens junctions and apical–basal cell polarity modules

2015 ◽  
Vol 112 (6) ◽  
pp. 1785-1790 ◽  
Author(s):  
Chih-Chao Yang ◽  
Hillary K. Graves ◽  
Ivan M. Moya ◽  
Chunyao Tao ◽  
Fisun Hamaratoglu ◽  
...  
Keyword(s):  
Cell Polarity ◽  
Basal Cell ◽  
Mammalian Cells ◽  
Adherens Junctions ◽  
Hippo Pathway ◽  
Tumor Formation ◽  
Nuclear Accumulation ◽  
Binding Motif ◽  
Downstream Effectors ◽  
The Hippo Pathway

Adherens junctions (AJs) and cell polarity complexes are key players in the establishment and maintenance of apical–basal cell polarity. Loss of AJs or basolateral polarity components promotes tumor formation and metastasis. Recent studies in vertebrate models show that loss of AJs or loss of the basolateral component Scribble (Scrib) cause deregulation of the Hippo tumor suppressor pathway and hyperactivation of its downstream effectors Yes-associated protein (YAP) and Transcriptional coactivator with PDZ-binding motif (TAZ). However, whether AJs and Scrib act through the same or independent mechanisms to regulate Hippo pathway activity is not known. Here, we dissect how disruption of AJs or loss of basolateral components affect the activity of the Drosophila YAP homolog Yorkie (Yki) during imaginal disc development. Surprisingly, disruption of AJs and loss of basolateral proteins produced very different effects on Yki activity. Yki activity was cell-autonomously decreased but non–cell-autonomously elevated in tissues where the AJ components E-cadherin (E-cad) or α-catenin (α-cat) were knocked down. In contrast, scrib knockdown caused a predominantly cell-autonomous activation of Yki. Moreover, disruption of AJs or basolateral proteins had different effects on cell polarity and tissue size. Simultaneous knockdown of α-cat and scrib induced both cell-autonomous and non–cell-autonomous Yki activity. In mammalian cells, knockdown of E-cad or α-cat caused nuclear accumulation and activation of YAP without overt effects on Scrib localization and vice versa. Therefore, our results indicate the existence of multiple, genetically separable inputs from AJs and cell polarity complexes into Yki/YAP regulation.

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