scholarly journals The Hippo signaling pathway in leukemia: function, interaction, and carcinogenesis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Negar Noorbakhsh ◽  
Bentolhoda Hayatmoghadam ◽  
Marzieh Jamali ◽  
Maryam Golmohammadi ◽  
Maria Kavianpour
Keyword(s):  
Signaling Pathways ◽  
Hippo Pathway ◽  
Treatment Resistance ◽  
Signaling Networks ◽  
Hippo Signaling ◽  
Complete Understanding ◽  
A Cell ◽  
The Hippo Pathway ◽  
Map Kinase Pathways ◽  
Shed Light

AbstractCancer can be considered as a communication disease between and within cells; nevertheless, there is no effective therapy for the condition, and this disease is typically identified at its late stage. Chemotherapy, radiation, and molecular-targeted treatment are typically ineffective against cancer cells. A better grasp of the processes of carcinogenesis, aggressiveness, metastasis, treatment resistance, detection of the illness at an earlier stage, and obtaining a better therapeutic response will be made possible. Researchers have discovered that cancerous mutations mainly affect signaling pathways. The Hippo pathway, as one of the main signaling pathways of a cell, has a unique ability to cause cancer. In order to treat cancer, a complete understanding of the Hippo signaling system will be required. On the other hand, interaction with other pathways like Wnt, TGF-β, AMPK, Notch, JNK, mTOR, and Ras/MAP kinase pathways can contribute to carcinogenesis. Phosphorylation of oncogene YAP and TAZ could lead to leukemogenesis, which this process could be regulated via other signaling pathways. This review article aimed to shed light on how the Hippo pathway interacts with other cellular signaling networks and its functions in leukemia.

scholarly journals Hippo Signaling Pathway as a Central Mediator of Receptors Tyrosine Kinases (RTKs) in Tumorigenesis

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2042
Author(s):  
Taha Azad ◽  
Reza Rezaei ◽  
Abera Surendran ◽  
Ragunath Singaravelu ◽  
Stephen Boulton ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Tyrosine Kinases ◽  
Hippo Pathway ◽  
Critical Role ◽  
Hippo Signaling ◽  
Malignant Growth ◽  
Rtk Signaling ◽  
Signaling Mechanisms ◽  
Complex Signaling ◽  
The Hippo Pathway

The Hippo pathway plays a critical role in tissue and organ growth under normal physiological conditions, and its dysregulation in malignant growth has made it an attractive target for therapeutic intervention in the fight against cancer. To date, its complex signaling mechanisms have made it difficult to identify strong therapeutic candidates. Hippo signaling is largely carried out by two main activated signaling pathways involving receptor tyrosine kinases (RTKs)—the RTK/RAS/PI3K and the RTK-RAS-MAPK pathways. However, several RTKs have also been shown to regulate this pathway to engage downstream Hippo effectors and ultimately influence cell proliferation. In this text, we attempt to review the diverse RTK signaling pathways that influence Hippo signaling in the context of oncogenesis.

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 YAP and endothelin-1 signaling: an emerging alliance in cancer

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Piera Tocci ◽  
Giovanni Blandino ◽  
Anna Bagnato
Keyword(s):  
Signaling Pathways ◽  
Cell Fate ◽  
Therapeutic Option ◽  
Hippo Pathway ◽  
Signaling Network ◽  
Nuclear Accumulation ◽  
Binding Motif ◽  
Mutant P53 ◽  
Endothelin 1 ◽  
The Hippo Pathway

AbstractThe rational making the G protein-coupled receptors (GPCR) the centerpiece of targeted therapies is fueled by the awareness that GPCR-initiated signaling acts as pivotal driver of the early stages of progression in a broad landscape of human malignancies. The endothelin-1 (ET-1) receptors (ET-1R), known as ETA receptor (ETAR) and ETB receptor (ETBR) that belong to the GPCR superfamily, affect both cancer initiation and progression in a variety of cancer types. By the cross-talking with multiple signaling pathways mainly through the scaffold protein β-arrestin1 (β-arr1), ET-1R axis cooperates with an array of molecular determinants, including transcription factors and co-factors, strongly affecting tumor cell fate and behavior. In this scenario, recent findings shed light on the interplay between ET-1 and the Hippo pathway. In ETAR highly expressing tumors ET-1 axis induces the de-phosphorylation and nuclear accumulation of the Hippo pathway downstream effectors, the paralogous transcriptional cofactors Yes-associated protein (YAP) and Transcriptional coactivator with PDZ-binding motif (TAZ). Recent evidence have discovered that ET-1R/β-arr1 axis instigates a transcriptional interplay involving YAP and mutant p53 proteins, which share a common gene signature and cooperate in a oncogenic signaling network. Mechanistically, YAP and mutp53 are enrolled in nuclear complexes that turn on a highly selective YAP/mutp53-dependent transcriptional response. Notably, ET-1R blockade by the FDA approved dual ET-1 receptor antagonist macitentan interferes with ET-1R/YAP/mutp53 signaling interplay, through the simultaneous suppression of YAP and mutp53 functions, hampering metastasis and therapy resistance. Based on these evidences, we aim to review the recent findings linking the GPCR signaling, as for ET-1R, to YAP/TAZ signaling, underlining the clinical relevance of the blockade of such signaling network in the tumor and microenvironmental contexts. In particular, we debate the clinical implications regarding the use of dual ET-1R antagonists to blunt gain of function activity of mutant p53 proteins and thereby considering them as a potential therapeutic option for mutant p53 cancers. The identification of ET-1R/β-arr1-intertwined and bi-directional signaling pathways as targetable vulnerabilities, may open new therapeutic approaches able to disable the ET-1R-orchestrated YAP/mutp53 signaling network in both tumor and stromal cells and concurrently sensitizes to high-efficacy combined therapeutics.

scholarly journals Increasing kinase domain proximity promotes MST2 autophosphorylation during Hippo signaling

2020 ◽  
Vol 295 (47) ◽  
pp. 16166-16179
Author(s):  
Thao Tran ◽  
Jaba Mitra ◽  
Taekjip Ha ◽  
Jennifer M. Kavran
Keyword(s):  
Single Molecule ◽  
Hippo Pathway ◽  
Signal Propagation ◽  
Kinase Domain ◽  
Specific Protein ◽  
Hippo Signaling ◽  
Membrane Recruitment ◽  
Chemically Induced Dimerization ◽  
The Hippo Pathway

The Hippo pathway plays an important role in developmental biology, mediating organ size by controlling cell proliferation through the activity of a core kinase cassette. Multiple upstream events activate the pathway, but how each controls this core kinase cassette is not fully understood. Activation of the core kinase cassette begins with phosphorylation of the kinase MST1/2 (also known as STK3/4). Here, using a combination of in vitro biochemistry and cell-based assays, including chemically induced dimerization and single-molecule pulldown, we revealed that increasing the proximity of adjacent kinase domains, rather than formation of a specific protein assembly, is sufficient to trigger autophosphorylation. We validate this mechanism in cells and demonstrate that multiple events associated with the active pathway, including SARAH domain–mediated homodimerization, membrane recruitment, and complex formation with the effector protein SAV1, each increase the kinase domain proximity and autophosphorylation of MST2. Together, our results reveal that multiple and distinct upstream signals each utilize the same common molecular mechanism to stimulate MST2 autophosphorylation. This mechanism is likely conserved among MST2 homologs. Our work also highlights potential differences in Hippo signal propagation between each activating event owing to differences in the dynamics and regulation of each protein ensemble that triggers MST2 autophosphorylation and possible redundancy in activation.

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 The Hippo Pathway: A Master Regulatory Network Important in Cancer

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1416
Author(s):  
Qiuping Liu ◽  
Xiaomeng Liu ◽  
Guanbin Song
Keyword(s):  
Metabolic Regulation ◽  
Human Cancer ◽  
Hippo Pathway ◽  
Tumor Development ◽  
Biological Significance ◽  
Cancer Development ◽  
Hippo Signaling ◽  
Complex Regulation ◽  
And Function ◽  
The Hippo Pathway

The Hippo pathway is pervasively activated and has been well recognized to play critical roles in human cancer. The deregulation of Hippo signaling involved in cancer development, progression, and resistance to cancer treatment have been confirmed in several human cancers. Its biological significance and deregulation in cancer have drawn increasing interest in the past few years. A fundamental understanding of the complexity of the Hippo pathway in cancer is crucial for improving future clinical interventions and therapy for cancers. In this review, we try to clarify the complex regulation and function of the Hippo signaling network in cancer development, including its role in signal transduction, metabolic regulation, and tumor development, as well as tumor therapies targeting the Hippo pathway.

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.

scholarly journals TEADs, Yap, Taz, Vgll4s transcription factors control the establishment of Left-Right asymmetry in zebrafish

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Jonathan Fillatre ◽  
Jean-Daniel Fauny ◽  
Jasmine Alexandra Fels ◽  
Cheng Li ◽  
Mary Goll ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Signaling Pathways ◽  
Transcriptional Control ◽  
Hippo Pathway ◽  
Hippo Signaling ◽  
Zebrafish Model ◽  
Transcription Cofactor ◽  
Expression Of Genes ◽  
Epigenetic Programming ◽  
Left Right Asymmetry

In many vertebrates, establishment of Left-Right (LR) asymmetry results from the activity of a ciliated organ functioning as the LR Organizer (LRO). While regulation of the formation of this structure by major signaling pathways has been described, the transcriptional control of LRO formation is poorly understood. Using the zebrafish model, we show that the transcription factors and cofactors mediating or regulating the transcriptional outcome of the Hippo signaling pathway play a pivotal role in controlling the expression of genes essential to the formation of the LRO including ligands and receptors of signaling pathways involved in this process and most genes required for motile ciliogenesis. Moreover, the transcription cofactor, Vgll4l regulates epigenetic programming in LRO progenitors by controlling the expression of writers and readers of DNA methylation marks. Altogether, our study uncovers a novel and essential role for the transcriptional effectors and regulators of the Hippo pathway in establishing LR asymmetry.

Drosophila Hcf regulates the Hippo signaling pathway via association with the histone H3K4 methyltransferase Trr

2019 ◽  
Vol 476 (4) ◽  
pp. 759-768 ◽  
Author(s):  
Zi Nan ◽  
Weiwei Yang ◽  
Jialan Lyu ◽  
Fang Wang ◽  
Qiannan Deng ◽  
...  
Keyword(s):  
Host Cell ◽  
Signaling Pathway ◽  
Hippo Pathway ◽  
Organ Size ◽  
Fundamental Aspect ◽  
Hippo Signaling ◽  
Hippo Signaling Pathway ◽  
Host Cell Factor ◽  
Histone H3k4 ◽  
The Hippo Pathway

Abstract Control of organ size is a fundamental aspect in biology and plays important roles in development. The Hippo pathway is a conserved signaling cascade that controls tissue and organ size through the regulation of cell proliferation and apoptosis. Here, we report on the roles of Hcf (host cell factor), the Drosophila homolog of Host cell factor 1, in regulating the Hippo signaling pathway. Loss-of-Hcf function causes tissue undergrowth and the down-regulation of Hippo target gene expression. Genetic analysis reveals that Hcf is required for Hippo pathway-mediated overgrowth. Mechanistically, we show that Hcf associates with the histone H3 lysine-4 methyltransferase Trithorax-related (Trr) to maintain H3K4 mono- and trimethylation. Thus, we conclude that Hcf positively regulates Hippo pathway activity through forming a complex with Trr and controlling H3K4 methylation.

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.

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