scholarly journals Apoptosis in Type 2 Diabetes: Can It Be Prevented? Hippo Pathway Prospects

2022 ◽  
Vol 23 (2) ◽  
pp. 636
Author(s):  
Agnieszka Kilanowska ◽  
Agnieszka Ziółkowska
Keyword(s):  
Hippo Pathway ◽  
Basic Research ◽  
Hippo Signaling ◽  
Β Cells ◽  
Slowing Down ◽  
Core Proteins ◽  
Wide Range ◽  
Potential Strategy ◽  
Apoptotic Pathways ◽  
The Hippo Pathway

Diabetes mellitus is a heterogeneous disease of complex etiology and pathogenesis. Hyperglycemia leads to many serious complications, but also directly initiates the process of β cell apoptosis. A potential strategy for the preservation of pancreatic β cells in diabetes may be to inhibit the implementation of pro-apoptotic pathways or to enhance the action of pancreatic protective factors. The Hippo signaling pathway is proposed and selected as a target to manipulate the activity of its core proteins in therapy-basic research. MST1 and LATS2, as major upstream signaling kinases of the Hippo pathway, are considered as target candidates for pharmacologically induced tissue regeneration and inhibition of apoptosis. Manipulating the activity of components of the Hippo pathway offers a wide range of possibilities, and thus is a potential tool in the treatment of diabetes and the regeneration of β cells. Therefore, it is important to fully understand the processes involved in apoptosis in diabetic states and completely characterize the role of this pathway in diabetes. Therapy consisting of slowing down or stopping the mechanisms of apoptosis may be an important direction of diabetes treatment in the future.

scholarly journals Apoptosis in Type 2 Diabetes, Can It be Prevented?

2021 ◽  
Author(s):  
Agnieszka Kilanowska ◽  
Agnieszka Ziółkowska
Keyword(s):  
Beta Cells ◽  
Hippo Pathway ◽  
Basic Research ◽  
Beta Cell Apoptosis ◽  
Hippo Signaling ◽  
Core Proteins ◽  
Wide Range ◽  
Potential Strategy ◽  
Apoptotic Pathways ◽  
The Hippo Pathway

Diabetes mellitus is a heterogeneous disease of complex etiology and pathogenesis. Hyperglycemia leads to many serious complications, but also directly initiates the process of β cell apoptosis. A potential strategy for the preservation of pancreatic β cells in diabetes may be to inhibit the implementation of pro-apoptotic pathways or to enhance the action of pancreatic protective factors. The HIPPO signaling pathway is proposed and selected as a target to manipulate the activity of its core proteins in therapy - basic research. MST1 and LATS2 as major upstream signaling kinases of the Hippo pathway are considered as target candidates for pharmacologically induced tissue regeneration and inhibition of apoptosis. Manipulating the activity of components of the HiPPO pathway offers a wide range of possibilities, and thus is a potential tool in the treatment of diabetes and the regeneration of β cells. Therefore, it is important to fully understand the processes involved in apoptosis in diabetic states and to fully characterize the role of this pathway in diabetes. Therapy consisting in slowing down or stopping the mechanisms of apoptosis may be an important direction of diabetes treatment shortly.

scholarly journals Interaction of the Hippo Pathway and Phosphatases in Tumorigenesis

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2438 ◽  
Author(s):  
Sahar Sarmasti Emami ◽  
Derek Zhang ◽  
Xiaolong Yang
Keyword(s):  
Signaling Pathway ◽  
Hippo Pathway ◽  
Underlying Mechanism ◽  
Hippo Signaling ◽  
Hippo Signaling Pathway ◽  
Cellular Processes ◽  
Wide Range ◽  
Future Direction ◽  
The Hippo Pathway

The Hippo pathway is an emerging tumor suppressor signaling pathway involved in a wide range of cellular processes. Dysregulation of different components of the Hippo signaling pathway is associated with a number of diseases including cancer. Therefore, identification of the Hippo pathway regulators and the underlying mechanism of its regulation may be useful to uncover new therapeutics for cancer therapy. The Hippo signaling pathway includes a set of kinases that phosphorylate different proteins in order to phosphorylate and inactivate its main downstream effectors, YAP and TAZ. Thus, modulating phosphorylation and dephosphorylation of the Hippo components by kinases and phosphatases play critical roles in the regulation of the signaling pathway. While information regarding kinase regulation of the Hippo pathway is abundant, the role of phosphatases in regulating this pathway is just beginning to be understood. In this review, we summarize the most recent reports on the interaction of phosphatases and the Hippo pathway in tumorigenesis. We have also introduced challenges in clarifying the role of phosphatases in the Hippo pathway and future direction of crosstalk between phosphatases and the Hippo pathway.

scholarly journals Targeting the Hippo Pathway and Cancer through the TEAD Family of Transcription Factors

Cancers ◽  
2018 ◽  
Vol 10 (3) ◽  
pp. 81 ◽  
Author(s):  
◽  
Keyword(s):  
Transcription Factors ◽  
Signaling Pathway ◽  
Transcriptional Activation ◽  
Therapeutic Potential ◽  
Hippo Pathway ◽  
Large Body ◽  
Hippo Signaling ◽  
Wide Range ◽  
The Hippo Pathway

The Hippo pathway is a critical transcriptional signaling pathway that regulates cell growth, proliferation and organ development. The transcriptional enhanced associate domain (TEAD) protein family consists of four paralogous transcription factors that function to modulate gene expression in response to the Hippo signaling pathway. Transcriptional activation of these proteins occurs upon binding to the co-activator YAP/TAZ whose entry into the nucleus is regulated by Lats1/2 kinase. In recent years, it has become apparent that the dysregulation and/or overexpression of Hippo pathway effectors is implicated in a wide range of cancers, including prostate, gastric and liver cancer. A large body of work has been dedicated to understanding the therapeutic potential of modulating the phosphorylation and localization of YAP/TAZ. However, YAP/TAZ are considered to be natively unfolded and may be intractable as drug targets. Therefore, TEAD proteins present themselves as an excellent therapeutic target for intervention of the Hippo pathway. This review summarizes the functional role of TEAD proteins in cancer and assesses the therapeutic potential of antagonizing TEAD function in vivo.

scholarly journals GPCR-Hippo Signaling in Cancer

Cells ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 426 ◽  
Author(s):  
Jiaqian Luo ◽  
Fa-Xing Yu
Keyword(s):  
Cancer Metastasis ◽  
Hippo Pathway ◽  
Hippo Signaling ◽  
Cancer Therapies ◽  
Aberrant Expression ◽  
Wide Range ◽  
Anti Cancer ◽  
Genetic Deletion ◽  
The Hippo Pathway ◽  
G Protein Coupled

The Hippo signaling pathway is involved in tissue size regulation and tumorigenesis. Genetic deletion or aberrant expression of some Hippo pathway genes lead to enhanced cell proliferation, tumorigenesis, and cancer metastasis. Recently, multiple studies have identified a wide range of upstream regulators of the Hippo pathway, including mechanical cues and ligands of G protein-coupled receptors (GPCRs). Through the activation related G proteins and possibly rearrangements of actin cytoskeleton, GPCR signaling can potently modulate the phosphorylation states and activity of YAP and TAZ, two homologous oncogenic transcriptional co-activators, and major effectors of the Hippo pathway. Herein, we summarize the network, regulation, and functions of GPCR-Hippo signaling, and we will also discuss potential anti-cancer therapies targeting GPCR-YAP signaling.

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.

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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