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Disease and the Hippo Pathway: Cellular and Molecular Mechanisms
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Disease and the Hippo Pathway: Cellular and Molecular Mechanisms

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (31 March 2019) | Viewed by 109479

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Dr. Carsten Gram Hansen

E-Mail Website
Guest Editor
University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh bioQuarter, Edinburgh, UK
Interests: YAP/TAZ; Hippo pathway; mechanotransduction; inflammation; Caveolae; cell dynamics; cancer and stem cells

Special Issue Information

Dear Colleagues,

The Hippo pathway is a highly dynamic cellular signaling nexus, integrating mechanotransduction, cell polarity, inflammation, and numerous types of paracrine signaling. The Hippo pathway plays central roles in multiple cell types and regulates regeneration, metabolism and development. If not tightly regulated, dysregulated Hippo pathway signaling drives the onset and progression of a range of diseases, including fibrosis and cancer. The molecular understanding of the Hippo pathway is rapidly evolving, emphasized by the relative recent seminal discovery of the LATS1/2 mediated, but Hippo independent, kinase regulation of YAP/TAZ via the MAP4K family. The aim of this Special Issue is to provide an overview of how a dysregulated Hippo pathway is a common driver of specific diseases, with a particular focus on the underlying molecular and cellular mechanisms that causes the Hippo pathway to go awry, and how this drives disease. We particularly welcome contributions, in the form of either original research articles or concise reviews, with mechanistic and functional insights into either specific diseases or common pathological phenomena caused by Hippo pathway dysregulation.

We hope that the articles will analyse disease-specific, as well as common themes, which will provide valuable insights into the fundamental molecular mechanisms in the dysfunctioning Hippo pathway, and thereby offer practical insights into potential future therapeutic intervention strategies.

Dr. Carsten Gram Hansen
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Hippo pathway
  • YAP/TAZ
  • disease mechanism
  • mechanotransduction
  • GPCR
  • inflammation
  • regeneration

Published Papers (11 papers)

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Editorial

Jump to: Review, Other

4 pages, 184 KiB  
Editorial
Special Issue on “Disease and the Hippo Pathway”
by Carsten Gram Hansen
Cells 2019, 8(10), 1179; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8101179 - 30 Sep 2019
Viewed by 2184
Abstract
The Hippo pathway is a cellular signalling network, which plays major roles in organ homeostasis and development [...] Full article
(This article belongs to the Special Issue Disease and the Hippo Pathway: Cellular and Molecular Mechanisms)

Review

Jump to: Editorial, Other

22 pages, 1334 KiB  
Review
Regulation of TEAD Transcription Factors in Cancer Biology
by Hyunbin D. Huh, Dong Hyeon Kim, Han-Sol Jeong and Hyun Woo Park
Cells 2019, 8(6), 600; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8060600 - 17 Jun 2019
Cited by 149 | Viewed by 16246
Abstract
Transcriptional enhanced associate domain (TEAD) transcription factors play important roles during development, cell proliferation, regeneration, and tissue homeostasis. TEAD integrates with and coordinates various signal transduction pathways including Hippo, Wnt, transforming growth factor beta (TGFβ), and epidermal growth factor receptor (EGFR) pathways. TEAD [...] Read more.
Transcriptional enhanced associate domain (TEAD) transcription factors play important roles during development, cell proliferation, regeneration, and tissue homeostasis. TEAD integrates with and coordinates various signal transduction pathways including Hippo, Wnt, transforming growth factor beta (TGFβ), and epidermal growth factor receptor (EGFR) pathways. TEAD deregulation affects well-established cancer genes such as KRAS, BRAF, LKB1, NF2, and MYC, and its transcriptional output plays an important role in tumor progression, metastasis, cancer metabolism, immunity, and drug resistance. To date, TEADs have been recognized to be key transcription factors of the Hippo pathway. Therefore, most studies are focused on the Hippo kinases and YAP/TAZ, whereas the Hippo-dependent and Hippo-independent regulators and regulations governing TEAD only emerged recently. Deregulation of the TEAD transcriptional output plays important roles in tumor progression and serves as a prognostic biomarker due to high correlation with clinicopathological parameters in human malignancies. In addition, discovering the molecular mechanisms of TEAD, such as post-translational modifications and nucleocytoplasmic shuttling, represents an important means of modulating TEAD transcriptional activity. Collectively, this review highlights the role of TEAD in multistep-tumorigenesis by interacting with upstream oncogenic signaling pathways and controlling downstream target genes, which provides unprecedented insight and rationale into developing TEAD-targeted anticancer therapeutics. Full article
(This article belongs to the Special Issue Disease and the Hippo Pathway: Cellular and Molecular Mechanisms)
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28 pages, 8104 KiB  
Review
MOB (Mps one Binder) Proteins in the Hippo Pathway and Cancer
by Ramazan Gundogdu and Alexander Hergovich
Cells 2019, 8(6), 569; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8060569 - 10 Jun 2019
Cited by 35 | Viewed by 6408
Abstract
The family of MOBs (monopolar spindle-one-binder proteins) is highly conserved in the eukaryotic kingdom. MOBs represent globular scaffold proteins without any known enzymatic activities. They can act as signal transducers in essential intracellular pathways. MOBs have diverse cancer-associated cellular functions through regulatory interactions [...] Read more.
The family of MOBs (monopolar spindle-one-binder proteins) is highly conserved in the eukaryotic kingdom. MOBs represent globular scaffold proteins without any known enzymatic activities. They can act as signal transducers in essential intracellular pathways. MOBs have diverse cancer-associated cellular functions through regulatory interactions with members of the NDR/LATS kinase family. By forming additional complexes with serine/threonine protein kinases of the germinal centre kinase families, other enzymes and scaffolding factors, MOBs appear to be linked to an even broader disease spectrum. Here, we review our current understanding of this emerging protein family, with emphases on post-translational modifications, protein-protein interactions, and cellular processes that are possibly linked to cancer and other diseases. In particular, we summarise the roles of MOBs as core components of the Hippo tissue growth and regeneration pathway. Full article
(This article belongs to the Special Issue Disease and the Hippo Pathway: Cellular and Molecular Mechanisms)
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16 pages, 1282 KiB  
Review
The Roles of Hippo Signaling Transducers Yap and Taz in Chromatin Remodeling
by Ryan E. Hillmer and Brian A. Link
Cells 2019, 8(5), 502; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8050502 - 24 May 2019
Cited by 43 | Viewed by 5506
Abstract
Hippo signaling controls cellular processes that ultimately impact organogenesis and homeostasis. Consequently, disease states including cancer can emerge when signaling is deregulated. The major pathway transducers Yap and Taz require cofactors to impart transcriptional control over target genes. Research into Yap/Taz-mediated epigenetic modifications [...] Read more.
Hippo signaling controls cellular processes that ultimately impact organogenesis and homeostasis. Consequently, disease states including cancer can emerge when signaling is deregulated. The major pathway transducers Yap and Taz require cofactors to impart transcriptional control over target genes. Research into Yap/Taz-mediated epigenetic modifications has revealed their association with chromatin-remodeling complex proteins as a means of altering chromatin structure, therefore affecting accessibility and activity of target genes. Specifically, Yap/Taz have been found to associate with factors of the GAGA, Ncoa6, Mediator, Switch/sucrose nonfermentable (SWI/SNF), and Nucleosome Remodeling and Deacetylase (NuRD) chromatin-remodeling complexes to alter the accessibility of target genes. This review highlights the different mechanisms by which Yap/Taz collaborate with other factors to modify DNA packing at specific loci to either activate or repress target gene transcription. Full article
(This article belongs to the Special Issue Disease and the Hippo Pathway: Cellular and Molecular Mechanisms)
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22 pages, 3694 KiB  
Review
Role of the Hippo Pathway in Fibrosis and Cancer
by Cho-Long Kim, Sue-Hee Choi and Jung-Soon Mo
Cells 2019, 8(5), 468; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8050468 - 16 May 2019
Cited by 73 | Viewed by 10964
Abstract
The Hippo pathway is the key player in various signaling processes, including organ development and maintenance of tissue homeostasis. This pathway comprises a core kinases module and transcriptional activation module, representing a highly conserved mechanism from Drosophila to vertebrates. The central MST1/2-LATS1/2 kinase [...] Read more.
The Hippo pathway is the key player in various signaling processes, including organ development and maintenance of tissue homeostasis. This pathway comprises a core kinases module and transcriptional activation module, representing a highly conserved mechanism from Drosophila to vertebrates. The central MST1/2-LATS1/2 kinase cascade in this pathway negatively regulates YAP/TAZ transcription co-activators in a phosphorylation-dependent manner. Nuclear YAP/TAZ bind to transcription factors to stimulate gene expression, contributing to the regenerative potential and regulation of cell growth and death. Recent studies have also highlighted the potential role of Hippo pathway dysfunctions in the pathology of several diseases. Here, we review the functional characteristics of the Hippo pathway in organ fibrosis and tumorigenesis, and discuss its potential as new therapeutic targets. Full article
(This article belongs to the Special Issue Disease and the Hippo Pathway: Cellular and Molecular Mechanisms)
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15 pages, 845 KiB  
Review
GPCR-Hippo Signaling in Cancer
by Jiaqian Luo and Fa-Xing Yu
Cells 2019, 8(5), 426; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8050426 - 08 May 2019
Cited by 63 | Viewed by 12934
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Disease and the Hippo Pathway: Cellular and Molecular Mechanisms)
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29 pages, 21766 KiB  
Review
The Roles of YAP/TAZ and the Hippo Pathway in Healthy and Diseased Skin
by Emanuel Rognoni and Gernot Walko
Cells 2019, 8(5), 411; https://doi.org/10.3390/cells8050411 - 03 May 2019
Cited by 60 | Viewed by 11341
Abstract
Skin is the largest organ of the human body. Its architecture and physiological functions depend on diverse populations of epidermal cells and dermal fibroblasts. Reciprocal communication between the epidermis and dermis plays a key role in skin development, homeostasis and repair. While several [...] Read more.
Skin is the largest organ of the human body. Its architecture and physiological functions depend on diverse populations of epidermal cells and dermal fibroblasts. Reciprocal communication between the epidermis and dermis plays a key role in skin development, homeostasis and repair. While several stem cell populations have been identified in the epidermis with distinct locations and functions, there is additional heterogeneity within the mesenchymal cells of the dermis. Here, we discuss the current knowledge of how the Hippo pathway and its downstream effectors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) contribute to the maintenance, activation and coordination of the epidermal and dermal cell populations during development, homeostasis, wound healing and cancer. Full article
(This article belongs to the Special Issue Disease and the Hippo Pathway: Cellular and Molecular Mechanisms)
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22 pages, 2776 KiB  
Review
The Role of YAP and TAZ in Angiogenesis and Vascular Mimicry
by Taha Azad, Mina Ghahremani and Xiaolong Yang
Cells 2019, 8(5), 407; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8050407 - 01 May 2019
Cited by 72 | Viewed by 9059
Abstract
Angiogenesis, the formation of new blood vessels from pre-existing vasculature, is a physiological process that begins in utero and continues throughout life in both good health and disease. Understanding the underlying mechanism in angiogenesis could uncover a new therapeutic approach in pathological angiogenesis. [...] Read more.
Angiogenesis, the formation of new blood vessels from pre-existing vasculature, is a physiological process that begins in utero and continues throughout life in both good health and disease. Understanding the underlying mechanism in angiogenesis could uncover a new therapeutic approach in pathological angiogenesis. Since its discovery, the Hippo signaling pathway has emerged as a key player in controlling organ size and tissue homeostasis. Recently, new studies have discovered that Hippo and two of its main effectors, Yes-associated protein (YAP) and its paralog transcription activator with PDZ binding motif (TAZ), play critical roles during angiogenesis. In this review, we summarize the mechanisms by which YAP/TAZ regulate endothelial cell shape, behavior, and function in angiogenesis. We further discuss how YAP/TAZ function as part of developmental and pathological angiogenesis. Finally, we review the role of YAP/TAZ in tumor vascular mimicry and propose directions for future work. Full article
(This article belongs to the Special Issue Disease and the Hippo Pathway: Cellular and Molecular Mechanisms)
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Figure 1

19 pages, 2355 KiB  
Review
Hippo Pathway in Mammalian Adaptive Immune System
by Takayoshi Yamauchi and Toshiro Moroishi
Cells 2019, 8(5), 398; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8050398 - 30 Apr 2019
Cited by 57 | Viewed by 18035
Abstract
The Hippo pathway was originally identified as an evolutionarily-conserved signaling mechanism that contributes to the control of organ size. It was then rapidly expanded as a key pathway in the regulation of tissue development, regeneration, and cancer pathogenesis. The increasing amount of evidence [...] Read more.
The Hippo pathway was originally identified as an evolutionarily-conserved signaling mechanism that contributes to the control of organ size. It was then rapidly expanded as a key pathway in the regulation of tissue development, regeneration, and cancer pathogenesis. The increasing amount of evidence in recent years has also connected this pathway to the regulation of innate and adaptive immune responses. Notably, the Hippo pathway has been revealed to play a pivotal role in adaptive immune cell lineages, as represented by the patients with T- and B-cell lymphopenia exhibiting defective expressions of the pathway component. The complex regulatory mechanisms of and by the Hippo pathway have also been evident as alternative signal transductions are employed in some immune cell types. In this review article, we summarize the current understanding of the emerging roles of the Hippo pathway in adaptive immune cell development and differentiation. We also highlight the recent findings concerning the dual functions of the Hippo pathway in autoimmunity and anti-cancer immune responses and discuss the key open questions in the interplay between the Hippo pathway and the mammalian immune system. Full article
(This article belongs to the Special Issue Disease and the Hippo Pathway: Cellular and Molecular Mechanisms)
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Graphical abstract

24 pages, 3061 KiB  
Review
The Hippo Pathway in Prostate Cancer
by Omar Salem and Carsten G. Hansen
Cells 2019, 8(4), 370; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8040370 - 23 Apr 2019
Cited by 60 | Viewed by 12038
Abstract
Despite recent efforts, prostate cancer (PCa) remains one of the most common cancers in men. Currently, there is no effective treatment for castration-resistant prostate cancer (CRPC). There is, therefore, an urgent need to identify new therapeutic targets. The Hippo pathway and its downstream [...] Read more.
Despite recent efforts, prostate cancer (PCa) remains one of the most common cancers in men. Currently, there is no effective treatment for castration-resistant prostate cancer (CRPC). There is, therefore, an urgent need to identify new therapeutic targets. The Hippo pathway and its downstream effectors—the transcriptional co-activators, Yes-associated protein (YAP) and its paralog, transcriptional co-activator with PDZ-binding motif (TAZ)—are foremost regulators of stem cells and cancer biology. Defective Hippo pathway signaling and YAP/TAZ hyperactivation are common across various cancers. Here, we draw on insights learned from other types of cancers and review the latest advances linking the Hippo pathway and YAP/TAZ to PCa onset and progression. We examine the regulatory interaction between Hippo-YAP/TAZ and the androgen receptor (AR), as main regulators of PCa development, and how uncontrolled expression of YAP/TAZ drives castration resistance by inducing cellular stemness. Finally, we survey the potential therapeutic targeting of the Hippo pathway and YAP/TAZ to overcome PCa. Full article
(This article belongs to the Special Issue Disease and the Hippo Pathway: Cellular and Molecular Mechanisms)
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Other

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14 pages, 5078 KiB  
Brief Report
Somatic Mutations of lats2 Cause Peripheral Nerve Sheath Tumors in Zebrafish
by Zachary J. Brandt, Paula N. North and Brian A. Link
Cells 2019, 8(9), 972; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8090972 - 25 Aug 2019
Cited by 10 | Viewed by 3155
Abstract
The cellular signaling pathways underlying peripheral nerve sheath tumor (PNST) formation are poorly understood. Hippo signaling has been recently implicated in the biology of various cancers, and is thought to function downstream of mutations in the known PNST driver, NF2. Utilizing CRISPR-Cas9 [...] Read more.
The cellular signaling pathways underlying peripheral nerve sheath tumor (PNST) formation are poorly understood. Hippo signaling has been recently implicated in the biology of various cancers, and is thought to function downstream of mutations in the known PNST driver, NF2. Utilizing CRISPR-Cas9 gene editing, we targeted the canonical Hippo signaling kinase Lats2. We show that, while germline deletion leads to early lethality, targeted somatic mutations of zebrafish lats2 leads to peripheral nerve sheath tumor formation. These peripheral nerve sheath tumors exhibit high levels of Hippo effectors Yap and Taz, suggesting that dysregulation of these transcriptional co-factors drives PNST formation in this model. These data indicate that somatic lats2 deletion in zebrafish can serve as a powerful experimental platform to probe the mechanisms of PNST formation and progression. Full article
(This article belongs to the Special Issue Disease and the Hippo Pathway: Cellular and Molecular Mechanisms)
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