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Hippo Signaling Pathway
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Hippo Signaling Pathway

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (30 April 2016) | Viewed by 61304

Special Issue Editor

Dr. Paul Reynolds

E-Mail Website
Guest Editor
School of Medicine, University of St Andrews, Medical and Biological Sciences Building, North Haugh, St Andrews, Fife KY16 9TF, UK
Interests: cell biology; cancer; pathology; Hippo signaling; drug resistance

Special Issue Information

Dear Colleagues,

The Salvador/Warts/Hippo (Hippo) signaling pathway has emerged in the last two decades as a tumor suppressor kinase cascade that regulates cell growth and organ size. Rapid progress has been made by connecting four seemingly disparate areas of research: 1) discovery by genetic screens in Drosophila of initial pathway kinases and scaffolding proteins and more recently new pathway components, 2) TEAD (TEA domain) transcription factors and their associated transcriptional coactivators YAP and TAZ, controlled by the Hippo pathway kinases mainly through YAP/TAZ phosphorylation, 3) studies in transgenic mice and other mammalian cells and 4) studies of human disease pathology. Hippo signaling is now seen as an increasingly complex signaling network that cross-talks with many other signaling pathways and is implicated in mechanotransduction, stem cells, tissue regeneration and cancer progression. Our increased understanding holds the promise of identifying new targets for cancer treatment.

This open access Special Issue provides an opportunity to review the different experimental strands that have contributed to our understanding of Hippo signaling. We also hope to include a broad range of current work, and welcome significant contributions of all kinds.

Dr. Paul A. Reynolds
Guest Editor

Manuscript Submission Information

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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. Genes is an international peer-reviewed open access monthly 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 2600 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
  • TEADs
  • polarity
  • GPCR
  • organ size
  • actin cytoskeleton
  • phosphorylation

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Published Papers (6 papers)

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Research

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2096 KiB  
Article
Unveiling Hidden Dynamics of Hippo Signalling: A Systems Analysis
by Sung-Young Shin and Lan K. Nguyen
Genes 2016, 7(8), 44; https://doi.org/10.3390/genes7080044 - 5 Aug 2016
Cited by 15 | Viewed by 6680
Abstract
The Hippo signalling pathway has recently emerged as an important regulator of cell apoptosis and proliferation with significant implications in human diseases. In mammals, the pathway contains the core kinases MST1/2, which phosphorylate and activate LATS1/2 kinases. The pro-apoptotic function of the MST/LATS [...] Read more.
The Hippo signalling pathway has recently emerged as an important regulator of cell apoptosis and proliferation with significant implications in human diseases. In mammals, the pathway contains the core kinases MST1/2, which phosphorylate and activate LATS1/2 kinases. The pro-apoptotic function of the MST/LATS signalling axis was previously linked to the Akt and ERK MAPK pathways, demonstrating that the Hippo pathway does not act alone but crosstalks with other signalling pathways to coordinate network dynamics and cellular outcomes. These crosstalks were characterised by a multitude of complex regulatory mechanisms involving competitive protein-protein interactions and phosphorylation mediated feedback loops. However, how these different mechanisms interplay in different cellular contexts to drive the context-specific network dynamics of Hippo-ERK signalling remains elusive. Using mathematical modelling and computational analysis, we uncovered that the Hippo-ERK network can generate highly diverse dynamical profiles that can be clustered into distinct dose-response patterns. For each pattern, we offered mechanistic explanation that defines when and how the observed phenomenon can arise. We demonstrated that Akt displays opposing, dose-dependent functions towards ERK, which are mediated by the balance between the Raf-1/MST2 protein interaction module and the LATS1 mediated feedback regulation. Moreover, Ras displays a multi-functional role and drives biphasic responses of both MST2 and ERK activities; which are critically governed by the competitive protein interaction between MST2 and Raf-1. Our study represents the first in-depth and systematic analysis of the Hippo-ERK network dynamics and provides a concrete foundation for future studies. Full article
(This article belongs to the Special Issue Hippo Signaling Pathway)
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Review

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1236 KiB  
Review
Targeting the Hippo Signaling Pathway for Tissue Regeneration and Cancer Therapy
by Wen Chun Juan and Wanjin Hong
Genes 2016, 7(9), 55; https://doi.org/10.3390/genes7090055 - 30 Aug 2016
Cited by 64 | Viewed by 20003
Abstract
The Hippo signaling pathway is a highly-conserved developmental pathway that plays an essential role in organ size control, tumor suppression, tissue regeneration and stem cell self-renewal. The YES-associated protein (YAP) and the transcriptional co-activator with PDZ-binding motif (TAZ) are two important transcriptional co-activators [...] Read more.
The Hippo signaling pathway is a highly-conserved developmental pathway that plays an essential role in organ size control, tumor suppression, tissue regeneration and stem cell self-renewal. The YES-associated protein (YAP) and the transcriptional co-activator with PDZ-binding motif (TAZ) are two important transcriptional co-activators that are negatively regulated by the Hippo signaling pathway. By binding to transcription factors, especially the TEA domain transcription factors (TEADs), YAP and TAZ induce the expression of growth-promoting genes, which can promote organ regeneration after injury. Therefore, controlled activation of YAP and TAZ can be useful for regenerative medicine. However, aberrant activation of YAP and TAZ due to deregulation of the Hippo pathway or overexpression of YAP/TAZ and TEADs can promote cancer development. Hence, pharmacological inhibition of YAP and TAZ may be a useful approach to treat tumors with high YAP and/or TAZ activity. In this review, we present the mechanisms regulating the Hippo pathway, the role of the Hippo pathway in tissue repair and cancer, as well as a detailed analysis of the different strategies to target the Hippo signaling pathway and the genes regulated by YAP and TAZ for regenerative medicine and cancer therapy. Full article
(This article belongs to the Special Issue Hippo Signaling Pathway)
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2180 KiB  
Review
Willing to Be Involved in Cancer
by Frank J. Gunn-Moore, Andrew M. Tilston-Lünel and Paul A. Reynolds
Genes 2016, 7(7), 37; https://doi.org/10.3390/genes7070037 - 18 Jul 2016
Cited by 7 | Viewed by 5538
Abstract
Genome sequencing is now a common procedure, but prior to this, screening experiments using protein baits was one of the routinely used methods that, occasionally, allowed the identification of new gene products. One such experiment uncovered the gene product called willin/human Expanded/FRMD6. Initial [...] Read more.
Genome sequencing is now a common procedure, but prior to this, screening experiments using protein baits was one of the routinely used methods that, occasionally, allowed the identification of new gene products. One such experiment uncovered the gene product called willin/human Expanded/FRMD6. Initial characterization studies found that willin bound phospholipids and was strongly co-localised with actin. However, subsequently, willin was found to be the closest human sequence homologue of the Drosophila protein Expanded (Ex), sharing 60% homology with the Ex FERM domain. This in turn suggested, and then was proven that willin could activate the Hippo signalling pathway. This review describes the increasing body of knowledge about the actions of willin in a number of cellular functions related to cancer. However, like many gene products involved in aspects of cell signalling, a convincing direct role for willin in cancer remains tantalisingly elusive, at present. Full article
(This article belongs to the Special Issue Hippo Signaling Pathway)
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1270 KiB  
Review
The MST/Hippo Pathway and Cell Death: A Non-Canonical Affair
by Emma Fallahi, Niamh A. O’Driscoll and David Matallanas
Genes 2016, 7(6), 28; https://doi.org/10.3390/genes7060028 - 17 Jun 2016
Cited by 67 | Viewed by 11321
Abstract
The MST/Hippo signalling pathway was first described over a decade ago in Drosophila melanogaster and the core of the pathway is evolutionary conserved in mammals. The mammalian MST/Hippo pathway regulates organ size, cell proliferation and cell death. In addition, it has been shown [...] Read more.
The MST/Hippo signalling pathway was first described over a decade ago in Drosophila melanogaster and the core of the pathway is evolutionary conserved in mammals. The mammalian MST/Hippo pathway regulates organ size, cell proliferation and cell death. In addition, it has been shown to play a central role in the regulation of cellular homeostasis and it is commonly deregulated in human tumours. The delineation of the canonical pathway resembles the behaviour of the Hippo pathway in the fly where the activation of the core kinases of the pathway prevents the proliferative signal mediated by the key effector of the pathway YAP. Nevertheless, several lines of evidence support the idea that the mammalian MST/Hippo pathway has acquired new features during evolution, including different regulators and effectors, crosstalk with other essential signalling pathways involved in cellular homeostasis and the ability to actively trigger cell death. Here we describe the current knowledge of the mechanisms that mediate MST/Hippo dependent cell death, especially apoptosis. We include evidence for the existence of complex signalling networks where the core proteins of the pathway play a central role in controlling the balance between survival and cell death. Finally, we discuss the possible involvement of these signalling networks in several human diseases such as cancer, diabetes and neurodegenerative disorders. Full article
(This article belongs to the Special Issue Hippo Signaling Pathway)
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199 KiB  
Review
The Regulatory Role of KIBRA and PTPN14 in Hippo Signaling and Beyond
by Kayla E. Wilson, Nuo Yang, Ashley L. Mussell and Jianmin Zhang
Genes 2016, 7(6), 23; https://doi.org/10.3390/genes7060023 - 27 May 2016
Cited by 30 | Viewed by 5947
Abstract
The Hippo signaling pathway regulates cellular proliferation and survival, thus exerting profound effects on normal cell fate and tumorigenesis. Pivotal effectors of this pathway are YAP/TAZ, transcriptional co-activators whose dysfunction contributes to the development of cancer. Complex networks of intracellular and extracellular signaling [...] Read more.
The Hippo signaling pathway regulates cellular proliferation and survival, thus exerting profound effects on normal cell fate and tumorigenesis. Pivotal effectors of this pathway are YAP/TAZ, transcriptional co-activators whose dysfunction contributes to the development of cancer. Complex networks of intracellular and extracellular signaling pathways that modulate YAP and TAZ activities have recently been identified. Among them, KIBRA and PTPN14 are two evolutionarily-conserved and important YAP/TAZ upstream regulators. They can negatively regulate YAP/TAZ functions separately or in concert. In this review, we summarize the current and emerging regulatory roles of KIBRA and PTPN14 in the Hippo pathway and their functions in cancer. Full article
(This article belongs to the Special Issue Hippo Signaling Pathway)
568 KiB  
Review
The Roles of NDR Protein Kinases in Hippo Signalling
by Alexander Hergovich
Genes 2016, 7(5), 21; https://doi.org/10.3390/genes7050021 - 18 May 2016
Cited by 77 | Viewed by 10714
Abstract
The Hippo tumour suppressor pathway has emerged as a critical regulator of tissue growth through controlling cellular processes such as cell proliferation, death, differentiation and stemness. Traditionally, the core cassette of the Hippo pathway includes the MST1/2 protein kinases, the LATS1/2 protein kinases, [...] Read more.
The Hippo tumour suppressor pathway has emerged as a critical regulator of tissue growth through controlling cellular processes such as cell proliferation, death, differentiation and stemness. Traditionally, the core cassette of the Hippo pathway includes the MST1/2 protein kinases, the LATS1/2 protein kinases, and the MOB1 scaffold signal transducer, which together regulate the transcriptional co-activator functions of the proto-oncoproteins YAP and TAZ through LATS1/2-mediated phosphorylation of YAP/TAZ. Recent research has identified additional kinases, such as NDR1/2 (also known as STK38/STK38L) and MAP4Ks, which should be considered as novel members of the Hippo core cassette. While these efforts helped to expand our understanding of Hippo core signalling, they also began to provide insights into the complexity and redundancy of the Hippo signalling network. Here, we focus on summarising our current knowledge of the regulation and functions of mammalian NDR kinases, discussing parallels between the NDR pathways in Drosophila and mammals. Initially, we provide a general overview of the cellular functions of NDR kinases in cell cycle progression, centrosome biology, apoptosis, autophagy, DNA damage signalling, immunology and neurobiology. Finally, we put particular emphasis on discussing NDR1/2 as YAP kinases downstream of MST1/2 and MOB1 signalling in Hippo signalling. Full article
(This article belongs to the Special Issue Hippo Signaling Pathway)
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