scholarly journals A protein tertiary structure mimetic modulator of the Hippo signalling pathway

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Hélène Adihou ◽  
Ranganath Gopalakrishnan ◽  
Tim Förster ◽  
Stéphanie M. Guéret ◽  
Raphael Gasper ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Protein Interactions ◽  
Tertiary Structure ◽  
Hippo Pathway ◽  
Signalling Pathway ◽  
Protein Protein Interactions ◽  
Protein Tertiary Structure ◽  
A Cell ◽  
Chemical Modulation ◽  
Hippo Signalling

Abstract Transcription factors are key protein effectors in the regulation of gene transcription, and in many cases their activity is regulated via a complex network of protein–protein interactions (PPI). The chemical modulation of transcription factor activity is a long-standing goal in drug discovery but hampered by the difficulties associated with the targeting of PPIs, in particular when extended and flat protein interfaces are involved. Peptidomimetics have been applied to inhibit PPIs, however with variable success, as for certain interfaces the mimicry of a single secondary structure element is insufficient to obtain high binding affinities. Here, we describe the design and characterization of a stabilized protein tertiary structure that acts as an inhibitor of the interaction between the transcription factor TEAD and its co-repressor VGL4, both playing a central role in the Hippo signalling pathway. Modification of the inhibitor with a cell-penetrating entity yielded a cell-permeable proteomimetic that activates cell proliferation via regulation of the Hippo pathway, highlighting the potential of protein tertiary structure mimetics as an emerging class of PPI modulators.

Proteomic Characterization of Protein-Protein Interactions

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Veenstra TD ◽  
Keyword(s):  
Protein Interactions ◽  
Disease Diagnosis ◽  
Cell System ◽  
Protein Protein Interactions ◽  
Novel Technologies ◽  
Cell Functions ◽  
Single Protein ◽  
A Cell ◽  
Molecular Components

Identifying all the molecular components within a living cell is the first step into understanding how it functions. To further understand how a cell functions requires identifying the interactions that occur between these components. This fact is especially relevant for proteins. No protein within a human cell functions on its own without interacting with another biomolecule - usually another protein. While Protein-Protein Interactions (PPI) have historically been determined by examining a single protein per study, novel technologies developed over the past couple of decades are enabling high-throughput methods that aim to describe entire protein networks within cells. In this review, some of the technologies that have led to these developments are described along with applications of these techniques. Ultimately the goal of these technologies is to map out the entire circuitry of PPI within human cells to be able to predict the global consequences of perturbations to the cell system. This predictive capability will have major impacts on the future of both disease diagnosis and treatment.

scholarly journals Glycyrrhizic Acid for COVID-19: Findings of Targeting Pivotal Inflammatory Pathways Triggered by SARS-CoV-2

2021 ◽  
Vol 12 ◽  
Author(s):  
Wenjiang Zheng ◽  
Xiufang Huang ◽  
Yanni Lai ◽  
Xiaohong Liu ◽  
Yong Jiang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Protein Interactions ◽  
Glycyrrhizic Acid ◽  
Enrichment Analysis ◽  
Host Factors ◽  
Pathway Enrichment Analysis ◽  
Protein Protein Interactions ◽  
Health Crisis ◽  
Inflammatory Pathways ◽  
Anti Inflammatory

Background: Coronavirus disease 2019 (COVID-19) is now a worldwide public health crisis. The causative pathogen is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Novel therapeutic agents are desperately needed. Because of the frequent mutations in the virus and its ability to cause cytokine storms, targeting the viral proteins has some drawbacks. Targeting cellular factors or pivotal inflammatory pathways triggered by SARS-CoV-2 may produce a broader range of therapies. Glycyrrhizic acid (GA) might be beneficial against SARS-CoV-2 because of its anti-inflammatory and antiviral characteristics and possible ability to regulate crucial host factors. However, the mechanism underlying how GA regulates host factors remains to be determined.Methods: In our report, we conducted a bioinformatics analysis to identify possible GA targets, biological functions, protein-protein interactions, transcription-factor-gene interactions, transcription-factor-miRNA coregulatory networks, and the signaling pathways of GA against COVID-19.Results: Protein-protein interactions and network analysis showed that ICAM1, MMP9, TLR2, and SOCS3 had higher degree values, which may be key targets of GA for COVID-19. GO analysis indicated that the response to reactive oxygen species was significantly enriched. Pathway enrichment analysis showed that the IL-17, IL-6, TNF-α, IFN signals, complement system, and growth factor receptor signaling are the main pathways. The interactions of TF genes and miRNA with common targets and the activity of TFs were also recognized.Conclusions: GA may inhibit COVID-19 through its anti-oxidant, anti-viral, and anti-inflammatory effects, and its ability to activate the immune system, and targeted therapy for those pathways is a predominant strategy to inhibit the cytokine storms triggered by SARS-CoV-2 infection.

scholarly journals Mitochondria: Regulators of Cell Death and Survival

2002 ◽  
Vol 2 ◽  
pp. 1569-1578 ◽  
Author(s):  
David J. Granville ◽  
Roberta A. Gottlieb
Keyword(s):  
Cell Death ◽  
Conformational Changes ◽  
Protein Interactions ◽  
Apoptotic Cell ◽  
Critical Role ◽  
Death Process ◽  
Protein Protein Interactions ◽  
Ionic Changes ◽  
A Cell ◽  
Cyt C

The past 5 years has seen an intense surge in research devoted toward understanding the critical role of mitochondria in the regulation of cell death. Apoptosis can be initiated by a wide array of stimuli, inducing multiple signaling pathways that, for the most part, converge at the mitochondrion. Although classically considered the powerhouses of the cell, it is now understood that mitochondria are also “gatekeepers” that ultimately determine the fate of the cell. The mitochondrial decision as to whether a cell lives or dies is complex, involving protein-protein interactions, ionic changes, reactive oxygen species, and other mechanisms that require further elucidation. Once the death process is initiated, mitochondria undergo conformational changes, resulting in the release of cytochrome c (cyt c), caspases, endonucleases, and other factors leading to the onset and execution of apoptosis. The present review attempts to outline the complex milieu of events regulating the mitochondrial commitment to and processes involved in the implementation of the executioner phase of apoptotic cell death.

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 A cell-penetrant lactam-stapled peptide for targeting eIF4E protein-protein interactions

2020 ◽  
Vol 205 ◽  
pp. 112655
Author(s):  
Erin E. Gallagher ◽  
Arya Menon ◽  
Alyah F. Chmiel ◽  
Kirsten Deprey ◽  
Joshua A. Kritzer ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Protein Protein Interactions ◽  
Stapled Peptide ◽  
A Cell

scholarly journals Mammalian Hippo signalling: a kinase network regulated by protein–protein interactions

2012 ◽  
Vol 40 (1) ◽  
pp. 124-128 ◽  
Author(s):  
Alexander Hergovich
Keyword(s):  
Protein Interactions ◽  
Tumour Suppressor ◽  
Protein Protein Interactions ◽  
Large Tumour ◽  
Serine Threonine Kinase ◽  
Ww Domains ◽  
Threonine Kinase ◽  
Signalling Molecules ◽  
Kinase Cascade ◽  
Hippo Signalling

The Hippo signal transduction cascade controls cell growth, proliferation and death, all of which are frequently deregulated in tumour cells. Since initial studies in Drosophila melanogaster were instrumental in defining Hippo signalling, the machinery was named after the central Ste20-like kinase Hippo. Moreover, given that loss of Hippo signalling components Hippo, Warts, and Mats resulted in uncontrolled tissue overgrowth, Hippo signalling was defined as a tumour-suppressor cascade. Significantly, all of the core factors of Hippo signalling have mammalian orthologues that functionally compensate for loss of their counterparts in Drosophila. Furthermore, studies in Drosophila and mammalian cell systems showed that Hippo signalling represents a kinase cascade that is tightly regulated by PPIs (protein–protein interactions). Several Hippo signalling molecules contain SARAH (Salvador/RASSF1A/Hippo) domains that mediate specific PPIs, thereby influencing the activities of MST1/2 (mammalian Ste20-like serine/threonine kinase 1/2) kinases, the human Hippo orthologues. Moreover, WW domains are present in several Hippo factors, and these domains also serve as interaction surfaces for regulatory PPIs in Hippo signalling. Finally, the kinase activities of LATS1/2 (large tumour-suppressor kinase 1/2), the human counterparts of Warts, are controlled by binding to hMOB1 (human Mps one binder protein 1), the human Mats. Therefore Hippo signalling is regulated by PPIs on several levels. In the present paper, I review the current understanding of how these regulatory PPIs are regulated and contribute to the functionality of Hippo signalling.

Analysing protein–protein interactions of the Myxococcus xanthus Dif signalling pathway using the yeast two-hybrid system

Microbiology ◽  
2005 ◽  
Vol 151 (5) ◽  
pp. 1535-1541 ◽  
Author(s):  
Hope L. Lancero ◽  
Schryl Castaneda ◽  
Nora B. Caberoy ◽  
Xiaoyuan Ma ◽  
Anthony G. Garza ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Genomic Library ◽  
Myxococcus Xanthus ◽  
Signalling Pathway ◽  
Protein Protein Interactions ◽  
Yeast Two Hybrid ◽  
Fruiting Body Formation ◽  
New Information ◽  
Chemotaxis Proteins ◽  
Two Hybrid

The dif operon is essential for fruiting body formation, fibril (exopolysaccharide) production and social motility of Myxococcus xanthus. The dif locus contains a gene cluster homologous to chemotaxis genes such as mcp (difA), cheW (difC), cheY (difD), cheA (difE) and cheC (difF), as well as an unknown ORF called difB. This study used yeast two-hybrid analysis to investigate possible interactions between Dif proteins, and determined that DifA, C, D and E interact in a similar fashion to chemotaxis proteins of Escherichia coli and Bacillus subtilis. It also showed that DifF interacted with DifD, and that the novel protein DifB did not interact with Dif proteins. Furthermore, DifA–F proteins were used to determine other possible protein–protein interactions in the M. xanthus genomic library. The authors not only confirmed the specific interactions among known Dif proteins, but also discovered two novel interactions between DifE and Nla19, and DifB and YidC, providing some new information about the Dif signalling pathway. Based on these findings, a model for the Dif signalling pathway is proposed.

One Hippo and many masters: differential regulation of the Hippo pathway in cancer

2014 ◽  
Vol 42 (4) ◽  
pp. 816-821 ◽  
Author(s):  
David Romano ◽  
David Matallanas ◽  
Dennie T. Frederick ◽  
Keith T. Flaherty ◽  
Walter Kolch
Keyword(s):  
Protein Interactions ◽  
Hippo Pathway ◽  
Promoter Hypermethylation ◽  
Protein Protein Interactions ◽  
Evolutionarily Conserved ◽  
Or Gene ◽  
Phosphoinositide 3 Kinase ◽  
Ras Isoforms ◽  
The Hippo Pathway

The Hippo/MST2 (mammalian sterile 20-like kinase 2) pathway is a signalling cascade evolutionarily conserved in its structure. Originally described in Drosophila melanogaster as a regulator of organ size, this pathway has greater functions in mammals. Disturbance of mammalian MST2 pathway is associated with tumorigenesis by affecting apoptosis, cell cycle and polarity. In addition, this pathway has been shown to cross-talk with mitogenic pathways at multiple levels. In the present mini-review, we discuss our contribution highlighting the regulation of MST2 signalling by frequently observed oncogenic perturbations affecting mitogenic pathways. In particular, we review the role of RAS isoforms and PI3K (phosphoinositide 3-kinase)/Akt in the regulation of MST2 activity by phosphorylation. We also put the emphasis on RAF-induced control of MST2 signalling by protein–protein interactions. Finally, we recapitulate some of the direct mechanisms, such as ubiquitin-dependent degradation or gene silencing by promoter hypermethylation, involved in MST2 pathway component down-regulation in cancers.

scholarly journals Protein–protein interactions in intracellular Ca2+-release channel function

1999 ◽  
Vol 337 (3) ◽  
pp. 345-361 ◽  
Author(s):  
John J. MACKRILL
Keyword(s):  
Protein Interactions ◽  
Ryanodine Receptors ◽  
Accessory Proteins ◽  
Protein Protein Interactions ◽  
Release Channel ◽  
Specific Effects ◽  
Complex Protein ◽  
A Cell ◽  
And Function ◽  
Opposing Effects

Release of Ca2+ ions from intracellular stores can occur via two classes of Ca2+-release channel (CRC) protein, the inositol 1,4,5-trisphosphate receptors (InsP3Rs) and the ryanodine receptors (RyRs). Multiple isoforms and subtypes of each CRC class display distinct but overlapping distributions within mammalian tissues. InsP3Rs and RyRs interact with a plethora of accessory proteins which modulate the activity of their intrinsic channels. Although many aspects of CRC structure and function have been reviewed in recent years, the properties of proteins with which they interact has not been comprehensively surveyed, despite extensive current research on the roles of these modulators. The aim of this article is to review the regulation of CRC activity by accessory proteins and, wherever possible, to outline the structural details of such interactions. The CRCs are large transmembrane proteins, with the bulk of their structure located cytoplasmically. Intra- and inter-complex protein–protein interactions between these cytoplasmic domains also regulate CRC function. Some accessory proteins modulate channel activity of all CRC subtypes characterized, whereas other have class- or even isoform-specific effects. Certain accessory proteins exert both direct and indirect forms of regulation on CRCs, occasionally with opposing effects. Others are themselves modulated by changes in Ca2+ concentration, thereby participating in feedback mechanisms acting on InsP3R and RyR activity. CRCs are therefore capable of integrating numerous signalling events within a cell by virtue of such protein–protein interactions. Consequently, the functional properties of InsP3Rs and RyRs within particular cells and subcellular domains are ‘customized ’ by the accessory proteins present.

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