scholarly journals The Interaction Network and Signaling Specificity of Two-Component System in Arabidopsis

2020 ◽  
Vol 21 (14) ◽  
pp. 4898
Author(s):  
Ruxue Huo ◽  
Zhenning Liu ◽  
Xiaolin Yu ◽  
Zongyun Li
Keyword(s):  
Signal Transduction ◽  
Molecular Mechanisms ◽  
Interaction Network ◽  
Response Regulators ◽  
Signaling Specificity ◽  
Protein Protein Interaction ◽  
Protein Levels ◽  
Two Component ◽  
Model Plant Arabidopsis Thaliana ◽  
External Signals

Two-component systems (TCS) in plants have evolved into a more complicated multi-step phosphorelay (MSP) pathway, which employs histidine kinases (HKs), histidine-containing phosphotransfer proteins (HPts), and response regulators (RRs) to regulate various aspects of plant growth and development. How plants perceive the external signals, then integrate and transduce the secondary signals specifically to the desired destination, is a fundamental characteristic of the MSP signaling network. The TCS elements involved in the MSP pathway and molecular mechanisms of signal transduction have been best understood in the model plant Arabidopsis thaliana. In this review, we focus on updated knowledge on TCS signal transduction in Arabidopsis. We first present a brief description of the TCS elements; then, the protein–protein interaction network is established. Finally, we discuss the possible molecular mechanisms involved in the specificity of the MSP signaling at the mRNA and protein levels.

scholarly journals FixJ family regulator AcfR of Azorhizobium caulinodans is involved in symbiosis with the host plant

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Wei Liu ◽  
Xue Bai ◽  
Yan Li ◽  
Haikun Zhang ◽  
Xiaoke Hu
Keyword(s):  
Signal Transduction ◽  
Host Plant ◽  
Type Strain ◽  
Wild Type Strain ◽  
Response Regulator ◽  
Azorhizobium Caulinodans ◽  
Wild Type ◽  
Response Regulators ◽  
Free Living ◽  
Two Component

Abstract Background A wide variety of bacterial adaptative responses to environmental conditions are mediated by signal transduction pathways. Two-component signal transduction systems are one of the predominant means used by bacteria to sense the signals of the host plant and adjust their interaction behaviour. A total of seven open reading frames have been identified as putative two-component response regulators in the gram-negative nitrogen-fixing bacteria Azorhizobium caulinodans ORS571. However, the biological functions of these response regulators in the symbiotic interactions between A. caulinodans ORS571 and the host plant Sesbania rostrata have not been elucidated to date. Results In this study, we identified and investigated a two-component response regulator, AcfR, with a phosphorylatable N-terminal REC (receiver) domain and a C-terminal HTH (helix-turn-helix) LuxR DNA-binding domain in A. caulinodans ORS571. Phylogenetic analysis showed that AcfR possessed close evolutionary relationships with NarL/FixJ family regulators. In addition, six histidine kinases containing HATPase_c and HisKA domains were predicted to interact with AcfR. Furthermore, the biological function of AcfR in free-living and symbiotic conditions was elucidated by comparing the wild-type strain and the ΔacfR mutant strain. In the free-living state, the cell motility behaviour and exopolysaccharide production of the ΔacfR mutant were significantly reduced compared to those of the wild-type strain. In the symbiotic state, the ΔacfR mutant showed a competitive nodule defect on the stems and roots of the host plant, suggesting that AcfR can provide A. caulinodans with an effective competitive ability for symbiotic nodulation. Conclusions Our results showed that AcfR, as a response regulator, regulates numerous phenotypes of A. caulinodans under the free-living conditions and in symbiosis with the host plant. The results of this study help to elucidate the involvement of a REC + HTH_LuxR two-component response regulator in the Rhizobium-host plant interaction.

Histidine kinases in signal transduction pathways of eukaryotes

1997 ◽  
Vol 110 (10) ◽  
pp. 1141-1145 ◽  
Author(s):  
W.F. Loomis ◽  
G. Shaulsky ◽  
N. Wang
Keyword(s):  
Signal Transduction ◽  
Response Regulator ◽  
Signal Transduction Pathways ◽  
Response Regulators ◽  
Histidine Kinases ◽  
Camp Phosphodiesterase ◽  
Wide Range ◽  
Two Component ◽  
Two Component Signal Transduction ◽  
Dependent Protein

Autophosphorylating histidine kinases are an ancient conserved family of enzymes that are found in eubacteria, archaebacteria and eukaryotes. They are activated by a wide range of extracellular signals and transfer phosphate moieties to aspartates found in response regulators. Recent studies have shown that such two-component signal transduction pathways mediate osmoregulation in Saccharomyces cerevisiae, Dictyostelium discoideum and Neurospora crassa. Moreover, they play pivotal roles in responses of Arabidopsis thaliana to ethylene and cytokinin. A transmembrane histidine kinase encoded by dhkA accumulates when Dictyostelium cells aggregate during development. Activation of DhkA results in the inhibition of its response regulator, RegA, which is a cAMP phosphodiesterase that regulates the cAMP dependent protein kinase PKA. When PKA is activated late in the differentiation of prespore cells, they encapsulate into spores. There is evidence that this two-component system participates in a feedback loop linked to PKA in prestalk cells such that the signal to initiate encapsulation is rapidly amplified. Such signal transduction pathways can be expected to be found in a variety of eukaryotic differentiations since they are rapidly reversible and can integrate disparate signals.

scholarly journals Gene Prioritization through Consensus Strategy, Enrichment Methodologies Analysis, and Networking for Osteosarcoma Pathogenesis

2020 ◽  
Vol 21 (3) ◽  
pp. 1053 ◽  
Author(s):  
Alejandro Cabrera-Andrade ◽  
Andrés López-Cortés ◽  
Gabriela Jaramillo-Koupermann ◽  
César Paz-y-Miño ◽  
Yunierkis Pérez-Castillo ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Bone Cancer ◽  
Interaction Network ◽  
Enrichment Analysis ◽  
Protein Protein Interaction ◽  
Pathogenic Genes ◽  
Total List ◽  
Consensus Strategy ◽  
Primary Bone ◽  
Molecular Etiology

Osteosarcoma is the most common subtype of primary bone cancer, affecting mostly adolescents. In recent years, several studies have focused on elucidating the molecular mechanisms of this sarcoma; however, its molecular etiology has still not been determined with precision. Therefore, we applied a consensus strategy with the use of several bioinformatics tools to prioritize genes involved in its pathogenesis. Subsequently, we assessed the physical interactions of the previously selected genes and applied a communality analysis to this protein–protein interaction network. The consensus strategy prioritized a total list of 553 genes. Our enrichment analysis validates several studies that describe the signaling pathways PI3K/AKT and MAPK/ERK as pathogenic. The gene ontology described TP53 as a principal signal transducer that chiefly mediates processes associated with cell cycle and DNA damage response It is interesting to note that the communality analysis clusters several members involved in metastasis events, such as MMP2 and MMP9, and genes associated with DNA repair complexes, like ATM, ATR, CHEK1, and RAD51. In this study, we have identified well-known pathogenic genes for osteosarcoma and prioritized genes that need to be further explored.

scholarly journals A Network Pharmacology Approach to Uncover the Mechanisms of Shen-Qi-Di-Huang Decoction against Diabetic Nephropathy

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Sha Di ◽  
Lin Han ◽  
Qing Wang ◽  
Xinkui Liu ◽  
Yingying Yang ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Interaction Network ◽  
Enrichment Analysis ◽  
Network Pharmacology ◽  
Pathway Enrichment Analysis ◽  
Protein Protein Interaction ◽  
Regulation Of Blood Pressure ◽  
Protein Protein Interaction Network

Shen-Qi-Di-Huang decoction (SQDHD), a well-known herbal formula from China, has been widely used in the treatment of diabetic nephropathy (DN). However, the pharmacological mechanisms of SQDHD have not been entirely elucidated. At first, we conducted a comprehensive literature search to identify the active constituents of SQDHD, determined their corresponding targets, and obtained known DN targets from several databases. A protein-protein interaction network was then built to explore the complex relations between SQDHD targets and those known to treat DN. Following the topological feature screening of each node in the network, 400 major targets of SQDHD were obtained. The pathway enrichment analysis results acquired from DAVID showed that the significant bioprocesses and pathways include oxidative stress, response to glucose, regulation of blood pressure, regulation of cell proliferation, cytokine-mediated signaling pathway, and the apoptotic signaling pathway. More interestingly, five key targets of SQDHD, named AKT1, AR, CTNNB1, EGFR, and ESR1, were significant in the regulation of the above bioprocesses and pathways. This study partially verified and predicted the pharmacological and molecular mechanisms of SQDHD on DN from a holistic perspective. This has laid the foundation for further experimental research and has expanded the rational application of SQDHD in clinical practice.

Effects of a Leukemia-Associated Gain-of-Function Mutation of SHP-2 Phosphatase on IL-3 Signaling.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2285-2285
Author(s):  
Wen-Mei Yu ◽  
Hanako Daino ◽  
Jing Chen ◽  
Kevin D. Bunting ◽  
Cheng-Kui Qu
Keyword(s):  
Signal Transduction ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Adaptor Proteins ◽  
Pi3 Kinase ◽  
Juvenile Myelomonocytic Leukemia ◽  
Myeloproliferative Disease ◽  
Gain Of Function ◽  
Protein Protein Interaction ◽  
Myeloid Progenitor Cells

Abstract Mutations in SHP-2 phosphatase that cause its hyper-activation have been identified in human leukemias, in particular, juvenile myelomonocytic leukemia (JMML) that is characterized by hypersensitivity of myeloid progenitor cells to granulocyte macrophage colony-stimulating factor and interleukin (IL)-3. However, the molecular mechanisms by which gain-of-function (GOF) mutations of SHP-2 induce leukemia are not fully understood. Our previous studies have shown that SHP-2 plays an essential role in IL-3 signal transduction in catalytic-dependent and -independent manners and that overexpression (5-to-6 fold) of wild-type (WT) SHP-2 attenuates IL-3-mediated hematopoietic cell function through dephosphorylation of STAT5. This raised the possibility that SHP-2-associated JMML was not solely attributed to the increased catalytic activities of SHP-2 GOF mutants. The SHP-2 mutants must have gained other additional functions. To test this possibility, we investigated effects of a GOF mutation (E76K, the most frequent SHP-2 mutation seen in JMML) of SHP-2 on IL-3 signal transduction in great detail by comparing signaling activities of SHP-2 E76K to WT SHP-2. Our results showed that SHP-2 E76K mutation caused myeloproliferative disease in mice, while overexpression of WT SHP-2 decreased hematopoietic potential of the transduced cells in recipient animals. E76K mutation in the N-terminal Src homology 2 domain significantly increased binding of the mutant SHP-2 to Grb2 and Gab2, two adaptor proteins coupling downstream Erk and PI3 kinase pathways to the proximity of the IL-3 receptor. As a result, IL-3-induced Erk and PI3 kinase pathways were highly activated by SHP-2 E76K mutation. In addition, Jak2 kinase activation was also markedly enhanced and due to the E76K mutation the substrate specificity of SHP-2 toward STAT5 was changed. Dephosphorylation of STAT5 by SHP-2 E76K was alleviated. These studies suggest that in addition to elevated catalytic activity, profound changes in protein-protein interaction capacities of GOF mutant SHP-2 play an important role in the pathogenesis of SHP-2-related leukemias.

scholarly journals The molecular mechanisms associated with PIN7, a protein-protein interaction network of seven pleiotropic proteins

2019 ◽  
Author(s):  
Jarmila Nahálková
Keyword(s):  
Signaling Pathway ◽  
Protein Interaction ◽  
Protein Interaction Network ◽  
Molecular Mechanisms ◽  
Interaction Network ◽  
Protein Protein Interaction ◽  
P53 Signaling ◽  
Age Related ◽  
P53 Signaling Pathway ◽  
Protein Protein Interaction Network

The protein-protein interaction network of seven pleiotropic proteins (PIN7) contains proteins with multiple functions in the aging and age-related diseases (TPPII, CDK2, MYBBP1A, p53, SIRT6, SIRT7, and BSG). At the present work, the pathway enrichment, the gene function prediction and the protein node prioritization analysis were applied for the examination of main molecular mechanisms driving PIN7 and the extended network. Seven proteins of PIN7 were used as an input for the analysis by GeneMania, a Cytoscape application, which constructs the protein interaction network. The software also extends it using the interactions retrieved from databases of experimental and predicted protein-protein and genetic interactions. The analysis identified the p53 signaling pathway as the most dominant mediator of PIN7. The extended PIN7 was also analyzed by Cytohubba application, which showed that the top-ranked protein nodes belong to the group of histone acetyltransferases and histone deacetylases. These enzymes are involved in the reverse epigenetic regulation mechanisms linked to the regulation of PTK2, NFκB, and p53 signaling interaction subnetworks of the extended PIN7. The analysis emphasized the role of PTK2 signaling, which functions upstream of the p53 signaling pathway and its interaction network includes all members of the sirtuin family. Further, the analysis suggested the involvement of molecular mechanisms related to metastatic cancer (prostate cancer, small cell lung cancer), hemostasis, the regulation of the thyroid hormones and the cell cycle G1/S checkpoint. The additional data-mining analysis showed that the small protein interaction network MYBBP1A-p53-TPPII-SIRT6-CD147 controls Warburg effect and MYBBP1A-p53-TPPII-SIRT7-BSG influences mTOR signaling and autophagy. Further investigations of the detail mechanisms of these interaction networks would be beneficial for the development of novel treatments for aging and age-related diseases.

scholarly journals Integrating protein networks and machine learning for disease stratification in the Hereditary Spastic Paraplegias

2021 ◽  
Author(s):  
Nikoleta Vavouraki ◽  
James E. Tomkins ◽  
Eleanna Kara ◽  
Henry Houlden ◽  
John Hardy ◽  
...  
Keyword(s):  
Machine Learning ◽  
Protein Interaction ◽  
Protein Interaction Network ◽  
Molecular Mechanisms ◽  
Topological Analysis ◽  
Interaction Network ◽  
Protein Protein Interaction ◽  
Hereditary Spastic Paraplegias ◽  
Core Proteins ◽  
Protein Protein Interaction Network

AbstractThe Hereditary Spastic Paraplegias are a group of neurodegenerative diseases characterized by spasticity and weakness in the lower body. Despite the identification of causative mutations in over 70 genes, the molecular aetiology remains unclear. Due to the combination of genetic diversity and variable clinical presentation, the Hereditary Spastic Paraplegias are a strong candidate for protein-protein interaction network analysis as a tool to understand disease mechanism(s) and to aid functional stratification of phenotypes. In this study, experimentally validated human protein-protein interactions were used to create a protein-protein interaction network based on the causative Hereditary Spastic Paraplegia genes. Network evaluation as a combination of both topological analysis and functional annotation led to the identification of core proteins in putative shared biological processes such as intracellular transport and vesicle trafficking. The application of machine learning techniques suggested a functional dichotomy linked with distinct sets of clinical presentations, suggesting there is scope to further classify conditions currently described under the same umbrella term of Hereditary Spastic Paraplegias based on specific molecular mechanisms of disease.

scholarly journals Comparison of the central human and mouse platelet signaling cascade by systems biological analysis

2020 ◽  
Author(s):  
Johannes Balkenhol ◽  
Kristin V. Kaltdorf ◽  
Elmina Mammadova-Bach ◽  
Attila Braun ◽  
Bernhard Nieswandt ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Interaction Network ◽  
Human Platelets ◽  
Fine Tuning ◽  
Protein Levels ◽  
Platelet Protein ◽  
Thrombosis Research ◽  
Platelet Signaling ◽  
Species Specific ◽  
Human And Mouse

Abstract Background Understanding the molecular mechanisms of platelet activation and aggregation is of high interest for basic and clinical hemostasis and thrombosis research. The central platelet protein interaction network is involved in major responses to exogenous factors. This is defined by systemsbiological pathway analysis as the central regulating signaling cascade of platelets (CC). Results The CC is systematically compared here between mouse and human and major differences were found. Genetic differences were analysed comparing orthologous human and mouse genes. We next analyzed different expression levels of mRNAs. Considering 4 mouse and 7 human high quality proteome data sets, we identified then those major mRNA expression differences (81%) which were supported by proteome data. CC is conserved regarding genetic completeness, but we observed major differences in mRNA and protein levels between both species. Looking at central interactors, human PLCB2, MMP9, BDNF, ITPR3 and SLC25A6 (always uniprot notation) show absence in all murine datasets. CC interactors GNG12, PRKCE and ADCY9 occur only in mice. Looking at the common proteins, TLN1, CALM3, PRKCB, APP, SOD2 and TIMP1 are higher abundant in human, whereas RASGRP2, ITGB2, MYL9, EIF4EBP1, ADAM17, ARRB2, CD9 and ZYX are higher abundant in mouse. Pivotal kinase SRC shows different regulation on mRNA and protein level as well as ADP receptor P2RY12. Conclusions Our results highlight species-specific differences in platelet signaling and points of specific fine-tuning in human platelets as well as murine-specific signalling differences.

scholarly journals Insights into Molecular Mechanisms Underlying NAFLD by Protein-Protein Interaction Network Analysis of the Differentially Expressed Genes in NASH Patients.

2021 ◽  
Author(s):  
Aida Najari ◽  
Aminiyanfar Masoud ◽  
Mobasheri Meysam ◽  
Tabassom Sobati
Keyword(s):  
Systems Biology ◽  
Disease Progression ◽  
Molecular Mechanisms ◽  
Interaction Network ◽  
Central Place ◽  
Hub Genes ◽  
Alcoholic Fatty Liver ◽  
Efficient Treatment ◽  
Protein Protein Interaction ◽  
Holistic Approaches

Abstract The efficient treatment of the disease such as non-alcoholic fatty liver disease as a global concern is impeded by the limited understanding of the disease complexity. We applied a systems-biology framework for a functional analysis of disease development using candidate genes. We identified, the keys dysregulation, pathways, and Hub-genes leading the disease. Moreover, we constructed a molecular disease network for the disease via integrating the pathways, providing an intuitional view to understand the development. In addition, the druggability of genes and their new application in terms of marker discovery or new drug discovery were examined. Our analyses identify a series of highly overexpressed genes, also featuring high centrality, yet being less underlined in the context of NAFLD development in the previous research. We also found several relatively low overexpressed genes, having a central place in the PPI network topology, whose potential involvement in non-alcoholic steatohepatitis might be undermined otherwise using network biology. Our results reveal that the biological processes related to disease progression are complex. Indeed, our pathway studies identified Hub genes, which may reinforce poly-pharmacological cross-talks followed by disease progression to irreversible stages holistic approaches via systems biology tools help us identify more reliable targets and disease-mediated genes integrated into translational studies and drug development in this area.

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