scholarly journals Complex Signaling Network in Regulation of Adenosine 5′-Phosphosulfate Reductase by Salt Stress in Arabidopsis Roots

2008 ◽  
Vol 146 (3) ◽  
pp. 1408-1420 ◽  
Author(s):  
Anna Koprivova ◽  
Kathryn Anne North ◽  
Stanislav Kopriva
Keyword(s):  
Salt Stress ◽  
Signaling Network ◽  
Complex Signaling

scholarly journals Parallel Tempering with Lasso for Model Reduction in Systems Biology

2019 ◽  
Author(s):  
Sanjana Gupta ◽  
Robin E.C. Lee ◽  
James R. Faeder
Keyword(s):  
Systems Biology ◽  
Model Reduction ◽  
Feedback Loops ◽  
Signaling Network ◽  
Parallel Tempering ◽  
Emergent Properties ◽  
Signaling Systems ◽  
Cellular Behaviors ◽  
Complex Signaling ◽  
The Bayesian Approach

AbstractSystems Biology models reveal relationships between signaling inputs and observable molecular or cellular behaviors. The complexity of these models, however, often obscures key elements that regulate emergent properties. We use a Bayesian model reduction approach that combines Parallel Tempering with Lasso regularization to identify minimal subsets of reactions in a signaling network that are sufficient to reproduce experimentally observed data. The Bayesian approach finds distinct reduced models that fit data equivalently. A variant of this approach based on Group Lasso is applied to the NF-κB signaling network to test the necessity of feedback loops for responses to pulsatile and continuous pathway stimulation. Taken together, our results demonstrate that Bayesian parameter estimation combined with regularization can isolate and reveal core motifs sufficient to explain data from complex signaling systems.

HER2: Biology, Detection, and Clinical Implications

2011 ◽  
Vol 135 (1) ◽  
pp. 55-62 ◽  
Author(s):  
Carolina Gutierrez ◽  
Rachel Schiff
Keyword(s):  
Breast Cancer ◽  
Tumor Development ◽  
Signaling Network ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Treatment Target ◽  
Valuable Treatment ◽  
Basic Biology ◽  
Her2 Signaling ◽  
Complex Signaling

Abstract Context—HER2 is a membrane tyrosine kinase and oncogene that is overexpressed and gene amplified in about 20% of breast cancers. When activated it provides the cell with potent proliferative and antiapoptosis signals and it is the major driver of tumor development and progression for this subset of breast cancer. When shown to be overexpressed or amplified by appropriate methods, HER2 is a valuable treatment target. Objectives—To review the basic biology of the HER2 signaling network, to discuss various approved methods for its detection in clinical specimens, and to describe the impressive results of therapies targeting HER2. Data Sources—Selected literature searchable on PubMed as well as older studies revealed by the literature review were reviewed. Conclusion—HER2 is an important member of a complex signaling network and when gene amplified, it results in an aggressive subtype of breast cancer. Patients with tumors found to overexpress HER2 protein or to be amplified for the gene are candidates for therapy that significantly reduces mortality.

scholarly journals A75 ON THE TRAIL OF ALTERNATIVE LIGANDS AND SIGNALING PATHWAYS FOR LGR5

2020 ◽  
Vol 3 (Supplement_1) ◽  
pp. 89-90
Author(s):  
S Dagenais Bellefeuille ◽  
G Arguin ◽  
F Gendron
Keyword(s):  
Signaling Network ◽  
Bioactive Molecules ◽  
Orphan Receptor ◽  
Hek293 Cells ◽  
Intestinal Lumen ◽  
Aberrant Expression ◽  
Alternative Pathways ◽  
Canonical Wnt ◽  
Complex Signaling ◽  
Stimulation Of

Abstract Background Leucine-rich G protein coupled receptor-5 (LGR5) is a GPCR originally identified as a marker for intestinal stem cells but is now associated to stemness in numerous other tissues. R-spondins (RSPO) are the only reported ligands of LGR5, which upon receptor binding, potentiates the canonical Wnt/b-catenin pathway. Surprisingly, despite the presence of classical GPCR features such as conserved DRY and NPXXY motifs RSPO binding to LGR5 does not induce classical GPCR behaviors such as coupling to heterotrimeric G-proteins or engagement of b-arrestins. For this reason, LGR5 is still considered to be an orphan receptor. Aims Aberrant expression of LGR5 is a common feature of many cancers, including gastrointestinal cancers, but it is still unclear why LGR5 is pro-tumorigenic in some cancers, while anti-tumorigenic in others. One potential explanation is that LGR5 does not only signals through the Wnt/b-catenin pathway, but also to alternative pathways. Thus, the goals of this study were 1), to elucidate LGR5 signaling networks and 2), to identify new LGR5 ligands and activity modulators. We suggested that the intestinal lumen content could be a source of bioactive molecules that could act as alternative LGR5 ligands Methods All experiments were performed on HEK293 cells expressing recombinant LGR5 (HEK293/LGR5) and compared to control cells expressing empty vector. Characterization of LGR5 signaling network was initiated with LC MS/MS spectrometric analyses using cells stimulated with Wnt3a and RSPO1. To identify new LGR5 modulators, commercially available bacteria-derived metabolites (BDM) were tested on HEK293/LGR5 cells stimulated with Wnt3a and RSPO1 and assessed using the TOP-Flash luciferase system. Finally, a mouse intestinal lumen extract (ILE) was investigated in whole-cell impedance assay to detect if it contained native BDM or potential host-derived LGR5 ligands. Results Mass spectrometric analyses revealed distinct protein expression and phosphorylation profiles in HEK293/LGR5 cells stimulated with Wnt3a and RSPO1. The TOP/Flash luciferase assays showed that the flavonoid derivative 3,4-dihydroxyphenylacetic acid (DOPAC) and lipopolysaccharide (LPS) acted as negative regulators of LGR5, while butyrate had no effect. Interestingly, stimulation of HEK293/LGR5 with ILE induced a Gαq-like response in the impedance assay, while control cells did not respond. Conclusions Stimulation of LGR5 with Wnt and RSPO triggered a complex signaling network. In agreement with our hypothesis, some BDM such as DOPAC and LPS were indeed activity modulators of LGR5. Moreover, a still unidentified compound present in the ILE triggered a selective GPCR-like response in HEK293/LGR5 cells. Future works aim at identifying this putative LGR5 ligand(s) and establish the LGR5 interactome using proximity labeling and mass spectrometry. Funding Agencies NSERC, Université de Sherbrooke, FRQS

scholarly journals Rho GTPase Signaling in Health and Disease: A Complex Signaling Network

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 401
Author(s):  
Cord Brakebusch
Keyword(s):  
G Proteins ◽  
Rho Gtpases ◽  
Rho Gtpase ◽  
Signaling Network ◽  
Ras Superfamily ◽  
Health And Disease ◽  
Complex Signaling ◽  
Small G Proteins

Rho GTPases are a family of small G-proteins of the Ras superfamily [...]

scholarly journals The FUR-like regulators PerRA and PerRB control a complex signaling network required for mammalian host-adaptation and virulence of Leptospira interrogans

2020 ◽  
Author(s):  
Andre A. Grassmann ◽  
Crispin Zavala-Alvarado ◽  
Everton Bettin ◽  
Mathieu Picardeau ◽  
Nadia Benaroudj ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
Double Mutant ◽  
Signaling Network ◽  
Leptospira Interrogans ◽  
Gene Products ◽  
Environmental Sensing ◽  
Human Leptospirosis ◽  
Multiple Genes ◽  
Complex Signaling

AbstractLeptospira interrogans, the causative agent of most cases of human leptospirosis, must respond to myriad environmental signals during its free-living and pathogenic lifestyles. Previously, we compared L. interrogans cultivated in vitro and in vivo using a dialysis membrane chamber (DMC) peritoneal implant model. From these studies emerged 166 genes that were differentially regulated in response to host signals, including perRA, one of two Peroxide stress response (PerR)-like regulators encoded by L. interrogans. Zavala-Alvarado et al. recently demonstrated that leptospires lacking both PerRA and PerRB are avirulent in hamsters. Herein, we establish that PerRA and PerRB also are required for renal colonization in C3H/HeJ mice. The finding that loss of virulence was observed only with the perRA/B double mutant suggests that these regulators serve redundant or overlapping functions in vivo. Our finding that the perRA/B double mutant survives at wild-type levels in DMCs is noteworthy as it demonstrates that the loss of virulence is not due to a metabolic lesion (i.e., metal starvation) but instead reflects dysregulation of virulence-related gene products. Comparative RNA-Seq analyses of perRA, perRB and perRA/B mutants cultivated within DMCs identified 106 genes that are dysregulated in the double mutant, including ligA, ligB and lvrA/B sensory histidine kinases. Decreased expression of LigA and LigB in the perRA/B mutant was not due to loss of LvrAB signal transduction. The majority of genes in the perRA and perRB single and double mutant DMC regulons were differentially expressed only in vivo, highlighting the importance of host-specific signals for regulating gene expression in L. interrogans. Importantly, the PerRA, PerRB and PerRA/B DMC regulons each contain multiple genes related to environmental sensing and/or transcriptional regulation. Collectively, our data suggest that PerRA and PerRB are part of a complex signaling network required by L. interrogans for adaptation to and survival within the host.Author SummaryLeptospirosis is a neglected tropical disease with a worldwide distribution. Globally, ∼1 million cases and ∼60,000 deaths are reported each year. The majority of cases of human leptospirosis are associated with Leptospira interrogans. Infection begins when a naïve reservoir (or incidental) host comes into direct or indirect contact with urine from an infected reservoir host. While infection in reservoir hosts, including rats and mice, is generally asymptomatic, incidental hosts, including humans, may develop clinical symptoms ranging from mild flu-like illness to fulminant disease. The gene products required by leptospires for infection remain poorly understood. Herein, we establish that the FUR family regulators PerRA and PerRB function either cooperatively or in parallel to promote survival and renal colonization in mice. By comparative transcriptomics, we identified >100 genes that were dysregulated in the perRA/B double mutant in vivo, including four virulence-related genes. Importantly, the PerRA, PerRB and PerRA/B DMC regulons contain multiple genes related to environmental sensing and/or transcriptional regulation. Our data suggest that PerRA and PerRB are part of a complex signaling network required by L. interrogans for adaptation to and survival within the host.

scholarly journals Modulation of insulin-like growth factor-1 receptor and its signaling network for the treatment of cancer: current status and future perspectives

2013 ◽  
pp. e3
Author(s):  
Meizhong Jin ◽  
Elizabeth Buck ◽  
Mark J. Mulvihill
Keyword(s):  
Clinical Trials ◽  
Monoclonal Antibodies ◽  
Growth Factor ◽  
Growth Factor Receptor ◽  
Signaling Network ◽  
Current Status ◽  
Insulin Like Growth Factor ◽  
Signaling Mechanisms ◽  
Epidermal Growth ◽  
Complex Signaling

Based on over three decades of pre-clinical data, insulin-like growth factor-1 receptor (IGF-1R) signaling has gained recognition as a promoter of tumorogenesis, driving cell survival and proliferation in multiple human cancers. As a result, IGF-1R has been pursued as a target for cancer treatment. Early pioneering efforts targeting IGF-1R focused on highly selective monoclonal antibodies, with multiple agents advancing to clinical trials. However, despite some initial promising results, recent clinical disclosures have been less encouraging. Moreover, recent studies have revealed that IGF-1R participates in a dynamic and complex signaling network, interacting with additional targets and pathways thereof through various crosstalk and compensatory signaling mechanisms. Such mechanisms of bypass signaling help to shed some light on the decreased effectiveness of selective IGF- 1R targeted therapies (e.g. monoclonal antibodies) and suggest that targeting multiple nodes within this signaling network might be necessary to produce a more effective therapeutic response. Additionally, such findings have led to the development of small molecule IGF-1R inhibitors which also co-inhibit additional targets such as insulin receptor and epidermal growth factor receptor. Such findings have helped to guide the design rationale of numerous drug combinations that are currently being evaluated in clinical trials.

Role of the Go/i signaling network in the regulation of neurite outgrowthThis paper is one of a selection of papers published in this Special issue, entitled Second Messengers and Phosphoproteins—12th International Conference.

2006 ◽  
Vol 84 (7) ◽  
pp. 687-694 ◽  
Author(s):  
John Cijiang He ◽  
Susana R. Neves ◽  
J. Dedrick Jordan ◽  
Ravi Iyengar
Keyword(s):  
Neurite Outgrowth ◽  
Cannabinoid Receptor ◽  
Second Messengers ◽  
Signaling Network ◽  
Neuronal Growth ◽  
Alternative Pathways ◽  
Cb1 Cannabinoid Receptor ◽  
Neuro2a Cells ◽  
Complex Signaling ◽  
Rap1 Activation

Neurite outgrowth is a complex differentiation process stimulated by many neuronal growth factors and transmitters and by electrical activity. Among these stimuli are ligands for G-protein-coupled receptors (GPCR) that function as neurotransmitters. The pathways involved in GPCR-triggered neurite outgrowth are not fully understood. Many of these receptors couple to Gαo, one of the most abundant proteins in the neuronal growth cones. We have studied the Go signaling network involved in neurite outgrowth in Neuro2A cells. Gαo can induce neurite outgrowth. The CB1 cannabinoid receptor, a Go/i-coupled receptor expressed endogenously in Neuro2A cells, triggers neurite outgrowth by activating Rap1, which promotes the Gαo-stimulated proteasomal degradation of Rap1GAPII. CB1-receptor-mediated Rap1 activation leads to the activation of a signaling network that includes the small guanosine triphosphate (GTP)ases Ral and Rac, the protein kinases Src, and c-Jun N-terminal kinase (JNK), which converge onto the activation of signal transducer and activator of transcription 3 (Stat3), a key transcription factor that mediates the gene expression process of neurite outgrowth in Neuro2A cells. This review describes current findings from our laboratory and also discusses alternative pathways that Go/i might mediate to trigger neurite outgrowth. We also analyze the role neurotransmitters, which stimulate Go/i to activate a complex signaling network controlling neurite outgrowth, play in regeneration after neuronal injury.

scholarly journals Understanding the Plant Immune System

2010 ◽  
Vol 23 (12) ◽  
pp. 1531-1536 ◽  
Author(s):  
Fumiaki Katagiri ◽  
Kenichi Tsuda
Keyword(s):  
Plant Immunity ◽  
Signaling Network ◽  
Immune Network ◽  
Plant Fitness ◽  
Wild Type ◽  
Signaling Mechanisms ◽  
Negative Effect ◽  
Key Driver ◽  
Complex Signaling ◽  
Plant Mutant

Plant immunity is controlled by a complex signaling network. Here, we discuss how the complexity of the network affects our views and approaches in studying the plant immune network. We propose that the mode of plant immunity is mainly determined by how the shared signaling network is used rather than by a signaling machinery specific to each mode, that balancing the robustness of immunity and the negative effect of immunity on plant fitness is a key driver in evolution of the immune network, that comparisons of plant mutant to wild-type phenotypes may not be very effective in elucidating the underlying signaling mechanisms, and that mechanistic understanding of the network can improve our ability to predict the performance of immunity.

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