scholarly journals Arrestin-3 scaffolding of the JNK3 cascade suggests a mechanism for signal amplification

2018 ◽  
Vol 116 (3) ◽  
pp. 810-815 ◽  
Author(s):  
Nicole A. Perry ◽  
Tamer S. Kaoud ◽  
Oscar O. Ortega ◽  
Ali I. Kaya ◽  
David J. Marcus ◽  
...  
Keyword(s):  
Bayesian Inference ◽  
Signal Amplification ◽  
Conveyor Belt ◽  
Computational Approach ◽  
Scaffold Proteins ◽  
Signaling Cascade ◽  
Signaling Proteins ◽  
Catalytic Phosphorylation ◽  
Upstream Kinase ◽  
Phosphorylation Rate

Scaffold proteins tether and orient components of a signaling cascade to facilitate signaling. Although much is known about how scaffolds colocalize signaling proteins, it is unclear whether scaffolds promote signal amplification. Here, we used arrestin-3, a scaffold of the ASK1-MKK4/7-JNK3 cascade, as a model to understand signal amplification by a scaffold protein. We found that arrestin-3 exhibited >15-fold higher affinity for inactive JNK3 than for active JNK3, and this change involved a shift in the binding site following JNK3 activation. We used systems biochemistry modeling and Bayesian inference to evaluate how the activation of upstream kinases contributed to JNK3 phosphorylation. Our combined experimental and computational approach suggested that the catalytic phosphorylation rate of JNK3 at Thr-221 by MKK7 is two orders of magnitude faster than the corresponding phosphorylation of Tyr-223 by MKK4 with or without arrestin-3. Finally, we showed that the release of activated JNK3 was critical for signal amplification. Collectively, our data suggest a “conveyor belt” mechanism for signal amplification by scaffold proteins. This mechanism informs on a long-standing mystery for how few upstream kinase molecules activate numerous downstream kinases to amplify signaling.

scholarly journals Increasing the time resolution of single-molecule experiments with Bayesian inference

2017 ◽  
Author(s):  
Colin D. Kinz-Thompson ◽  
Ruben L. Gonzalez
Keyword(s):  
Bayesian Inference ◽  
Single Molecule ◽  
Time Resolution ◽  
Rate Constants ◽  
Computational Approach ◽  
Biomolecular Systems ◽  
Time Resolved ◽  
The Given ◽  
Kinetics Of ◽  
Resolution Data

AbstractMany time-resolved, single-molecule biophysics experiments seek to characterize the kinetics of biomolecular systems exhibiting dynamics that challenge the time resolution of the given technique. Here we present a general, computational approach to this problem that employs Bayesian inference to learn the underlying dynamics of such systems, even when they are much faster than the time resolution of the experimental technique being used. By accurately and precisely inferring rate constants, our Bayesian Inference for the Analysis of Sub-temporal-resolution Data (BIASD) approach effectively enables the experimenter to super-resolve the poorly resolved dynamics that are present in their data.

Abstract 438: Hydrogen Sulfide Promotes Mitochondrial Biogenesis Through the Regulation of AMP-activated Protein Kinase

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Yuuki Shimizu ◽  
Rohini Polavarapu ◽  
John Calvert
Keyword(s):  
Hydrogen Sulfide ◽  
Mitochondrial Biogenesis ◽  
Target Genes ◽  
Nuclear Dna ◽  
Citrate Synthase ◽  
Serine Phosphorylation ◽  
Signaling Cascade ◽  
Disease States ◽  
Upstream Kinase ◽  
High Concentrations

Background: Hydrogen sulfide (H 2 S) possesses numerous cellular actions that account for its cardioprotective effects. A mechanism of particular interest is its effects on the mitochondria. At low concentrations, H 2 S donates electrons to the electron transport chain, whereas at high concentrations it inhibits mitochondrial respiration. H 2 S therapy improves mitochondrial function and prevents the loss of mitochondria following the onset of myocardial ischemia. However, it is not known if these improvements are associated with simply a reduction in injury or if mitochondrial biogenesis is involved. Therefore, the purpose of this study was to determine if H 2 S regulates/induces mitochondrial biogenesis in the heart. Methods and Results: C57BL/6J mice (8 weeks of age) were given an orally active H 2 S donor (SG-1002; 20 mg/kg/day) in their chow for 4 weeks. For these studies we focused our analysis on an AMPK-PGC1α signaling cascade. SG-1002 significantly increased the phosphorylation of AMPK, the serine phosphorylation of PGC1α, and increased the nuclear localization of PGC1α. This was associated with an increase in the gene expression of PGC1α target genes associated with mitochondrial biogenesis, an increase in mitochondrial to nuclear DNA ratios and an increase in citrate synthase activity. SG-1002 failed to elicit these changes in AMPK deficient mice. Therefore, we sought to determine how SG-1002 activated AMPK. SG-1002 did not alter the phosphorylation of LKB1, an upstream kinase of AMPK, and did not alter the levels of AMP (activator of AMPK). SG-1002 did not alter the expression of protein phosphatase 2A (PP2A; dephosphorylates AMPK), but it did significantly decrease the activity of PP2A). This decrease was accompanied by an increase in the sulfhydration of PP2A, suggesting that this modification is inhibitory. Conclusion: These data suggest that H 2 S augments mitochondrial biogenesis in the heart via an AMPK-PGC1α signaling cascade. This is important because mitochondrial abnormalities are associated with a number of disease states (diabetes and heart failure) where H 2 S levels are decreased. Therefore, strategies aimed at increasing H 2 S levels could potentially induce the generation of new, healthy mitochondria.

scholarly journals Interaction of Alzheimer's β-Amyloid Precursor Family Proteins with Scaffold Proteins of the JNK Signaling Cascade

2002 ◽  
Vol 277 (22) ◽  
pp. 20070-20078 ◽  
Author(s):  
Hidenori Taru ◽  
Ko-ichi Iijima ◽  
Momoko Hase ◽  
Yutaka Kirino ◽  
Yoshimasa Yagi ◽  
...  
Keyword(s):  
Scaffold Proteins ◽  
Signaling Cascade ◽  
Jnk Signaling ◽  
Β Amyloid

Regulation of stress-associated scaffold proteins JIP1 and JIP3 on the c-Jun NH2-terminal kinase in ischemia–reperfusion

2010 ◽  
Vol 88 (11) ◽  
pp. 1084-1092 ◽  
Author(s):  
Bing Xu ◽  
Yaling Zhou ◽  
Karmin O ◽  
Patrick C. Choy ◽  
Grant N. Pierce ◽  
...  
Keyword(s):  
Protein Expression ◽  
Cell Model ◽  
Ischemia Reperfusion ◽  
Scaffold Proteins ◽  
Signaling Cascade ◽  
Interacting Proteins ◽  
H9c2 Cells ◽  
Signaling Specificity ◽  
Sirna Treatment ◽  
A Cell

Ischemia–reperfusion (IR)-induced cell apoptosis involves the activation of c-Jun NH2-terminal kinase (JNK). The activation of JNK requires the presence of scaffold proteins called JNK-interacting proteins (JIP), which bind several members of a signaling cascade for proper signaling specificity. In this study, the expression of scaffold proteins JIP1 and JIP3 and their roles in the regulation of JNK activity were investigated in simulated IR in a cell model (H9c2). JIP1 protein expression was significantly decreased, whereas JIP3 protein expression was increased in IR H9c2 cells. Adenovirus-induced overexpression of JIP1 reduced IR-induced JNK activity and apoptosis. Conversely, overexpression of JIP3 increased JNK activity and apoptosis following IR. Depletion of endogenous JIP1 by siRNA treatment increased the IR-induced JNK activity, whereas siRNA-mediated depletion of endogenous JIP3 inhibited JNK activity. These results suggest that JIP1 and JIP3 play important roles in the activation of JNK during simulated IR challenge in H9c2 cells.

Amplification systems of weak interaction biosensors: applications and prospects

Sensor Review ◽  
2015 ◽  
Vol 35 (1) ◽  
pp. 30-42 ◽  
Author(s):  
Xingya Wang ◽  
Guangchang Pang
Keyword(s):  
G Protein ◽  
Weak Interaction ◽  
Signal Amplification ◽  
Signaling Cascade ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
Content Type ◽  
Amplification Method ◽  
Amplification System ◽  
Cascade Amplification

Purpose – This paper aims to provide a detailed review of weak interaction biosensors and several common biosensor methods for magnifying signals, as well as judiciously guide readers through selecting an appropriate detecting system and signal amplification method according to their research and application purpose. Design/methodology/approach – This paper classifies the weak interactions between biomolecules, summarizes the common signal amplification methods used in biosensor design and compares the performance of different kinds of biosensors. It highlights a potential electrochemical signal amplification method: the G protein signaling cascade amplification system. Findings – Developed biosensors which, based on various principles, have their own strengths and weaknesses have met the basic detection requirements for weak interaction between biomolecules: the selectivity, sensitivity and detection limit of biosensors have been consistently improving with the use of new signal amplification methods. However, most of the weak interaction biosensors stop at the research stage; there are only a minority realization of final commercial application. Originality/value – This paper evaluates the status of research and application of weak interaction biosensors systematically. The G protein signaling cascade amplification system proposal offers a new avenue for the research and development of electrochemical biosensors.

Redistribution of Signaling Proteins within Lipid Rafts and Cross-Talk to the Insulin Signaling Cascade by the Antidiabetic Drug Glimepiride

2004 ◽  
Vol 2004 (Fall) ◽  
Author(s):  
G�nter M�ller ◽  
Susanne Wied ◽  
Christian Jung ◽  
Andrea Schulz ◽  
Norbert Tennagels ◽  
...  
Keyword(s):  
Lipid Rafts ◽  
Cross Talk ◽  
Insulin Signaling ◽  
Signaling Cascade ◽  
Signaling Proteins ◽  
Antidiabetic Drug

scholarly journals Filamin A: key actor in platelet biology

Blood ◽  
2019 ◽  
Vol 134 (16) ◽  
pp. 1279-1288 ◽  
Author(s):  
Jean-Philippe Rosa ◽  
Hana Raslova ◽  
Marijke Bryckaert
Keyword(s):  
Gastrointestinal Tract ◽  
Cardiovascular System ◽  
Adhesion Molecules ◽  
Scaffold Proteins ◽  
Signaling Proteins ◽  
Filamin A ◽  
Critical Importance ◽  
Wide Range ◽  
The Brain

Abstract Filamins are scaffold proteins for signaling proteins and adhesion molecules, and mutations in filamin A (FLNa) cause a wide range of defects in the brain, cardiovascular system, gastrointestinal tract, and skeleton, as well as in megakaryocytes. Rosa and colleagues review the important role of FLNa in platelet development and its critical importance to proplatelet production by megakaryocytes.

scholarly journals Cooperation of two distinct coupling proteins creates chemosensory network connections

2017 ◽  
Vol 114 (11) ◽  
pp. 2970-2975 ◽  
Author(s):  
Samar Abedrabbo ◽  
Juan Castellon ◽  
Kieran D. Collins ◽  
Kevin S. Johnson ◽  
Karen M. Ottemann
Keyword(s):  
Helicobacter Pylori ◽  
Signal Amplification ◽  
Kinase Activity ◽  
Bacterial Chemotaxis ◽  
Higher Order ◽  
Scaffold Proteins ◽  
Receiver Domain ◽  
Network Connections ◽  
Coupling Protein ◽  
Chemotaxis System

Although it is appreciated that bacterial chemotaxis systems rely on coupling, also called scaffold, proteins to both connect input receptors with output kinases and build interkinase connections that allow signal amplification, it is not yet clear why many systems use more than one coupling protein. We examined the distinct functions for multiple coupling proteins in the bacterial chemotaxis system of Helicobacter pylori, which requires two nonredundant coupling proteins for chemotaxis: CheW and CheV1, a hybrid of a CheW and a phosphorylatable receiver domain. We report that CheV1 and CheW have largely redundant abilities to interact with chemoreceptors and the CheA kinase, and both similarly activated CheA’s kinase activity. We discovered, however, that they are not redundant for formation of the higher order chemoreceptor arrays that are known to form via CheA–CheW interactions. In support of this possibility, we found that CheW and CheV1 interact with each other and with CheA independent of the chemoreceptors. Therefore, it seems that some microbes have modified array formation to require CheW and CheV1. Our data suggest that multiple coupling proteins may be used to provide flexibility in the chemoreceptor array formation.

scholarly journals Signaling Proteins That Regulate Spermatogenesis Are the Emerging Target of Toxicant-Induced Male Reproductive Dysfunction

2021 ◽  
Vol 12 ◽  
Author(s):  
Sheng Gao ◽  
Xiaolong Wu ◽  
Lingling Wang ◽  
Tiao Bu ◽  
Adolfo Perrotta ◽  
...  
Keyword(s):  
Cadmium Chloride ◽  
Endocrine Disrupting Chemicals ◽  
Signaling Cascade ◽  
Signaling Proteins ◽  
Environmental Toxicants ◽  
Reproductive Dysfunction ◽  
Male Contraceptive ◽  
Physiological Conditions ◽  
Endocrine Disrupting ◽  
Induced Defects

There is emerging evidence that environmental toxicants, in particular endocrine disrupting chemicals (EDCs) such as cadmium and perfluorooctanesulfonate (PFOS), induce Sertoli cell and testis injury, thereby perturbing spermatogenesis in humans, rodents and also widelife. Recent studies have shown that cadmium (e.g., cadmium chloride, CdCl2) and PFOS exert their disruptive effects through putative signaling proteins and signaling cascade similar to other pharmaceuticals, such as the non-hormonal male contraceptive drug adjudin. More important, these signaling proteins were also shown to be involved in modulating testis function based on studies in rodents. Collectively, these findings suggest that toxicants are using similar mechanisms that used to support spermatogenesis under physiological conditions to perturb Sertoli and testis function. These observations are physiologically significant, since a manipulation on the expression of these signaling proteins can possibly be used to manage the toxicant-induced male reproductive dysfunction. In this review, we highlight some of these findings and critically evaluate the possibility of using this approach to manage toxicant-induced defects in spermatrogenesis based on recent studies in animal models.

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