A5080847489- Protein Kinase Regulation and GTPase Signaling
- Nitric Oxide and Endothelin Effects
- Metabolism and Genetic Disorders
- Diet and metabolism studies
- Fatty Acid Research and Health
- Mitochondrial Function and Pathology
- Liver Disease Diagnosis and Treatment
- Eicosanoids and Hypertension Pharmacology
- PI3K/AKT/mTOR signaling in cancer
- Cardiomyopathy and Myosin Studies
- Biomarkers in Disease Mechanisms
- Melanoma and MAPK Pathways
- vaccines and immunoinformatics approaches
- Renin-Angiotensin System Studies
- Ion channel regulation and function
- Erythrocyte Function and Pathophysiology
- Cellular Mechanics and Interactions
- Cardiovascular, Neuropeptides, and Oxidative Stress Research
- Alcoholism and Thiamine Deficiency
- Connexins and lens biology
- Phosphodiesterase function and regulation
- Metabolomics and Mass Spectrometry Studies
- SARS-CoV-2 and COVID-19 Research
- Bacillus and Francisella bacterial research
- Peroxisome Proliferator-Activated Receptors
University of Virginia
2009-2024
National Institute of Allergy and Infectious Diseases
2021-2023
National Institutes of Health
2023
Berry (United States)
2015
University of Pittsburgh
2014
Versiti Blood Center of Wisconsin
2014
Palladin Institute of Biochemistry
2000-2005
National Academy of Sciences of Ukraine
2001-2005
The ATP-releasing channel Panx1 is specifically involved in blood pressure regulation by adrenergic signaling.
Agonist activation of the small GTPase, RhoA, and its effector Rho kinase leads to down-regulation smooth muscle (SM) myosin light chain phosphatase activity, an increase in (RLC20) phosphorylation force. Cyclic nucleotides can reverse this process. We report a new mechanism cAMP-mediated relaxation through Epac, GTP exchange factor for GTPase Rap1 resulting activity suppression RhoA activity. An Epac-selective cAMP analog, 8-pCPT-2′-O-Me-cAMP ("007"), significantly reduced agonist-induced...
Objective— Hemoglobin α (Hb α) and endothelial nitric oxide synthase (eNOS) form a macromolecular complex at myoendothelial junctions; the functional role of this interaction remains undefined. To test if coupling eNOS Hb regulates signaling, vascular reactivity, blood pressure using mimetic peptide to disrupt interaction. Approach Results— In silico modeling identified conserved sequence By mutating portions α, we specific that binds eNOS. A X) was generated complex. Using in vitro binding...
In normal and diseased vascular smooth muscle (SM), the RhoA pathway, which is activated by multiple agonists through G protein-coupled receptors (GPCRs), plays a central role in regulating basal tone peripheral resistance. This occurs inhibition of myosin light chain phosphatase, leading to increased phosphorylation regulatory chain. Although it thought that specific GPCRs may couple distinct guanine nucleotide exchange factors (GEFs), thus raising possibility selective targeting GEFs for...
Since the outbreak of COVID-19 pandemic, widespread infections have allowed SARS-CoV-2 to evolve in human, leading emergence multiple circulating variants. Some these variants show increased resistance vaccine-elicited immunity, convalescent plasma, or monoclonal antibodies. In particular, mutations spike drawn attention. To facilitate isolation neutralizing antibodies and monitoring vaccine effectiveness against variants, we designed produced biotin-labeled molecular probes variant spikes...
Objective— Small GTPase Ras-related protein 1 (Rap1b) controls several basic cellular phenomena, and its deletion in mice leads to cardiovascular defects, including impaired adhesion of blood cells defective angiogenesis. We found that Rap1b −/− develop cardiac hypertrophy hypertension. Therefore, we examined the function regulation pressure. Approach Results— developed elevated pressure, but maintained a normal heart rate. Correcting pressure with losartan, an angiotensin II type receptor...
Objective- Sympathetic nerve innervation of vascular smooth muscle cells (VSMCs) is a major regulator arteriolar vasoconstriction, resistance, and blood pressure. Importantly, α-adrenergic receptor stimulation, which uniquely couples with Panx1 (pannexin 1) channel-mediated ATP release in resistance arteries, also requires localization to membrane caveolae. Here, we test whether Cav1 (caveolin-1) promotes channel function (stimulus-dependent adrenergic vasoconstriction) important for...
Abstract Since the outbreak of COVID-19 pandemic, widespread infections have allowed SARS-CoV-2 to evolve in human, leading emergence multiple circulating variants. Some these variants show increased resistance vaccines, convalescent plasma, or monoclonal antibodies. In particular, mutations spike drawn attention. To facilitate isolation neutralizing antibodies and monitoring vaccine effectiveness against variants, we designed produced biotin-labeled molecular probes variant spikes their...
Targeted degradation regulates the activity of transcriptional repressor Bcl6 and its ability to suppress oxidative stress inflammation. Here, we report that abundance endothelial is determined by interaction with Golgi-localized pannexin 3 (Panx3) protects against vascular stress. Consistent data from obese, hypertensive humans, mice an cell-specific deficiency in
Phospho-telokin is a target of elevated cyclic nucleotide concentrations that lead to relaxation gastrointestinal and some vascular smooth muscles (SM). Here, we demonstrate in telokin-null SM, both Ca(2+)-activated contraction Ca(2+) sensitization force induced by GST-MYPT1(654-880) fragment inhibiting myosin light chain phosphatase were antagonized the addition recombinant S13D telokin, without changing inhibitory phosphorylation status endogenous MYPT1 (the regulatory subunit phosphatase)...
Abstract Background The Dbl-family of guanine nucleotide exchange factors (GEFs) activate the cytosolic GTPases Rho family by enhancing rate GTP for GDP on cognate GTPase. This catalytic activity resides in DH (Dbl-homology) domain, but typically GEFs are multidomain proteins containing other modules. It is believed that autoinhibited cytosol due to supramodular architecture, and become activated diverse signaling pathways through conformational change exposure as protein translocated...
Members of the RSK family kinases constitute attractive targets for drug design, but a lack structural information regarding mechanism selective inhibitors impedes progress in this field. The crystal structure N-terminal kinase domain (residues 45-346) mouse RSK2, or RSK2(NTKD), has recently been described complex with one only two known inhibitors, rare naturally occurring flavonol glycoside, kaempferol 3-O-(3'',4''-di-O-acetyl-α-L-rhamnopyranoside), as SL0101. Based on structure, it was...
The kinase RSK2 promotes contractility in smooth muscle cells resistance arteries.
This study identifies signaling pathways that play key roles in the formation and maintenance of epicardial cells, a source progenitors for coronary smooth muscle cells (SMCs). After epithelial to mesenchymal transition (EMT), invade myocardium form SMCs. RhoA/Rho kinase activity is required EMT differentiation into SMCs, whereas cAMP known inhibit by an unknown mechanism. We use outgrowth from E9.5 isolated mouse proepicardium (PE) explants, wild type Epac1 null E12.5 heart adult rat...
In the canonical model of smooth muscle (SM) contraction, contractile force is generated by phosphorylation myosin regulatory light chain (RLC20) kinase (MLCK). Moreover, targeting subunit (MYPT1) RLC20 phosphatase (MLCP) RhoA-dependent ROCK kinase, inhibits activity and consequently dephosphorylation with concomitant increase in force, at constant intracellular [Ca2+]. This pathway referred to as Ca2+-sensitization. There is, however, emerging evidence suggesting that additional Ser/Thr...
Ribosomal S6 kinases (RSK) play important roles in cell signaling through the mitogen-activated protein kinase (MAPK) pathway. Each of four RSK isoforms (RSK1-4) is a single polypeptide chain containing two domains connected by linker sequence with regulatory phosphorylation sites. Here, we demonstrate that full-length RSK2-which implicated several types cancer, and which linked to genetic Coffin-Lowry syndrome-can be overexpressed high yields Escherichia coli as fusion maltose binding...
Introduction: Phosphorylation of smooth muscle (SM) myosin regulatory light chain (RLC 20 ) is a critical switch leading to SM contraction. The canonical view held that only the short isoform kinase (MLCK1) catalyzed this reaction. It now accepted auxiliary kinases may contribute vascular tone and contractility. We have previously reported p90 ribosomal S6 (RSK2) functions as such kinase, in parallel with MLCK1, contributing ∼25% maximal myogenic force resistance arteries. Thus, RSK2 be...
This study reports a new mechanism of cAMP mediated relaxation Ca2+sensitized force, in smooth muscle (SM) through Epac, GTP exchange factor for the small GTPase Rap1 which results suppression RhoA activity. We find that Epac selective analogue, 8-pCPT-2′-O-Me-cAMP (007), significantly reduced agonist-induced contractile both intact and permeabilized vascular, gut airway SM. Responses to 007 were independent PKA PKG. Activation resulted increased Rap1·GTP accompanied by significant decrease...
Smooth muscle (SM) contractile force is generated through phosphorylation of the myosin regulatory light chain (RLC20) by kinase. However, emerging evidence also suggests that additional Ser/Thr kinases may contribute to pathways regulate SM contractility. Recently, we published 90 kDa ribosomal S6 kinase (RSK), extensively studied in cancers epithelial origin, a major new player regulation RSKs are unusual having two catalytic domains separated linker multiple sites and activated cascade...