A5002315252- Sphingolipid Metabolism and Signaling
- Cellular transport and secretion
- Lipid Membrane Structure and Behavior
- Endoplasmic Reticulum Stress and Disease
- Erythrocyte Function and Pathophysiology
- Mitochondrial Function and Pathology
- Lipid metabolism and biosynthesis
- RNA and protein synthesis mechanisms
- ATP Synthase and ATPases Research
- Lysosomal Storage Disorders Research
- Photosynthetic Processes and Mechanisms
- Biotin and Related Studies
- RNA Interference and Gene Delivery
- Glycosylation and Glycoproteins Research
- Receptor Mechanisms and Signaling
- Neurogenesis and neuroplasticity mechanisms
- Autophagy in Disease and Therapy
- Cell death mechanisms and regulation
- Biomedical Research and Pathophysiology
- Plant Virus Research Studies
- Pancreatic function and diabetes
- Cancer-related Molecular Pathways
- Drug Transport and Resistance Mechanisms
- Cholesterol and Lipid Metabolism
- Toxin Mechanisms and Immunotoxins
Virginia Commonwealth University
2017-2025
Children's Hospital of Richmond at VCU
2021
University of Louisville
2007-2019
University of Louisville Hospital
2008-2014
James Graham Brown Foundation
2012
South Australia Pathology
2000-2008
Hanson Institute
1997-2008
Open Targets
2006
Baxter (United States)
2003
The University of Adelaide
2000
Sphingosine kinase (SK) 1 catalyzes the formation of bioactive lipid sphingosine 1-phosphate, and has been implicated in several biological processes mammalian cells, including enhanced proliferation, inhibition apoptosis, oncogenesis. Human SK (hSK) possesses high instrinsic catalytic activity which can be further increased by a diverse array cellular agonists. We have shown previously that this activation occurs as direct consequence extracellular signal-regulated 1/2-mediated...
The regulation of metabolism and growth must be tightly coupled to guarantee the efficient use energy anabolic substrates throughout cell cycle. Fructose 2,6-bisphosphate (Fru-2,6-BP) is an allosteric activator 6-phosphofructo-1-kinase (PFK-1), a rate-limiting enzyme essential control point in glycolysis. concentration Fru-2,6-BP mammalian cells set by four 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFB1-4), which interconvert fructose 6-phosphate Fru-2,6-BP. relative functions...
Sphingolipids compose a lipid family critical for membrane structure as well intra- and intercellular signaling. De novo sphingolipid biosynthesis is initiated by the enzyme serine palmitoyltransferase (SPT), which resides in endoplasmic reticulum (ER) membrane. In both yeast mammalian species, SPT activity homeostatically regulated through small ER proteins, Orms ORMDLs cells. These proteins form stable complexes with SPT. yeast, homeostatic regulation of relies, at least part, on...
Abstract The ORM/ORMDL family proteins function as regulatory subunits of the serine palmitoyltransferase (SPT) complex, which is initiating and rate-limiting enzyme in sphingolipid biosynthesis. This complex tightly regulated by cellular levels, but sensing mechanism unknown. Here we show that purified human SPT-ORMDL complexes are inhibited central metabolite ceramide. We have solved cryo-EM structure SPT-ORMDL3 a ceramide-bound state. Structure-guided mutational analyses reveal essential...
A class of integral membrane proteins, referred to as ‘tail‐anchored proteins’, are inserted into phospholipid bilayers via a single segment hydrophobic amino acids at the C‐terminus, thereby displaying large functional domain in cytosol. This attachment strategy allows eukaryotic cells position wide range cytoplasmic activities close surface an intracellular membrane. Tail‐anchored proteins often, but not always, demonstrate selective distribution specific organelles. membrane‐specific is...
Sphingosine kinase (SK) catalyzes the formation of sphingosine 1-phosphate (S1P), a lipid messenger that plays an important role in variety mammalian cell processes, including inhibition apoptosis and stimulation proliferation. Basal levels S1P cells are generally low but can increase rapidly when exposed to various agonists through rapid transient activation SK activity. To date, elucidation exact signaling pathways affected by these elevated has relied on use inhibitors known have direct...
Sphingosine 1-phosphate (S1P) is a novel lipid messenger that has important roles in wide variety of mammalian cellular processes including growth, differentiation and death. Basal levels S1P cells are generally low, but can increase rapidly transiently when exposed to mitogenic agents other stimuli. This largely due increased activity sphingosine kinase (SK), the enzyme catalyses its formation. In current study we have purified, cloned characterized first human SK obtain better...
Intracellular proteins with a carboxy‐terminal transmembrane domain and the amino‐terminus oriented toward cytosol are known as ‘tail‐anchored’ proteins. Tail‐anchored have been of considerable interest because several important classes proteins, including vesicle‐targeting/fusion SNAREs apoptosis‐related Bcl‐2 family, among others, utilize this unique membrane‐anchoring motif. Here, we use bioinformatic technique to develop comprehensive list potentially tail‐anchored in human genome. Our...
Screening of a library derived from primary human endothelial cells revealed novel isoform vesicle-associated membrane protein-1 (VAMP-1), protein involved in the targeting and/or fusion transport vesicles to their target membrane. We have termed this VAMP-1B and designated previously described VAMP-1A. appears be an alternatively spliced form VAMP-1. A similar rat splice variant VAMP-1 (also VAMP-1B) has recently been reported. Five different cultured cell lines, lineages, all contained but...
Gut-associated inflammation plays a crucial role in the progression of colon cancer. Here, we identify novel pathogen–host interaction that promotes gut and development We find enteropathogenic bacteria-secreted particles (ET-BSPs) stimulate intestinal epithelium to produce IDENs (intestinal mucosa-derived exosome-like nanoparticles) containing elevated levels sphingosine-1-phosphate, CCL20 prostaglandin E2 (PGE2). PGE2 are required for recruitment proliferation, respectively, Th17 cells,...
Sphingosine-1-phosphate (S1P) regulates various molecular and cellular events in cultured endothelial cells, such as cytoskeletal restructuring, cell-extracellular matrix interactions, intercellular junction interactions. We utilized the venular leakage model of cremaster muscle vascular bed Sprague-Dawley rats to investigate role S1P signaling regulation microvascular permeability. is mediated by family G protein-coupled receptors (S1P 1-5 receptors). 1 2 receptors, which transduce...
The ORM1 (Saccharomyces cerevisiae)-like proteins (ORMDLs) and their yeast orthologs, the Orms, are negative homeostatic regulators of initiating enzyme in sphingolipid biosynthesis, serine palmitoyltransferase (SPT). Genome-wide association studies have established a strong correlation between elevated expression endoplasmic reticulum protein ORMDL3 risk for childhood asthma. Here we test notion that levels decrease biosynthesis. This was tested cultured human bronchial epithelial cells...
Sphingolipids play crucial roles in cell membrane structure and multiple signaling pathways. Sphingolipid de novo biosynthesis is mediated by the serine palmitoyltransferase (SPT) enzyme complex. Homeostatic regulation of this complex dependent on its regulatory subunit, ORMDLs, which there are three isoforms. It well established that ORMDLs regulate SPT activity, but it still unclear whether ORMDL isoforms have distinct functions properties. Here, we focus understanding physiological...
Tail-anchored proteins are inserted into intracellular membranes via a C-terminal transmembrane domain. The topology of the protein is such that insertion must occur post-translationally, since sequence not available for membrane until after translation tail-anchored polypeptide completed. Here, we show targeting information in one protein, translocase outer mitochondrial 22, contained short region flanking An equivalent sufficient to specify localisation Bcl2 and SNARE secretory membranes....
The lysosomotropic amine primaquine has previously been shown to inhibit both secretory and recycling processes of cells in culture. We have used a cell-free assay that reconstitutes glycoprotein transport through the Golgi apparatus investigate mechanism action primaquine. In this assay, inhibits protein at half-maximal concentration 50 microM, similar reported disrupt secretion cultured cells. Kinetic analysis inhibition indicates its point is an early step vesicular mechanism. Primaquine...
Glycolipid transport between compartments of the Golgi apparatus has been reconstituted in a cell free system. Transport lactosylceramide (galactose beta 1-4-glucose-ceramide) was followed from donor to an acceptor population. The major glycolipid CHO cells is GM3 (sialic acid alpha 2-3 galactose 1-4-glucose-ceramide). Donor membranes were derived Chinese hamster ovary (CHO) mutant (Lec2) deficient CMP-sialic transporter, and therefore contained as predominant glycolipid. Acceptor prepared...