A5004605481- Sphingolipid Metabolism and Signaling
- Endoplasmic Reticulum Stress and Disease
- Cellular transport and secretion
- Lipid Membrane Structure and Behavior
- ATP Synthase and ATPases Research
- Pancreatic function and diabetes
- Phagocytosis and Immune Regulation
- Enzyme function and inhibition
- Calcium signaling and nucleotide metabolism
- Liver Disease Diagnosis and Treatment
- Enzyme Structure and Function
- Genetics and Neurodevelopmental Disorders
- Adenosine and Purinergic Signaling
- RNA and protein synthesis mechanisms
- Drug Transport and Resistance Mechanisms
- Plant-derived Lignans Synthesis and Bioactivity
- Neuroblastoma Research and Treatments
- Microtubule and mitosis dynamics
- Research on Leishmaniasis Studies
- Protein Structure and Dynamics
- Autophagy in Disease and Therapy
- Retinal Development and Disorders
- Protein Kinase Regulation and GTPase Signaling
- Carbohydrate Chemistry and Synthesis
- Cancer Treatment and Pharmacology
Oncode Institute
2019-2023
The Netherlands Cancer Institute
2016-2023
University of York
2020
Autotaxin (ATX; ENPP2) produces lysophosphatidic acid (LPA) that regulates multiple biological functions via cognate G protein-coupled receptors LPAR1-6. ATX/LPA promotes tumor cell migration and metastasis LPAR1 T motility LPAR2, yet its actions in the immune microenvironment remain unclear. Here, we show ATX secreted by melanoma cells is chemorepulsive for tumor-infiltrating lymphocytes (TILs) circulating CD8+ ex vivo, with functioning as an LPA-producing chaperone. Mechanistically,...
Autotaxin (ATX; ENPP2) produces the lipid mediator lysophosphatidic acid (LPA) that signals through disparate EDG (LPA1-3) and P2Y (LPA4-6) G protein-coupled receptors. ATX/LPA promotes several (patho)physiological processes, including in pulmonary fibrosis, thus serving as an attractive drug target. However, it remains unclear if clinical outcome depends on how different types of ATX inhibitors modulate signaling axis. Here, we show "tunnel" is crucial for conferring key aspects dictates...
Autotaxin (ATX) is a secreted glycoprotein and the only member of ectonucleotide pyrophosphatase/phosphodiesterase family that converts lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA). LPA controls key responses, such as cell migration, proliferation, survival, implicating ATX-LPA signaling in various (patho)physiological processes establishing it drug target. ATX structural functional studies have revealed an orthosteric allosteric site, called "pocket" "tunnel,"...
Autotaxin produces the bioactive lipid lysophosphatidic acid (LPA) and is a drug target of considerable interest for numerous pathologies. We report expedient, structure-guided evolution weak physiological allosteric inhibitors (bile salts) into potent competitive that do not interact with catalytic site. Functional data confirms our lead compound attenuates LPA mediated signaling in cells reduces synthesis vivo, providing promising natural product derived scaffold discovery.
Autotaxin (ATX) is a secreted enzyme responsible for the hydrolysis of lysophosphatidylcholine (LPC) to bioactive lysophosphatidic acid (LPA) and choline. The ATX-LPA signaling pathway implicated in cell survival, migration, proliferation; thus, inhibition ATX recognized therapeutic target number diseases including fibrotic diseases, cancer, inflammation, among others. Many developed synthetic inhibitors have resembled lipid chemotype native ligand; however, small been described that deviate...
Autotaxin (ATX) facilitates the hydrolysis of lysophosphatidylcholine to lysophosphatidic acid (LPA), a bioactive phospholipid, which diverse range cellular effects in multiple tissue types. Abnormal LPA expression can lead progression diseases such as cancer and fibrosis. Previously, we identified potent ATX steroid-derived hybrid (partially orthosteric allosteric) inhibitor did not form interactions with catalytic site. Herein, describe design, synthesis, biological evaluation focused...
GDE2 (also known as GDPD5) is a multispanning membrane phosphodiesterase with phospholipase D-like activity that cleaves select glycosylphosphatidylinositol (GPI)-anchored proteins and thereby promotes neuronal differentiation both in vitro vivo prognostic marker neuroblastoma, while loss of leads to progressive neurodegeneration mice; however, its regulation remains unclear. Here, we report that, immature cells, undergoes constitutive endocytosis travels back along fast slow recycling...
Autotaxin (ATX) is a secreted phosphodiesterase that has been implicated in remarkably wide array of pathologies, especially fibrosis and cancer. While ATX inhibitors have entered the clinical arena, validated probe for positron emission tomography (PET) currently lacking. With aim to develop suitable ATX-targeted PET radioligand, we synthesized focused library fluorinated imidazo[1,2-a]pyridine derivatives, determined their inhibition constants, confirmed binding mode by crystallographic...
Summary Autotaxin (ATX) is secreted by diverse cell types to produce lysophosphatidic acid (LPA) that regulates multiple biological functions via G protein-coupled receptors LPAR1-6. ATX/LPA promotes tumor migration and metastasis mainly LPAR1; however, its actions in the immune microenvironment remain unclear. Here, we show ATX melanoma cells chemorepulsive for tumor-infiltrating lymphocytes circulating CD8 + T ex vivo , with functioning as an LPA-producing chaperone. Mechanistically,...
Comparison of homologous structure models is a key step in analyzing protein structure. With wealth structures, comparison becomes tedious process, and often only small (user-biased) selection data used. A multitude structural superposition algorithms are then typically used to visualize the structures together 3D compare them. Here, Local Annotation Homology-Matched Amino acids ( LAHMA ) website (https://lahma.pdb-redo.eu) presented, which compares any model with all its close homologs from...
SUMMARY Autotaxin (ATX; ENPP2) produces the lipid mediator lysophosphatidic acid (LPA) that signals through disparate EDG (LPA 1-3 ) and P2Y 4-6 G protein-coupled receptors. ATX/LPA promote several (patho)physiological processes, including in pulmonary fibrosis, thus serving as attractive drug targets. However, it remains unclear if clinical outcome depends on how different ATX inhibitors modulate signaling axis. Here, we show binding to “tunnel” specifically abrogate key aspects of...
Abstract Autotaxin is a secreted phosphodiesterase that converts lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA). LPA controls key cellular responses such as migration, proliferation and survival, implicating ATX-LPA signalling in various (patho)physiological processes establishing it drug target. ATX structural functional studies have revealed an orthosteric allosteric site, the “pocket” “tunnel”. Here, we revisit kinetics of catalytic cycle light regulation, dissecting...
Autotaxin (ATX) is a secreted lysophospholipase D, catalysing the conversion of lysophosphatidylcholine (LPC) to bioactive lysophosphatidic acid (LPA). LPA acts through two families G protein-coupled receptors (GPCRs) controlling key cellular responses, and implicated in many physiological processes pathologies. ATX has therefore been established as an important drug target pharmaceutical industry. Structural biochemical studies have shown that it bimetallic nucleophilic catalytic site,...
Summary GDE2 is a six-transmembrane glycerophosphodiesterase with phospholipase D-like activity that cleaves select glycosylphosphatidylinositol (GPI)-anchored proteins and thereby influences biological signaling cascades. promotes neuronal differentiation cell-autonomously through glypican cleavage prognostic marker in neuroblastoma, while deficiency causes progressive neurodegeneration mice developmental defects zebrafish. However, the regulation of remains unclear. Here we show...
Autotaxin (ATX; ENPP2) produces the lipid mediator lysophosphatidic acid (LPA) that signals through disparate EDG (LPA 1-3 ) and P2Y 4-6 G protein-coupled receptors. ATX/LPA promote several (patho)physiological processes, including in pulmonary fibrosis, thus serving as attractive drug targets. However, it remains unclear if clinical outcome depends on how different ATX inhibitors modulate signaling axis. Here, we show binding to "tunnel" specifically abrogate key aspects of signaling. We...
Abstract An important but rather underexplored pathway implicated in liver disease is the lysophosphatidic acid (LPA) signaling axis. LPA acts through G-protein coupled receptors inducing downstream pathways related to cell proliferation, differentiation, and migration, predominantly produced by extracellular phosphodiesterase, Autotaxin (ATX). ATX has gained significant attention lately with an impressive number of inhibitors (type I-IV) reported. Here, we aim evaluate therapeutic potential...
Autotaxin (ATX/ENPP2) has attracted widespread attention as a target for various pathologies, notably idiopathic pulmonary fibrosis (IPF). ATX is predominantly (~90%) responsible the extracellular production of signaling molecule lysophosphatidic acid (LPA), which acts through two specific families G protein-coupled receptors. We show that ATX, even when catalytically inactive, more potent than LPA alone in inducing downstream events cells. While catalytic activity dispensable ATX-mediated...