Autotaxin-Lysophosphatidic Acid: From Inflammation to Cancer Development

Lysophosphatidic acid (LPA) is a ubiquitous lysophospholipid and one of the main membrane-derived lipid signaling molecules. LPA acts as an autocrine/paracrine messenger through at least six G protein-coupled receptors (GPCRs), known as LPA1–6, to induce various cellular processes including wound healing, differentiation, proliferation, migration, and survival. LPA receptors and autotaxin (ATX), a secreted phosphodiesterase that produces this phospholipid, are overexpressed in many cancers and impact several features of the disease, including cancer-related inflammation, development, and progression. Many ongoing studies aim to understand ATX-LPA axis signaling in cancer and its potential as a therapeutic target. In this review, we discuss the evidence linking LPA signaling to cancer-related inflammation and its impact on cancer progression.

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Mechanisms of cross-talk between G-protein-coupled receptors resulting in enhanced release of intracellular Ca2+

Biochemical Journal ◽

10.1042/bj20030312 ◽

2003 ◽

Vol 374 (2) ◽

pp. 281-296 ◽

Cited By ~ 126

Author(s):

Tim D. WERRY ◽

Graeme F. WILKINSON ◽

Gary B. WILLARS

Keyword(s):

G Protein ◽

Cross Talk ◽

Cell Function ◽

Feedback Regulation ◽

G Protein Coupled Receptors ◽

Negative Feedback Regulation ◽

Cellular Processes ◽

Heterologous Desensitization ◽

G Protein Coupled

Alteration in [Ca2+]i (the intracellular concentration of Ca2+) is a key regulator of many cellular processes. To allow precise regulation of [Ca2+]i and a diversity of signalling by this ion, cells possess many mechanisms by which they are able to control [Ca2+]i both globally and at the subcellular level. Among these are many members of the superfamily of GPCRs (G-protein-coupled receptors), which are characterized by the presence of seven transmembrane domains. Typically, those receptors able to activate PLC (phospholipase C) enzymes cause release of Ca2+ from intracellular stores and influence Ca2+ entry across the plasma membrane. It has been well documented that Ca2+ signalling by one type of GPCR can be influenced by stimulation of a different type of GPCR. Indeed, many studies have demonstrated heterologous desensitization between two different PLC-coupled GPCRs. This is not surprising, given our current understanding of negative-feedback regulation and the likely shared components of the signalling pathway. However, there are also many documented examples of interactions between GPCRs, often coupling preferentially to different signalling pathways, which result in a potentiation of Ca2+ signalling. Such interactions have important implications for both the control of cell function and the interpretation of in vitro cell-based assays. However, there is currently no single mechanism that adequately accounts for all examples of this type of cross-talk. Indeed, many studies either have not addressed this issue or have been unable to determine the mechanism(s) involved. This review seeks to explore a range of possible mechanisms to convey their potential diversity and to provide a basis for further experimental investigation.

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The complex role of Prostaglandin E2-EP receptor signaling in wound healing

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00185.2020 ◽

2020 ◽

Author(s):

Kristy E. Gilman ◽

Kirsten H. Limesand

Keyword(s):

Wound Healing ◽

G Protein ◽

Lipid Mediators ◽

G Protein Coupled Receptors ◽

Prostaglandin E ◽

Receptor Signaling ◽

Wound Healing Response ◽

Ep Receptor ◽

G Protein Coupled

Prostaglandins are critical lipid mediators involved in the wound healing response, with prostaglandin E2 (PGE2) being the most complex and exhibiting the most diverse physiological outputs. PGE2 signals via four G-protein coupled receptors, termed EP-receptors 1-4, that induce distinct signaling pathways upon activation and lead to an array of different outputs. Recent studies examining the role of PGE2 and EP receptor signaling in wound healing following various forms of tissue damage are discussed in this review.

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Lysophosphatidic Acid and Hematopoiesis: From Microenvironmental Effects to Intracellular Signaling

International Journal of Molecular Sciences ◽

10.3390/ijms21062015 ◽

2020 ◽

Vol 21 (6) ◽

pp. 2015 ◽

Cited By ~ 1

Author(s):

Kuan-Hung Lin ◽

Jui-Chung Chiang ◽

Ya-Hsuan Ho ◽

Chao-Ling Yao ◽

Hsinyu Lee

Keyword(s):

Stem Cells ◽

G Protein ◽

Lysophosphatidic Acid ◽

Intracellular Signaling ◽

Lineage Tracing ◽

G Protein Coupled Receptors ◽

Hematopoietic Stem ◽

Extracellular Microenvironment ◽

G Protein Coupled ◽

Prevention And Therapy

Vertebrate hematopoiesis is a complex physiological process that is tightly regulated by intracellular signaling and extracellular microenvironment. In recent decades, breakthroughs in lineage-tracing technologies and lipidomics have revealed the existence of numerous lipid molecules in hematopoietic microenvironment. Lysophosphatidic acid (LPA), a bioactive phospholipid molecule, is one of the identified lipids that participates in hematopoiesis. LPA exhibits various physiological functions through activation of G-protein-coupled receptors. The functions of these LPARs have been widely studied in stem cells, while the roles of LPARs in hematopoietic stem cells have rarely been examined. Nonetheless, mounting evidence supports the importance of the LPA-LPAR axis in hematopoiesis. In this article, we have reviewed regulation of hematopoiesis in general and focused on the microenvironmental and intracellular effects of the LPA in hematopoiesis. Discoveries in these areas may be beneficial to our understanding of blood-related disorders, especially in the context of prevention and therapy for anemia.

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Lysophospholipids in the limelight

The Journal of Cell Biology ◽

10.1083/jcb.200206094 ◽

2002 ◽

Vol 158 (2) ◽

pp. 197-199 ◽

Cited By ~ 74

Author(s):

Wouter H. Moolenaar

Keyword(s):

Growth Factor ◽

Cell Motility ◽

Tumor Progression ◽

G Protein ◽

Lysophosphatidic Acid ◽

Cell Types ◽

G Protein Coupled Receptors ◽

Serum Phospholipid ◽

A Cell ◽

G Protein Coupled

Lysophosphatidic acid (LPA) is a serum phospholipid that evokes growth factor–like responses in many cell types through the activation of its G protein–coupled receptors. Although much is known about LPA signaling, it has remained unclear where and how bioactive LPA is produced. Umezu-Goto et al. (2002)(this issue, page 227) have purified a serum lysophospholipase D that generates LPA from lysophosphatidylcholine and found it to be identical to autotaxin, a cell motility–stimulating ectophosphodiesterase implicated in tumor progression. This result is surprising, as there was previously no indication that autotaxin could act as a phospholipase.

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Molecular Identification and Characterization of G Protein-Coupled Receptors for Lysophosphatidic Acid and Sphingosine 1-Phosphate

Annals of the New York Academy of Sciences ◽

10.1111/j.1749-6632.2000.tb06535.x ◽

2006 ◽

Vol 905 (1) ◽

pp. 25-33 ◽

Cited By ~ 28

Author(s):

SONGZHU AN

Keyword(s):

G Protein ◽

Molecular Identification ◽

Lysophosphatidic Acid ◽

G Protein Coupled Receptors ◽

Sphingosine 1 Phosphate ◽

G Protein Coupled ◽

Identification And Characterization

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Ligand Docking Methods to Recognize Allosteric Inhibitors for G-protein Coupled Receptors

10.20944/preprints202012.0085.v1 ◽

2020 ◽

Author(s):

K Harini ◽

S Jayashree ◽

Vikas Tiwari ◽

Sneha Vishwanath ◽

Ramanathan Sowdhamini

Keyword(s):

Binding Site ◽

G Protein ◽

Drug Targets ◽

G Protein Coupled Receptors ◽

Ligand Docking ◽

Computational Docking ◽

Cellular Processes ◽

Activation Mechanisms ◽

Approved Drugs ◽

G Protein Coupled

G-protein coupled receptors (GPCRs) are large protein families known to be important in many cellular processes. They are well known for their allosteric activation mechanisms. They are drug targets for several FDA-approved drugs. We have investigated the diversity of the ligand binding site for these class of proteins against their cognate ligands using computational docking, even if their structures are known in the ligand-complexed form. The cognate ligand of some of these receptors dock at allosteric binding site, with better score than the binding at the conservative site. Further, ligands obtained from GLASS database, which consists of experimentally verified GPCR ligands, also show allosteric binding to GPCRs. The allosteric binders show strong affinity to the binding site, though the residues at the binding site are not conserved across GPCR subfamilies.

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Ligand Docking Methods to Recognize Allosteric Inhibitors for G-Protein-Coupled Receptors

Bioinformatics and Biology Insights ◽

10.1177/11779322211037769 ◽

2021 ◽

Vol 15 ◽

pp. 117793222110377

Author(s):

K Harini ◽

S Jayashree ◽

Vikas Tiwari ◽

Sneha Vishwanath ◽

Ramanathan Sowdhamini

Keyword(s):

Binding Site ◽

G Protein ◽

Drug Targets ◽

Drug Binding ◽

G Protein Coupled Receptors ◽

Ligand Docking ◽

Amino Acid Residues ◽

Computational Docking ◽

Cellular Processes ◽

G Protein Coupled

G-protein-coupled receptors (GPCRs) are membrane proteins which play an important role in many cellular processes and are excellent drug targets. Despite the existence of several US Food and Drug Administration (FDA)-approved GPCR-targeting drugs, there is a continuing challenge of side effects owing to the nonspecific nature of drug binding. We have investigated the diversity of the ligand binding site for this class of proteins against their cognate ligands using computational docking, even if their structures are known already in the ligand-complexed form. The cognate ligand of some of these receptors dock at allosteric binding site with better score than the binding at the conservative site. Interestingly, amino acid residues at such allosteric binding site are not conserved across GPCR subfamilies. Such a computational approach can assist in the prediction of specific allosteric binders for GPCRs.

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