Nontransformed cells depend on growth factors for their survival, proliferation and differentiation. In addition to polypeptide growth factors, an emerging group of naturally occurring phospholipid growth factors have been discovered. Within this group, lysophosphatidic acid (LPA, 1-acyl-2-lyso-sn-glycero-3-phosphate), nature's simplest phospholipid, was found to elicit growth factor-like effects in almost every cell type spanning the phylogenetic tree, from Dictyostelium to humans. These biological effects include: 1) the mitogenic or antimitogenic regulation of the cell cycle, 2) regulation of Ca2+ homeostasis, 3) regulation of cell shape, migration, and tumor cell invasiveness, and 4) the prevention of apoptosis. LPA elicits these effects via multiple G protein-coupled receptors, which have distinct pharmacological and signal transduction properties. LPA is generated from activated and injured cells, including platelets; blood serum is consequently a very rich source. In addition to LPA, serum contains at least eight other lipids that constitute approximately 90% of the biological activity. In contrast, plasma is rich in endogenous antagonists of LPA. The first objective of this proposal is to elucidate the chemical structure of these lipid agonists and antagonists present in human serum and plasma. The structure of the chromatographically purified lipids will be elucidated by mass-, infrared-, and NMR spectrometry. The biological effects of the newly identified agonists and antagonists on the cell cycle, Ca2+ homeostasis, cell shape, and apoptosis will be determined. The second objective is to characterize the structure-activity relationship and signal transduction properties of four putative LPA receptors, and two that have already been identified. Preliminary evidence indicates that these receptors are selectively activated by three naturally occurring lipids, LPA, 1-0-cis- alk-1'-enyl-2-lyso-sn-glycero-3-phosphate, and 1-acyl-2,3-cyclic-sn- glycero-3-phosphate. The Hep G2 human hematoma cell line, which is devoid of these lipid receptors, was used to generate clonal cell lines that stably express each of these receptors. These cell lines will be used to determine the agonist/antagonist specificity and the signal transduction properties of each receptor. New information from these proposed studies will facilitate the assessment of the physiological role of these lipids, provide novel pharmacological tools for their analysis, and pave the way toward expanded therapeutic applications. The FDA has approved clinical trials of HK-Cardisol, an LPA-containing preservative for organ explants. The biotechnology industry has just begun to explore the utilization of LPA to prevent apoptosis associated with myocardial ischemia, chemotherapy, and AIDS.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL061469-02
Application #
6125980
Study Section
Medical Biochemistry Study Section (MEDB)
Project Start
1998-12-01
Project End
2002-11-30
Budget Start
1999-12-01
Budget End
2000-11-30
Support Year
2
Fiscal Year
2000
Total Cost
$237,816
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Physiology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Zhang, Honglu; Xu, Xiaoyu; Gajewiak, Joanna et al. (2009) Dual activity lysophosphatidic acid receptor pan-antagonist/autotaxin inhibitor reduces breast cancer cell migration in vitro and causes tumor regression in vivo. Cancer Res 69:5441-9
Valentine, William J; Fujiwara, Yuko; Tsukahara, Ryoko et al. (2008) Lysophospholipid signaling: beyond the EDGs. Biochim Biophys Acta 1780:597-605
Fujiwara, Yuko (2008) Cyclic phosphatidic acid - a unique bioactive phospholipid. Biochim Biophys Acta 1781:519-24
Gajewiak, Joanna; Tsukahara, Ryoko; Fujiwara, Yuko et al. (2008) Synthesis, pharmacology, and cell biology of sn-2-aminooxy analogues of lysophosphatidic acid. Org Lett 10:1111-4
Valentine, William J; Fells, James I; Perygin, Donna H et al. (2008) Subtype-specific residues involved in ligand activation of the endothelial differentiation gene family lysophosphatidic acid receptors. J Biol Chem 283:12175-87
Dopico, Alex M; Tigyi, Gabor J (2007) A glance at the structural and functional diversity of membrane lipids. Methods Mol Biol 400:1-13
Gajewiak, Joanna; Tsukahara, Ryoko; Tsukahara, Tamotsu et al. (2007) Alkoxymethylenephosphonate analogues of (Lyso) phosphatidic acid stimulate signaling networks coupled to the LPA2 receptor. ChemMedChem 2:1789-98
Jiang, Guowei; Xu, Yong; Fujiwara, Yuko et al. (2007) Alpha-substituted phosphonate analogues of lysophosphatidic acid (LPA) selectively inhibit production and action of LPA. ChemMedChem 2:679-90
Uchiyama, Ayako; Mukai, Mutsuko; Fujiwara, Yuko et al. (2007) Inhibition of transcellular tumor cell migration and metastasis by novel carba-derivatives of cyclic phosphatidic acid. Biochim Biophys Acta 1771:103-12
Pyne, Nigel J; Waters, Catherine M; Long, Jaclyn S et al. (2007) Receptor tyrosine kinase-G-protein coupled receptor complex signaling in mammalian cells. Adv Enzyme Regul 47:271-80

Showing the most recent 10 out of 45 publications