Lysophosphatidic Acid Receptors

Contos, James J. A.; Ishii, Isao; Chun, Jerold

doi:10.1124/mol.58.6.1188

Cited by 380 publications

(382 citation statements)

References 48 publications

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“…LPA binds to ubiquitous seven-transmembrane domain receptor(s) of the Edg/LP subfamily of GPCRs [54,55] and activates multiple heterotrimeric G proteins which are responsible for transducing LPA signals into a broad spectrum of biological responses [56,57]. Our results show that LPA, which promotes Ras-dependent but PKC-independent stimulation of the Raf/ MEK/ERK pathway, induces dramatic FAK phosphorylation at Ser-910 in IEC-18 cells, without producing any change in the phosphorylation of FAK at Tyr-397.…”

Section: Discussionmentioning

confidence: 99%

Differential FAK phosphorylation at Ser-910, Ser-843 and Tyr-397 induced by angiotensin II, LPA and EGF in intestinal epithelial cells

Jiang

Sinnett‐Smith

2007

Cellular Signalling

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A rapid increase in the tyrosine phosphorylation of the non-receptor tyrosine kinase FAK is a prominent early event in fibroblasts stimulated by a variety of signaling molecules. However, a variety of epithelial cells, including intestinal epithelial cells, show a high basal level of tyrosine phosphorylated FAK that is only slightly further increased by addition of G protein-coupled receptors (GPCR) agonists or growth factors. In this study, we determined whether these stimuli could elicit FAK phosphorylation at serine residues, including Ser-910 and Ser-843. Our results show that multiple agonists including angiotensin II (ANGII), lysophosphatidic acid (LPA), phorbol esters and EGF induced a striking stimulation of FAK phosphorylation at Ser-910 in rat intestinal epithelial IEC-18 cells via an ERK-dependent pathway. In striking contrast, none of these stimuli promoted a significant further increase in FAK phosphorylation at Tyr-397 in these cells. These results were extended using cultures of polarized human colonic epithelial T84 cells. We found that either carbachol or EGF promoted a striking ERK-dependent phosphorylation of FAK at Ser-910, but these agonists caused only slight stimulation of FAK at Tyr-397 in T84 cells. In addition, we demonstrated that GPCR agonists also induced a dramatic increase of FAK phosphorylation at Ser-843 in either IEC-18 or T84 cells. Our results indicate that Ser-910 and Ser-843, rather than Tyr-397, are prominent sites differentially phosphorylated in response to neurotransmitters, bioactive lipids, tumor promoters and growth factors in intestinal epithelial cells.

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Section: Discussionmentioning

confidence: 99%

Differential FAK phosphorylation at Ser-910, Ser-843 and Tyr-397 induced by angiotensin II, LPA and EGF in intestinal epithelial cells

Jiang

Sinnett‐Smith

2007

Cellular Signalling

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“…For example, elevated serum levels of lysophosphatidic acid (LPA) are found in more than 90% of ovarian cancer patients and the level of LPA in plasma has been proposed as a potential biomarker for this disease (Budnik and Mukhopadhyay, 2002). In addition, LPA signalling may have a role in the progression of ovarian cancer cells through stimulation of cellular proliferation, enhanced cellular survival and suppression of apoptosis (Contos et al, 2000). It seems therefore likely that the higher LPA receptor expression found in OSPC relative to USPC may represent a distinctive marker that plays a role in transduction of growth-promoting signals from high local concentrations of LPA (Contos et al, 2000;Budnik and Mukhopadhyay, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, LPA signalling may have a role in the progression of ovarian cancer cells through stimulation of cellular proliferation, enhanced cellular survival and suppression of apoptosis (Contos et al, 2000). It seems therefore likely that the higher LPA receptor expression found in OSPC relative to USPC may represent a distinctive marker that plays a role in transduction of growth-promoting signals from high local concentrations of LPA (Contos et al, 2000;Budnik and Mukhopadhyay, 2002). Consistent with this view, phospholipase C, another gene that is differentially overexpressed in OSPC relative to USPC has been previously reported to contribute to LPA production in ovarian cancer cells (Budnik and Mukhopadhyay, 2002).…”

Section: Discussionmentioning

confidence: 99%

Discrimination between uterine serous papillary carcinomas and ovarian serous papillary tumours by gene expression profiling

et al. 2004

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“…They are involved in many intracellular processes, and are important intermediates in lipid biosynthesis (1). For example, binding of LPA to its receptors evokes various cellular responses, and the local formation of (L)PA is part of signaling cascades, in particular in the regulation of membrane dynamics such as fusion and fission events, either indirectly through the recruitment of downstream effectors or directly by mediating (local) changes in the biophysical properties of the membrane (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12).…”

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confidence: 99%

What Makes the Bioactive Lipids Phosphatidic Acid and Lysophosphatidic Acid So Special?

et al. 2005

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Phosphatidic acid and lysophosphatidic acid are minor but important anionic bioactive lipids involved in a number of key cellular processes, yet these molecules have a simple phosphate headgroup.To find out what is so special about these lipids, we determined the ionization behavior of phosphatidic acid (PA) and lysophosphatidic acid (LPA) in extended (flat) mixed lipid bilayers using magic angle spinning 31 P NMR. Our data show two surprising results. First, despite identical phosphomonoester headgroups, LPA carries more negative charge than PA when present in a phosphatidylcholine bilayer. Dehydroxy-LPA [1-oleoyl-3-(phosphoryl)propanediol] behaves in a manner identical to that of PA, indicating that the difference in negative charge between LPA and PA is caused by the hydroxyl on the glycerol backbone of LPA and its interaction with the phosphomonoester headgroup. Second, deprotonation of phosphatidic acid and lysophosphatidic acid was found to be strongly stimulated by the inclusion of phosphatidylethanolamine in the bilayer, indicating that lipid headgroup charge depends on local lipid composition and will vary between the different subcellular locations of (L)PA. Our findings can be understood in terms of a hydrogen bond formed within the phosphomonoester headgroup of (L)PA and its destabilization by competing intra-or intermolecular hydrogen bonds. We propose that this hydrogen bonding property of (L)PA is involved in the various cellular functions of these lipids.Phosphatidic acid (PA) 1 and the related lipid lysophosphatidic acid (LPA) are important minor lipid species in the cell. They are involved in many intracellular processes, and are important intermediates in lipid biosynthesis (1). For example, binding of LPA to its receptors evokes various cellular responses, and the local formation of (L)PA is part of signaling cascades, in particular in the regulation of membrane dynamics such as fusion and fission events, either indirectly through the recruitment of downstream effectors or directly by mediating (local) changes in the biophysical properties of the membrane (2-12).PA and LPA have a relatively simple chemical structure consisting of only a glycerol, one (LPA) or two (PA) acyl chains, and a phosphate, and it is interesting to note that these simple phospholipids are involved in such diverse processes, and are able to bind specifically to so many different types of proteins (3, 13). The question then is what is so special about these lipids. An obvious suggestion relates to the phosphate headgroup, which is attached to the glycerol backbone as a phosphomonoester, a unique feature of these lipids. Phosphomonoesters have two pK a 's, one of which is expected to be in the physiological pH range. As a consequence, small changes in (physiological) pH will affect the charge and influence the molecular shape and lipid phase behavior of these lipids (14,15). Under physiological conditions at neutral pH, phosphatidic acid is a cone (type II)-shaped lipid with a negative spontaneous curvature clos...

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Lysophosphatidic Acid Receptors

Cited by 380 publications

References 48 publications

Differential FAK phosphorylation at Ser-910, Ser-843 and Tyr-397 induced by angiotensin II, LPA and EGF in intestinal epithelial cells

Differential FAK phosphorylation at Ser-910, Ser-843 and Tyr-397 induced by angiotensin II, LPA and EGF in intestinal epithelial cells

Discrimination between uterine serous papillary carcinomas and ovarian serous papillary tumours by gene expression profiling

What Makes the Bioactive Lipids Phosphatidic Acid and Lysophosphatidic Acid So Special?

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