Lysophospholipid receptor activation of RhoA and lipid signaling pathways

Abstract

The lysophospholipids sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA) signal through G-protein coupled receptors (GPCRs) which couple to multiple G-proteins and their effectors. These GPCRs are quite efficacious in coupling to the Gα12/13 family of G-proteins, which stimulate guanine nucleotide exchange factors (GEFs) for RhoA. Activated RhoA subsequently regulates downstream enzymes that transduce signals which affect the actin cytoskeleton, gene expression, cell proliferation and cell survival. Remarkably many of the enzymes regulated downstream of RhoA either use phospholipids as substrates (e.g. phospholipase D, phospholipase C-epsilon, PTEN, PI3 kinase) or are regulated by phospholipid products (e.g. protein kinase D, Akt). Thus lysophospholipids signal from outside of the cell and control phospholipid signaling processes within the cell that they target. Here we review evidence suggesting an integrative role for RhoA in responding to lysophospholipids upregulated in the pathophysiological environment, and in transducing this signal to cellular responses through effects on phospholipid regulatory or phospholipid regulated enzymes.

Lysophosphatidic Acid Receptor–2 Deficiency Confers Protection against Bleomycin-Induced Lung Injury and Fibrosis in Mice

“…LPA signals through its G-protein-coupled receptors, and so far, in humans, six LPA receptors (LPA [1][2][3][4][5][6] ) have been cloned and characterized (11)(12)(13)(14). Recent studies have demonstrated a positive role for LPA and LPA 1 in the pathogenesis of fibrosis (15,16).…”

FTY720 Phosphate Activates Sphingosine-1-Phosphate Receptor 2 and Selectively Couples to Gα12/13/Rho/ROCK to Induce Myofibroblast Contraction

“…Rho/ROCK signaling results in cellular responses, including modulation of gene transcription, rearrangement of the myosin-actin cytoskeleton, cell contraction, and fibrosis (Siehler, 2009;Kozasa et al, 2011;Knipe et al, 2015). S1P is a well established activator of the Rho/ROCK signaling pathway and is linked to multiple phenotypic changes in fibroblasts and vascular smooth muscle cells (Hu et al, 2006;Siehler, 2009;Xiang et al, 2013). S1P was shown to induce fibroblast-to-myofibroblast transformation and increase collagen expression via S1P 2 receptor-mediated Rho signaling in lung and cardiac fibroblasts (Urata et al, 2005;Gellings Lowe et al, 2009).…”

Bioactive Lysophospholipids: Role in Regulation of Aqueous Humor Outflow and Intraocular Pressure in the Context of Pathobiology and Therapy of Glaucoma

“…60 Bioactive LPA regulates a wide variety of cellular processes, including cell proliferation, differentiation, migration, transcription, and survival, by activating different signaling pathways that are mediated by Ras, Rho, and Rac, adenylyl cyclase, PLC, PLD, AKT, and PI3 kinases. 48,52,[56][57][58]60 By activating these different intracellular molecules via their cognate GPCRs, lysophospholipids regulate multiple and redundant cellular processes. 60 LPA has been also shown to mediate its intracellular effects by regulating calcium influx and peroxisome proliferator-activated receptor-gamma nuclear receptor activity.…”

“…LPA and S1P act at the extracellular and intracellular levels, mediating their biological effects via different G-protein-coupled receptors (GPCRs), which are linked to the subunits of Ga12/13, Gq/11 and Gi heterotrimeric G-proteins. 45,48,51,60 There are several wellcharacterized and cognate subtypes of GPCRs for S1P and LPA, including S1P [1][2][3][4][5] and LPA [1][2][3][4][5][6] , respectively. 45,51,57 These different GPCRs belong to either EDG or P2Y receptor clusters and are expressed widely in different tissues and cell types.…”

“…45,46,[48][49][50][51][52][53][54][55][56][57][58][59][60] Lysophospholipids refer to any phospholipids that are missing one of their 2 O-acyl chains. They are divided into 2 major groups: lysoglycerophospholipids and lysosphingolipids with LPA and S1P being prominent representatives of the 2 classes, respectively.…”