Sharpening the edges of understanding the structure/function of the LPA1 receptor: Expression in cancer and mechanisms of regulation☆

Abstract

Since the molecular cloning of the vzg-1/Edg-2/LPA1 gene, studies have attempted to characterize LPA1 receptor functionality into a single categorical role, different from the other Edg-family LPA receptors. The desire to categorize LPA1 function has highlighted its complexity and demonstrated that the LPA1 receptor does not have one absolute function throughout every system. The central nervous system is highly enriched in the LPA1 receptor, suggesting an integral role in neuronal processes. Metastatic and invasive breast cancer also appears to have LPA-mediated LPA1 receptor functions that enhance phenotypes associated with tumorigenesis. LPA1 possesses a number of motifs conserved among G protein-coupled receptors (GPCRs): a DRY-like motif, a PDZ domain, Ser/Thr predicted sites of phosphorylation, a dileucine motif, double cysteines in the tail and conserved residues that stabilize structure and determine ligand binding. The third intracellular loop of the LPA1 receptor may be the crux of receptor signaling and attenuation with phosphorylation of Thr-236 potentially a key determinant of basal LPA1 signaling. Mutagenesis data supports the notion that Thr-236 regulates this process since mutating Thr-236 to Ala-236 increased basal and LPAmediated serum response factor (SRF) signaling activity and Lys-236 further increased this basal signaling. Here we describe progress on defining the major functions of the LPA1 receptor, discuss a context dependent dualistic role as both a negative regulator in cancer and a proto-oncogene, outline its structural components at the molecular amino-acid level and present mutagenesis data on the third intracellular loop of the receptor.

Lysophosphatidic acid stimulates cell migration, invasion, and colony formation as well as tumorigenesis/metastasis of mouse ovarian cancer in immunocompetent mice

“…Whereas LPA 1 plays a very important role in migration of breast, pancreatic, and prostate cancer cells (25,26), our data suggest that LPA 2 and LPA 3 are more important in cell adhesion, migration, and invasion of EOC cells, which are consistent with reports showing that LPA 1 is involved in the negative growth regulation in ovarian cancer cells and that LPA 2 and LPA 3 , but not LPA 1 , expression is up-regulated in last-stage EOC (27). In addition, we have shown that either inhibitors and/or dominantnegative forms of G i protein, phosphatidylinositol 3-kinase, or cytosolic phospholipase A 2 (cPLA 2 ) completely or nearly completely block LPA-induced cell migration in human EOC cells, suggesting that these three molecules play a pivotal role in this process (2,10,11,24).…”

“…4). To date, at least six LPA receptors have been identified (27). These receptors may have overlapping or even opposing effects in vitro and in vivo.…”

Lysophosphatidic acid augments human hepatocellular carcinoma cell invasion through LPA1 receptor and MMP-9 expression

“…However, ovarian cancer show a significant reduction in LPA1 levels as compared with normal tissues . In addition, LPA2 and LPA3 appear to have a greater role in ovarian cancer aggressiveness as compared with LPA1 (Sengupta et al, 2003;Ren et al, 2006;Murph et al, 2008;Yu et al, 2008). In our current study, we demonstrated higher levels of LPA1 transcripts in HCC cells than that of LPA2 or LPA3.…”

Pharmacokinetic and Pharmacodynamic Characterization of an Oral Lysophosphatidic Acid Type 1 Receptor-Selective Antagonist

“…LPA 1 is a member of the endothelial differentiation gene family (Hecht et al, 1996;An et al, 1997) and exhibits widespread tissue distribution with high levels of expression in the brain, heart, small intestine, kidney, ovary, testis, prostate, colon, thymus, and pancreas (Yang et al, 2002;Anliker and Chun, 2004). Furthermore, increased LPA 1 signaling has been implicated in a number of disease processes (Shida et al, 2003;Inoue et al, 2004;Boucharaba et al, 2006;Murph et al, 2008;Pradère et al, 2008;Tager et al, 2008), making this receptor a novel target for therapeutic intervention. However, there are currently no selective LPA 1 antagonists being used clinically.…”