Both human and mouse LPA2 genes are present as a single copy and are divided among three exons with start and stop sites in the second and third exons, respectively (Contos and Chun, 2000). Introns are located upstream of the start codon and separate the coding region from the transmembrane domain VI. As seen by Northern blot analysis, there are two transcripts sizes for both human and mouse LPA2. In human, the transcript sizes are ~1.8kb and ~10kb and in mouse the transcript sizes are ~3kb and ~7kb (An et al., 1998).

Human LPA2 encodes a protein with a predicted 351 amino acid residues and molecular weight of 39.1 kDa. There is 90.8% sequence homology between mouse and human LPA2 amino acid sequences and 60% amino acid similarity with LPA1. Mouse LPA2 encodes a protein with a predicted 348 amino acids and molecular weight of 38.9 kDa.

LPA2 is a G-protein coupled receptor (GPCR) that belongs to the endothelial differentiation gene (Edg) family of receptors. It was first identified in 1998 following a search in the GenBank for homologs to human EDG2 (LPA1) (An et al., 1998; Contos and Chun, 1998).

LPA2 has a more restricted expression pattern than that of LPA1. More information is currently available for LPA2 mRNA expression than protein expression, and there is a current need for well-validated LPA2-specific antibodies.
Human: LPA2 mRNA is expressed in a variety of tissues including human testis, leukocytes, prostate, spleen, thymus, pancreas, and bone marrow (An et al., 1998; Fang et al., 2002). The expression of LPA2 has also been noted in freshly isolated human blood CD4+ T cells, B cells, and Jurkat T cells (Zheng et al., 2000; Goetzl et al., 2000; Rubenfeld et al., 2006) as well as monocyte-derived dendritic cells (Chen et al., 2006; Oz-Arslan et al., 2006). Interestingly, Zheng et al. reported that LPA2 expression decreases in PMA-activated CD4+ T cells, while others reported increased expression of LPA2 after T cell activation, hence future studies are needed to dissect the expression of LPA2 during the activation of T cells (Zheng et al., 2000; Rubenfeld et al., 2006). LPA2 is also expressed on the apical surface of intestinal epithelial cells (Li et al., 2005) and in the airway epithelia cells of human lung tissue (Barekzi et al., 2006). In addition, LPA2 is expressed in epithelial cell lines: A549 and BEAS-2B (Barekzi et al., 2006). Interestingly, IL-13 and IFN-gamma reduced LPA2 mRNA levels in the A549 cell line (Barekzi et al., 2006).
In addition to its normal expression, LPA is also commonly increased in a number of human malignancies. LPA2 is aberrantly expressed in various cancer cells including ovarian cancer cell lines (Fang et al., 2000; Fang et al., 2002; Goetzl et al., 1999), the cervical cancer cell lines CaSki, HeLa, and SiHa (Chen et al., 2011), colorectal cancer (Shida et al., 2004), thyroid cancer (Schulte et al., 2001) and invasive ductal carcinoma breast cancer (Kitayama et al., 2004; Chen et al., 2007). It has been noted that LPA2 overexpression is more commonly seen in postmenopausal breast cancer patients than in premenopausal patients (Kitayama et al., 2004). It is also expressed in nasal polyp tissue from subjects with chronic hyperplastic eosinophilic sinusitis (CHES) (Barekzi et al., 2006).
In mice, LPA2 mRNA is expressed in kidney, uterus, and testis at relatively high levels, and moderately expressed in the lung. Lower levels of LPA2 are also seen in spleen, thymus, stomach, brain, and heart.

LPA2 is a GPCR that spans the plasma membrane seven times and contains three extracellular loops and three intracellular loops. LPA2 is unique from the other LPA receptors as it contains two distinct protein-protein interaction domains in the carboxyl-terminal tail (aa 296-351). In the proximal region, LPA2 contains a di-leucine motif and several putative palmitoylated cysteine residues. This region is responsible for associating with zinc-finger proteins, including TRIP6 (Xu et al., 2004) and the proapoptotic Siva-1 protein (Lin et al., 2007). In the distal region, there are several serine and threonine residues that can be phosphorylated by G protein-coupled receptor kinases (GRKs) and may be involved in β-arrestin binding and receptor internalization. The last four amino acids of this region (DSTL) contains a class I PDZ-binding motif and mediates interactions with a number of proteins such as Na+/H+ exchanger regulatory factor 2 (NHERF2) (Oh et al., 2004; Yun et al., 2005), PDZ-RhoGEF and LARG (Yamada et al., 2005), and MAGI-3 (Zhang et al., 2007).

LPA2 is a GPCR that couples with and activates three heterotrimeric G proteins: Gi, Gq, G12/13. These G proteins transmit signals through downstream signaling molecules that include phosphatidylinositol 3-kinase, phospholipase C, Ras, Rac, and Rho. Activation of LPA2 therefore induces a range of cellular responses including cell survival and differentiation, cell migration, and roles in cancer metastasis.
For example, LPA2 signaling is associated with cell survival and proliferation in ovarian cancer cells (Goetzl et al., 1999) and rescues intestinal epithelial cells-6 (IEC-6) from apoptosis through inhibition of caspase-3 activation (Deng et al., 2002). Likewise, LPA2 targets the pro-apoptotic Siva-1 protein for LPA-dependent ubiquitination and degradation, thereby down regulating the pro-apoptotic activity of Siva-1 during the DNA damage response (Lin et al., 2007).
LPA2 is also involved in promoting cell motility. Jurkat cells that express LPA2 were reported to have enhanced trans-Matrigel migration (Zheng et al., 2001). It has also been shown that LPA binding to LPA2 leads to the recruitment of TRIP6, a focal adhesion molecule, to the C terminus of LPA2 at the plasma membrane. This promotes its targeting to focal adhesions and co-localization with actin, thereby regulating LPA-induced cell migration (Xu et al., 2004; Lai et al., 2005). The PTPL1 phosphatase dephosphorylates TRIP6 and attenuates LPA-induced cell migration, thus acting as a negative regulator of cell motility (Lai et al., 2007). LPA2 has also been identified to be involved in regulating smooth muscle cell migration in the context of vascular injury (Panchatcharam et al., 2008).
Recently, two groups have implicated LPA2 signaling in TGF-β activation in mouse models of lung fibrosis and ischemia-reperfusion injury. These studies have shown that LPA2 signaling through Gαq in human epithelial cells and proximal tubule cells activates RhoA and Rho kinase, leading to the activation of αvβ6 integrin. This in turn, leads to the binding of latent TGF-β to αvβ6, and subsequent activation of TGF-β (Xu et al., 2009; Geng et al., 2012).
LPA2 signaling has emerged as a potential factor in many cancer pathways. There is high expression of LPA2 in human thyroid cancer (Schulte et al., 2001), colorectal cancer (Shida et al., 2004), as well as in human invasive breast ductal carcinoma (Kitayama et al., 2004). LPA2 is involved in tumor growth and tumor angiogenesis of in vivo cervical cancer cells (Chen et al., 2011) (Yu et al., 2008). LPA2 mediates mitogenic signals and cytokine production in human colonic epithelial cells (Yun et al., 2005). In pancreatic cancer cells, signaling through LPA2 leads to the inhibition of EGF-induced migration and invasion (Komachi et al., 2009). It also mediates chemotaxis in a Rho-dependent manner in breast carcinoma cells (Chen et al., 2007). In ovarian cancer cells, LPA2 signaling through Gαi/src leads to transactivation of EGFR and COX-2 expression, and increased ovarian cancer motility and aggressiveness (Jeong et al., 2008). A role for LPA2 and endometrial cancer invasion and MMP7 activation has also been shown (Mayer Hope et al., 2009).
It has been reported that homozygous knock-out lpa2^-/- mice display no obvious phenotypic abnormalities and are born at expected frequencies (Contos et al., 2002). Zhao et al. reported that heterozygous lpa2^+/- mice are partially protected from lung inflammation following Schistosoma egg allergen (SEA) challenge (Zhao et al., 2009). However, Emo et al. revealed that allergic lung inflammation is significantly greater in lpa2^-/- mice, suggesting that LPA2 plays a role in suppressing dendritic cell activation and allergic immune responses (Emo et al., 2012).

LPA2 has ~60% homology to LPA1.

The first human LPA2 cDNA clone was derived from an ovarian tumor library, however it differed from reported human LPA2 sequences (An et al., 1998). The protein product from the ovarian tumor lacks the last four amino acids (DSTL) and is 31 amino acid residues longer at the C-terminus relative to the predicted protein product. The extra amino acids are the result of a guanine nucleotide deletion in the fourth to last codon (Contos and Chun, 2000). Additionally, in two human colon cancer cell lines, DLD1 and SW48, LPA2 and LPA4 were found to contain five mutations of G/C to A/T transitions (Tsujino et al., 2010). These mutated LPA2 receptors may alter LPA2 signaling through its respective G proteins and downstream pathways, and play a role in cancer progression.