LPAR4 Membrane Protein Introduction

Introduction of LPAR4

LPAR4, encoded by LPAR4 gene, is a member of seven transmembrane G-protein coupled receptor family. It is coupled with G_α proteins, including G_12/13, G_q/11, G_i/o, and G_s to mediate cell signaling transduction and regulate multiple biological processes. LPAR4 has a different amino acid sequence from other lysophospholipid receptors, and with slight homology to others but high similarity to P2Y purinergic receptors. Due to an affinity with lysophosphatidic acid (LPA), LPAR4 is also classified into LPAR subtype. LPAR4 is most expressed in human ovary, while less prominent in thymus, pancreas, brain, heart, small intestine, testis, prostate, colon, and spleen.

Function of LPAR4 Membrane Protein

The activated LPAR4 by LPA stimulates G proteins activation and mediates intracellular signaling molecules action, such as increasing adenylyl cyclase activities and calcium ions levels, thereby mediating cell signal transduction and pleiotropic metabolic activities. The receptor interacting with G_12/13 stimulates the activation of Rho/ROCK pathway participating in the regulation of neurite retraction induction and stress fiber formation. And the receptor can promote cell aggregation and N-cadherin-dependent cell adhesion via ROCK pathway. Moreover, the receptor also regulates the differentiation of immortalized hippocampal progenitor cells and monocytic. Besides, the deficiency of LPAR4 during mice embryo development may induce the dysfunctions of circulatory and lymphatic system, suggesting that LPAR4 is also involved in the mediation of circulatory and lymphatic system development. Recent studies have shown that LPAR4 plays a very important role in the progression of multiple types of cancer, such as papillary carcinoma, head and neck squamous cell carcinoma cells, colon cancer, and may act as a potential diagnostic and therapeutic targets for cancer.

Fig.1 Schematic illustration of LPA/GPCR signaling pathways. (Braun, 2015)

Application of LPAR4 Membrane Protein in Literature

1. Kowalczyk-Zieba I., et al. LPAR2 and LPAR4 are the main receptors responsible for LPA actions in ovarian endometriotic cysts. Reproductive Sciences. 2018. PubMed ID: 29621954
   
   

   The study indicates that the high production of LPAR2 and LPAR4 is observed in ovarian endometriotic cysts and positive correlations of both these receptors with the expression of E2 and P4 receptors. Hence, LPAR2 and LPAR4 are mainly responsible for LPA activation in ovarian endometriotic cysts and those receptors may serve as the promising biomarkers for the endometriotic cysts.

2. Jiang C., et al. Microrna-139-5p inhibits epithelial-mesenchymal transition and fibrosis in post-menopausal women with interstitial cystitis by targeting LPAR4 via the PI3K/Akt signaling pathway. Journal of Cellular Biochemistry. 2018, 119(8):6429-6441. PubMed ID: 29240250
   
   

   The study indicates that the epithelial-mesenchymal transition and fibrosis are inhibited in post-menopausal women with interstitial cystitis by microRNA-139-5p targeting LPAR4 via the PI3K/Akt signaling pathway.

3. Takara K., et al. Lysophosphatidic acid receptor 4 activation augments drug delivery in tumors by tightening endothelial cell-cell contact. Cell Reports. 2017, 20(9):2072-2086. PubMed ID: 28854359
   
   

   The authors reveal that vascular normalization in tumors may improve drug delivery and anti-tumor immunity. And LPA4 activation is associated with the formation of a vascular network. Hence, LPA4 activation may enhance drug delivery in tumors.

4. Brown A., et al. Lysophosphatidic acid receptor mRNA levels in heart and white adipose tissue are associated with obesity in mice and humans. Plos One. 2017, 12(12):e0189402. PubMed ID: 29236751
   
   

   The findings show that obesity is associated with increased LPA4, LPA5 and/or LPA6 levels in mice ventricles and cardiomyocytes. Moreover, LPA4, LPA5, and LPA6 mRNA levels in human heart and adipose tissue are also related to obesity. Thus, it is reported that LPA receptor signaling is correlated with obesity.

5. Takahashi K., et al. Lysophosphatidic acid (LPA) signaling via LPA4 and LPA6 negatively regulates cell motile activities of colon cancer cells. Biochem Biophys Res Commun. 2017, 483(1):652-657. PubMed ID: 27993681
   
   

   The study finds that the inhibition of LPA4 and LPA6 can increase cell motile activities of DLD1 and HCT116 cells, as well as long-term 5-FU, treated cells.

LPAR4 Preparation Options

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Reference

1. Braun A H and Coffey R J. (2015). Lysophosphatidic acid, a disintegrin and metalloprotease-17 and heparin-binding epidermal growth factor-like growth factor in ovarian cancer: the first word, not the last. Clinical Cancer Research An Official Journal of the American Association for Cancer Research. 11(13), 4639-43.

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