Lysophosphatidic acid explained

A lysophosphatidic acid (LPA) is a phospholipid derivative that can act as a signaling molecule.^{[1] [2] [3] [4]}

Function

See also: Lysophospholipid receptor. LPA acts as a potent mitogen due to its activation of three high-affinity G-protein-coupled receptors called LPAR1, LPAR2, and LPAR3 (also known as EDG2, EDG4, and EDG7). Additional, newly identified LPA receptors include LPAR4 (P2RY9, GPR23), LPAR5 (GPR92) and LPAR6 (P2RY5, GPR87).

Clinical significance

Because of its ability to stimulate cell proliferation, aberrant LPA-signaling has been linked to cancer in numerous ways. Dysregulation of autotaxin or the LPA receptors can lead to hyperproliferation, which may contribute to oncogenesis and metastasis.^[5]

LPA may be the cause of pruritus (itching) in individuals with cholestatic (impaired bile flow) diseases.

GTPase activation

Downstream of LPA receptor activation, the small GTPase Rho can be activated, subsequently activating Rho kinase. This can lead to the formation of stress fibers and cell migration through the inhibition of myosin light-chain phosphatase.

Metabolism

There are a number of potential routes to its biosynthesis, but the most well-characterized is by the action of a lysophospholipase D called autotaxin, which removes the choline group from lysophosphatidylcholine.

Lysophosphatidic acids are also intermediates in the synthesis of phosphatidic acids.

See also

• Autotaxin
• GPR35
• Phosphatidic acid
• Sphingosine-1-phosphate
• Gintonin

Further reading

• 10.1053/j.gastro.2010.05.009 . Lysophosphatidic Acid is a Potential Mediator of Cholestatic Pruritus . 2010 . Kremer . Andreas E. . Martens . Job J.W.W. . Kulik . Wim . Ruëff . Franziska . Kuiper . Edith M.M. . Van Buuren . Henk R. . Van Erpecum . Karel J. . Kondrackiene . Jurate . Prieto . Jesus . Rust . Christian . Geenes . Victoria L. . Williamson . Catherine . Moolenaar . Wouter H. . Beuers . Ulrich . Oude Elferink . Ronald P.J. . Gastroenterology . 139 . 3 . 1008–18, 1018.e1 . 20546739. 8 .
• Wouter H. . Moolenaar . Lysophosphatidic Acid, a Multifunctional Phospholipid Messenger . The Journal of Biological Chemistry . 7768880 . 10.1074/jbc.270.22.12949 . 1995 . 270 . 22 . 12949–52. free .
• 10.1038/nrc1143 . The emerging role of lysophosphatidic acid in cancer . 2003 . Mills . Gordon B. . Moolenaar . Wouter H. . Nature Reviews Cancer . 3 . 8 . 582–91 . 12894246. 29079135 .
• 10.1038/sj.bjc.6605588 . Lysophosphatidic acid production and action: Critical new players in breast cancer initiation and progression . 2010 . Panupinthu . N . Lee . H Y . Mills . G B . British Journal of Cancer . 102 . 6 . 941–6 . 20234370 . 2844037.
• 10.1038/onc.2010.517 . Lysophosphatidic acid augments human hepatocellular carcinoma cell invasion through LPA1 receptor and MMP-9 expression . 2010 . Park . S Y . Jeong . K J . Panupinthu . N . Yu . S . Lee . J . Han . J W . Kim . J M . Lee . J-S . Kang . J . Park . C G . Mills . G B . Lee . H Y . Oncogene . 30 . 11 . 1351–9 . 21102517. 8 . free .
• 10.1152/ajpregu.1997.273.2.R703 . Yakubu . M A . Liliom . K . Tigyi . G J . Leffler . C W . Role of lysophosphatidic acid in endothelin-1-and hematoma-induced alteration of cerebral microcirculation . American Journal of Physiology. Regulatory, Integrative and Comparative Physiology . 1997 . 273 . 2 . R703–R709 .
• 10.1152/ajpheart.1995.268.5.H2048 . Tigyi . G J . Hong . L . Yakubu . M . Parfenova . H . Shibata . M . Leffler . C W . Lysophosphatidic acid alters cerebrovascular reactivity in piglets . American Journal of Physiology. Heart and Circulatory Physiology . 1995 . 268 . 5 . H2048–H2055 . 7771554 .

Notes and References

1. van Corven . Emile J.. Groenink . Alida . Jalink. Kees. Eichholtz. Thomas. Moolenaar. Wouter H.. 1989-10-06 . Lysophosphatidate-induced cell proliferation: Identification and dissection of signaling pathways mediated by G proteins . Cell . 59 . 1 . 45–54 . 10.1016/0092-8674(89)90868-4 . 2551506. 25154850.
2. Tsukahara . Tamotsu . Tsukahara . Ryoko . Haniu . Hisao . Matsuda . Yoshikazu . Murakami-Murofushi . Kimiko . 2015-09-05 . Cyclic phosphatidic acid inhibits the secretion of vascular endothelial growth factor from diabetic human coronary artery endothelial cells through peroxisome proliferator-activated receptor gamma . Molecular and Cellular Endocrinology . en . 412 . 320–329 . 10.1016/j.mce.2015.05.021 . 26007326 . 0303-7207. 10069/35888 . 10454566 . free .
3. Moolenaar . Wouter H. . 1995-06-02 . Lysophosphatidic Acid, a Multifunctional Phospholipid Messenger ∗ . Journal of Biological Chemistry . English . 270 . 22 . 12949–12952 . 10.1074/jbc.270.22.12949 . 0021-9258 . 7768880. free .
4. Tigyi . Gabor . Parrill . Abby L. . 2003-11-01 . Molecular mechanisms of lysophosphatidic acid action . Progress in Lipid Research . en . 42 . 6 . 498–526 . 10.1016/S0163-7827(03)00035-3 . 14559069 . 0163-7827.
5. Benesch. MG. Ko. YM. McMullen. TP. Brindley. DN. Autotaxin in the crosshairs: taking aim at cancer and other inflammatory conditions. FEBS Letters. 2014. 588. 16. 2712–27. 10.1016/j.febslet.2014.02.009. 24560789. 35544825. free. 2014FEBSL.588.2712B .