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Pathway Description
Lysophosphatidic Acid LPA2 Signalling
Bos taurus
Category:
Protein Pathway
Sub-Categories:
Immunological
Gene Regulatory
Cytokine Signaling
Cytoskeletal Signaling
Kinase Signaling
Cellular Response
Created: 2018-08-31
Last Updated: 2019-08-16
Lysophosphatidic acid (LPA) is a water-soluble phospholipid derivative and a potent signalling molecule that binds to six known lysophosphatidic acid receptors (LPARs), named LPA1-LPA6. All six receptors belong to the G protein-coupled receptor (GPCR) superfamily which initiates intracellular signalling cascades via four G protein classes differentiated by their α subunit type: Gαs, Gαi/o, Gαq/11, Gα12/13. GPCRs mediate a wide range of biological processes, including cell survival, proliferation, migration, and differentiation, vascular regulation, and cytokine release. Due to LPA's physiological importance, abnormal LPA signalling likely contributes to the pathophysiology of many diseases. LPA biosynthesis proceeds through two major pathways: (1) the conversion of lysophospholipids (e.g. LPC, LPE, LPS) into LPA via autotaxin (ATX/Enpp2) and (2) the conversion of phosphatidic acid (PA) into LPA via phospholipase A1 or A2 (PLA1/PLA2). The binding of LPA to an LPAR allosterically activates the heterotrimeric G protein by exchanging GDP for GTP at the G protein's alpha subunit. This results in the dissociation of a Gα-GTP monomer and a Gβγ dimer from the receptor which allows both complexes to begin signalling cascades via downstream effectors. LPA1 signalling has been implicated in important processes such as cell survival, proliferation, adhesion, migration, immune function, and myelination. This receptor can couple with the G proteins Gαi/o, Gαq/11, and Gα12/13. The Gαi/o subunit inhibits the enzyme adenylyl cyclase (AC) which catalyzes the production of the important secondary messenger 3',5'-cyclic AMP (cAMP) from adenosine triphosphate (ATP). Other downstream effectors of Gαi/o include the MAPK/ERK pathway, the PI3K/Akt pathway, and P13K/Rac signalling. The Gαq/11 subunit activates phospholipase C (PLC) which cleaves the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2) into the secondary messengers inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 diffuses through the cytoplasm to the ER and binds to the inositol 1,4,5-trisphosphate (Ins3P) receptor, releasing calcium from the endoplasmic reticulum into the cytoplasm. Both calcium and DAG activate the kinase activity of protein kinase C beta (PKC). Among many other functions, PKC activates NF-κB. This leads to increased antigen presentation and increased expression of pro-inflammatory cytokines, cell adhesion molecules, and chemotactic factors. The Gα12/13 subunit regulates cell motility and cytoskeletal remodelling by activating the Rho/ROCK and Rho/SRF pathways.
References
Lysophosphatidic Acid LPA2 Signalling References
Krupinski J, Coussen F, Bakalyar HA, Tang WJ, Feinstein PG, Orth K, Slaughter C, Reed RR, Gilman AG: Adenylyl cyclase amino acid sequence: possible channel- or transporter-like structure. Science. 1989 Jun 30;244(4912):1558-64. doi: 10.1126/science.2472670.
Pubmed: 2472670
Tang WJ, Krupinski J, Gilman AG: Expression and characterization of calmodulin-activated (type I) adenylylcyclase. J Biol Chem. 1991 May 5;266(13):8595-603.
Pubmed: 2022671
Masada N, Ciruela A, Macdougall DA, Cooper DM: Distinct mechanisms of regulation by Ca2+/calmodulin of type 1 and 8 adenylyl cyclases support their different physiological roles. J Biol Chem. 2009 Feb 13;284(7):4451-63. doi: 10.1074/jbc.M807359200. Epub 2008 Nov 24.
Pubmed: 19029295
Katan M, Kriz RW, Totty N, Philp R, Meldrum E, Aldape RA, Knopf JL, Parker PJ: Determination of the primary structure of PLC-154 demonstrates diversity of phosphoinositide-specific phospholipase C activities. Cell. 1988 Jul 15;54(2):171-7. doi: 10.1016/0092-8674(88)90549-1.
Pubmed: 2455601
Ryu SH, Kim UH, Wahl MI, Brown AB, Carpenter G, Huang KP, Rhee SG: Feedback regulation of phospholipase C-beta by protein kinase C. J Biol Chem. 1990 Oct 15;265(29):17941-5.
Pubmed: 2211670
Fong HK, Hurley JB, Hopkins RS, Miake-Lye R, Johnson MS, Doolittle RF, Simon MI: Repetitive segmental structure of the transducin beta subunit: homology with the CDC4 gene and identification of related mRNAs. Proc Natl Acad Sci U S A. 1986 Apr;83(7):2162-6. doi: 10.1073/pnas.83.7.2162.
Pubmed: 3083416
Sugimoto K, Nukada T, Tanabe T, Takahashi H, Noda M, Minamino N, Kangawa K, Matsuo H, Hirose T, Inayama S, et al.: Primary structure of the beta-subunit of bovine transducin deduced from the cDNA sequence. FEBS Lett. 1985 Oct 28;191(2):235-40. doi: 10.1016/0014-5793(85)80015-6.
Pubmed: 2414128
Cuello F, Schulze RA, Heemeyer F, Meyer HE, Lutz S, Jakobs KH, Niroomand F, Wieland T: Activation of heterotrimeric G proteins by a high energy phosphate transfer via nucleoside diphosphate kinase (NDPK) B and Gbeta subunits. Complex formation of NDPK B with Gbeta gamma dimers and phosphorylation of His-266 IN Gbeta. J Biol Chem. 2003 Feb 28;278(9):7220-6. doi: 10.1074/jbc.M210304200. Epub 2002 Dec 16.
Pubmed: 12486123
Robishaw JD, Kalman VK, Moomaw CR, Slaughter CA: Existence of two gamma subunits of the G proteins in brain. J Biol Chem. 1989 Sep 25;264(27):15758-61.
Pubmed: 2506169
Gautam N, Baetscher M, Aebersold R, Simon MI: A G protein gamma subunit shares homology with ras proteins. Science. 1989 May 26;244(4907):971-4. doi: 10.1126/science.2499046.
Pubmed: 2499046
Wilcox MD, Schey KL, Busman M, Hildebrandt JD: Determination of the complete covalent structure of the gamma 2 subunit of bovine brain G proteins by mass spectrometry. Biochem Biophys Res Commun. 1995 Jul 17;212(2):367-74. doi: 10.1006/bbrc.1995.1979.
Pubmed: 7626050
Macrae AD, Premont RT, Jaber M, Peterson AS, Lefkowitz RJ: Cloning, characterization, and chromosomal localization of rec1.3, a member of the G-protein-coupled receptor family highly expressed in brain. Brain Res Mol Brain Res. 1996 Dec;42(2):245-54. doi: 10.1016/s0169-328x(96)00128-3.
Pubmed: 9013780
Yoo SH, Oh YS, Kang MK, Huh YH, So SH, Park HS, Park HY: Localization of three types of the inositol 1,4,5-trisphosphate receptor/Ca(2+) channel in the secretory granules and coupling with the Ca(2+) storage proteins chromogranins A and B. J Biol Chem. 2001 Dec 7;276(49):45806-12. doi: 10.1074/jbc.M107532200. Epub 2001 Oct 2.
Pubmed: 11584008
Marks AR, Tempst P, Chadwick CC, Riviere L, Fleischer S, Nadal-Ginard B: Smooth muscle and brain inositol 1,4,5-trisphosphate receptors are structurally and functionally similar. J Biol Chem. 1990 Dec 5;265(34):20719-22.
Pubmed: 2174422
Schlossmann J, Ammendola A, Ashman K, Zong X, Huber A, Neubauer G, Wang GX, Allescher HD, Korth M, Wilm M, Hofmann F, Ruth P: Regulation of intracellular calcium by a signalling complex of IRAG, IP3 receptor and cGMP kinase Ibeta. Nature. 2000 Mar 9;404(6774):197-201. doi: 10.1038/35004606.
Pubmed: 10724174
Coffer PJ, Woodgett JR: Molecular cloning and characterisation of a novel putative protein-serine kinase related to the cAMP-dependent and protein kinase C families. Eur J Biochem. 1991 Oct 15;201(2):475-81. doi: 10.1111/j.1432-1033.1991.tb16305.x.
Pubmed: 1718748
Coffer PJ, Woodgett JR: Molecular cloning and characterisation of a novel putative protein-serine kinase related to the cAMP-dependent and protein kinase C families. Eur J Biochem. 1992 May 1;205(3):1217.
Pubmed: 1533586
Gao T, Furnari F, Newton AC: PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth. Mol Cell. 2005 Apr 1;18(1):13-24. doi: 10.1016/j.molcel.2005.03.008.
Pubmed: 15808505
This pathway was propagated using PathWhiz -
Pon, A. et al. Pathways with PathWhiz (2015) Nucleic Acids Res. 43(Web Server issue): W552–W559.
Propagated from SMP0063753
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