|Written||2009-04||Mandi M Murph, Harish Radhakrishna|
|University of Georgia College of Pharmacy, Department of Pharmaceutical, Biomedical Sciences, 250 W Green Street, Rm 376 Athens, Georgia 30602 USA (MMM); Global Research & Technology, The Coca-Cola Company, 1 Coca-Cola Plaza Atlanta, GA 30313 USA (HR)|
(Note : for Links provided by Atlas : click)
|Location||9q31.3 [Link to chromosome band 9q31]|
|Location_base_pair||Starts at 110873252 and ends at 111038085 bp from pter ( according to hg19-Feb_2009) [Mapping LPAR1.png]|
|Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)|
|ADAMTS17 (15q26.3) / LPAR1 (9q31.3)||NAA15 (4q31.1) / LPAR1 (9q31.3)||NDRG1 (8q24.22) / LPAR1 (9q31.3)|
|SNX30 (9q32) / LPAR1 (9q31.3)|
|Note||mRNA length 3104 or 3182 bp, depending on alternative splicing.|
| Figure of the LPAR1, a G protein-coupled receptor, spanning the plasma membrane seven times. The receptor has three numbered extracellular and intracellular loops that are involved in signal transduction. Also shown are the amino terminus and carboxyl terminal tail.|
Three regions of the carboxyl terminal tail have been shown to be important for the LPAR1 signaling and receptor regulation. LPAR1 contains a canonical Type 1 PDZ binding domain (a.a. 362-364) at the extreme C-terminus. This domain has been shown to be required for LPA-induced cell proliferation and activation of Rho family GTPases via PDZ-Rho guanine nucleotide exchange factors. Further upstream in the carboxyl terminal tail, LPAR1 contains a di-leucine sequence (a.a. 351 and 352), which is required for phorbol ester-induced internalization. Still further upstream lies a serine-rich cluster (a.a. 341-347) that is required for beta-arrestin association, which is critical for signal attenuation and receptor endocytosis.
|Description||LPAR1 is an abbreviation for the LPA1 receptor, the first receptor cloned and identified from a growing number of LPA receptors that includes the Edg-family and the purinergic receptors.|
|Expression|| LPAR1 is ubiquitously expressed throughout cells and tissues in the body.|
High level of expression is found in amygdale, prefrontal cortex, caudate nucleus, hypothalamus, medulla oblongata, olfactory bulb, parietal lobe, spinal cord and thalamus.
Moderately high level of expression is found in adipocytes, cingulated cortex, occipital lobe, pons, whole brain, globus pallidus, subthalamic nucleus, temporal lobe, appendix, monocytes and smooth muscle.
Slightly above median level of expression is found in bronchial epithelial cells, cerebellum peduncies, dorsal root ganglia, ciliary ganglion, uterus, uterus corpus, atrioventricular node, fetal lung, fetal thyroid, skeletal muscle, cardiac myocytes, salivary gland, tongue and lymph node.
It is also expressed in tissues during neuronal development.
The expression of LPAR1 is increased in blister skin compared to normal skin.
The mRNA of LPAR1 is significantly increased 8 days after unilateral uretheral obstruction in mice kidneys where expression is higher in the medulla than the cortex.
The expression of LPAR1 is variable in cancer.
|Localisation|| It is a requirement of G protein-coupled receptor functioning that receptors are embedded into membranes for proper structure. The LPAR1 spans the plasma membrane seven times in a barrel conformation with three extracellular and three intracellular loops. At steady state, LPAR1 is located on the plasma membrane at the cell surface until it binds LPA, which triggers dynamin2-dependent, clathrin-mediated endocytosis into the cell. LPAR1 requires membrane cholesterol for association with beta-arrestin, which targets the receptor to clathrin-coated pits for internalization. In addition to LPA, phorbol ester stimulation of protein kinase C also induces internalization of LPAR1, but this does not require beta-arrestin. Rather, phorbol ester-dependent internalization of LPAR1 requires AP-2 clathrin adaptors. The LPAR1 is subsequently sorted through Rab-5 dependent early and recycling endosomes before it is recycled back to the cell surface or degraded in lysosomes.|
The receptor may also be localized to the nuclear membrane in the cell. Some evidence indicates that a portion of the total cellular LPAR1 localizes to the nuclear membrane in PC12 cells, micro-vascular endothelial cells, and human bronchial epithelial cells. The exact function of this nuclear LPAR1 pool is not known.
|Function|| The LPAR1 binds LPA and initiates G protein-dependent signal transduction cascades throughout the cell that result in a number of functional outcomes, depending on the specific cell or tissue type. The G alpha proteins involved are Gi, Gq and G 12/13.|
The receptor has critical functions that have been elucidated through gene knock-out studies in mice. LPAR1-null mice have deficiencies in olfactory development that impairs their ability to locate maternal nipples and initiate suckling required for survival. The lack of olfactant detection leads to 50% lethality among pups. Other LPAR1-null mice demonstrate alterations in neurotransmitters that mimic models of schizophrenia. LPAR1-null mice are 10-15% shorter than wild-type mice and have gross anatomical defects due to bone development, including incisor overgrowth that affects ability to feed.
The LPAR1 functions in normal cortical development and commits cortical neuroblasts to differentiate through the neural lineage. It may also play a role in the formation of dendritic spine synapses.
Through autotoxin-generated LPA, LPAR1 mediates neuropathic pain induced by nerve injury.
Activation of the LPAR1 functions in the inflammatory response; receptor activation stimulates the recruitment of macrophages.
The LPAR1 positively regulates motility in a variety of cell types, exerting a dominant signal in the absence of LPAR4.
|Homology||The LPAR1 has significant homology with LPAR2 (57%) and LPAR3 (51%), members of the original or classical endothelial differentiation gene (Edg) family. It has approximately 33-38% homology with individual sphingosine 1-phosphate receptors and no significant homology with the purinergic family of receptors that also bind LPA.|
|Note|| There are several single nucleotide polymorphisms (SNPs) reported within the LPAR1 gene and several of these are associated with altered phenotype and disease states.|
A functional SNP located in the promoter region of the gene (-2,820G/A; rs10980705) is associated with increased susceptibility to knee osteoarthritis in Japanese by showing an increase in binding and activity.
A change in amino acid sequence at position 125 from glutamine to glutamate in the LPAR1 will result in the ability of the receptor to recognize both S1P and LPA.
A change in amino acid sequence at position 236 from threonine to lysine in the LPAR1 will result in the enhanced activation of serum response factor.
Mutations in the LPAR1 were detected in a small percentage of adenomas and adenocarcinomas of rats given BHP in their drinking water. Missense mutations in the LPAR1 were detected in rat hepatocellular carcinomas induced by N-nitrosodiethylamine and choline-deficient l-amino acid-defined diets.
Deletion of the PDZ domain of the receptor prevents signal attenuation that controls LPA-mediated receptor activation and cell proliferation.
5. Implicated in
|Note||Overexpression of the LPAR1 in mice contributes to the tumorigenicity and aggressiveness of ovarian cancer.|
|Prognosis||Upregulation of the LPAR1 appears to enhance tumor progression in the previous examples.|
|Oncogenesis||The LPAR1 is a proto-oncogene contributing to the metastatic potential of breast cancers and may require signals from ErbB2/HER2 dimerization. In a study designed to assess the functional consequences of overexpression as it relates to breast carcinogenesis, 1000 selected/suspected cDNAs were inserted into immortalized MCF-10A cells and a derivative cell line, MCF-10A.B2 expressing an inducibly active variant of ErbB2. The study examined three assays (cell proliferation, migration and 3-D matrigel acinar morphogenesis) and the LPAR1 scored positive in all three; thus, it was determined to be a proto-oncogene in this disease. Several observations are of interest: first, the LPAR1 induced migration in the absence of ErbB2 activation but not in the absence of dimerization which suggests that the LPAR1 may require weak signals from ligand-independent dimerization of ErbB2 to induce migration; second, in the acinar morphogenesis assay, phenotypical changes of cells with the LPAR1 included the formation of features of invasive tumor cells, such as disorganized acinar structure, large structures and protrusive behavior; third, the LPAR1 was capable of establishing abnormal 3-D morphogenesis in the absence of conditions to dimerize ErbB2.|
|Note||The LPAR1 mediates fibroblast migration and recruitment in the injured lung. The chemotactic activity of fibroblasts is dependent on LPAR1 expression.|
|Disease|| Pulmonary fibrosis |
The concentration of LPA is elevated in bronchoalveolar lavage samples from patients with idiopathic pulmonary fibrosis. The fibroblasts of these patients require expression of LPAR1 for the chemotactic activity present in this pathology. Data suggests that LPAR1-null mice are substantially protected from fibroblast accumulation. This corresponds to lung injury where aberrant wound-healing responses exacerbate pulmonary fibrosis pathogenesis.
|Prognosis||LPAR1 links lung injury with pulmonary fibrosis development.|
|Phosphorylation and desensitization of the lysophosphatidic acid receptor LPA1.|
|Avendano-Vazquez SE, Garcia-Caballero A, Garcia-Sainz JA.|
|Biochem J. 2005 Feb 1;385(Pt 3):677-84.|
|Requirement for the lpA1 lysophosphatidic acid receptor gene in normal suckling behavior.|
|Contos JJ, Fukushima N, Weiner JA, Kaushal D, Chun J.|
|Proc Natl Acad Sci U S A. 2000 Nov 21;97(24):13384-9.|
|Absence of LPA1 signaling results in defective cortical development.|
|Estivill-Torrus G, Llebrez-Zayas P, Matas-Rico E, Santin L, Pedraza C, De Diego I, Del Arco I, Fernandez-Llebrez P, Chun J, De Fonseca FR.|
|Cereb Cortex. 2008 Apr;18(4):938-50. Epub 2007 Jul 26.|
|Lysophosphatidic acid stimulates neuronal differentiation of cortical neuroblasts through the LPA1-G(i/o) pathway.|
|Fukushima N, Shano S, Moriyama R, Chun J.|
|Neurochem Int. 2007 Jan;50(2):302-7. Epub 2006 Oct 23.|
|Modulation of pro-inflammatory gene expression by nuclear lysophosphatidic acid receptor type-1.|
|Gobeil F Jr, Bernier SG, Vazquez-Tello A, Brault S, Beauchamp MH, Quiniou C, Marrache AM, Checchin D, Sennlaub F, Hou X, Nader M, Bkaily G, Ribeiro-da-Silva A, Goetzl EJ, Chemtob S.|
|J Biol Chem. 2003 Oct 3;278(40):38875-83. Epub 2003 Jul 7.|
|LPA1 receptor-deficient mice have phenotypic changes observed in psychiatric disease.|
|Harrison SM, Reavill C, Brown G, Brown JT, Cluderay JE, Crook B, Davies CH, Dawson LA, Grau E, Heidbreder C, Hemmati P, Hervieu G, Howarth A, Hughes ZA, Hunter AJ, Latcham J, Pickering S, Pugh P, Rogers DC, Shilliam CS, Maycox PR.|
|Mol Cell Neurosci. 2003 Dec;24(4):1170-9.|
|Role of LPA4/p2y9/GPR23 in negative regulation of cell motility.|
|Lee Z, Cheng CT, Zhang H, Subler MA, Wu J, Mukherjee A, Windle JJ, Chen CK, Fang X.|
|Mol Biol Cell. 2008 Dec;19(12):5435-45. Epub 2008 Oct 8.|
|A functional SNP in EDG2 increases susceptibility to knee osteoarthritis in Japanese.|
|Mototani H, Iida A, Nakajima M, Furuichi T, Miyamoto Y, Tsunoda T, Sudo A, Kotani A, Uchida A, Ozaki K, Tanaka Y, Nakamura Y, Tanaka T, Notoya K, Ikegawa S.|
|Hum Mol Genet. 2008 Jun 15;17(12):1790-7. Epub 2008 Mar 6.|
|Identification of the orphan GPCR, P2Y(10) receptor as the sphingosine-1-phosphate and lysophosphatidic acid receptor.|
|Murakami M, Shiraishi A, Tabata K, Fujita N.|
|Biochem Biophys Res Commun. 2008 Jul 11;371(4):707-12. Epub 2008 May 6.|
|Lysophosphatidic acid decreases the nuclear localization and cellular abundance of the p53 tumor suppressor in A549 lung carcinoma cells.|
|Murph MM, Hurst-Kennedy J, Newton V, Brindley DN, Radhakrishna H.|
|Mol Cancer Res. 2007 Nov;5(11):1201-11.|
|Sharpening the edges of understanding the structure/function of the LPA1 receptor: expression in cancer and mechanisms of regulation.|
|Murph MM, Nguyen GH, Radhakrishna H, Mills GB.|
|Biochim Biophys Acta. 2008 Sep;1781(9):547-57. Epub 2008 Apr 29. (REVIEW)|
|Agonist-induced endocytosis of lysophosphatidic acid-coupled LPA1/EDG-2 receptors via a dynamin2- and Rab5-dependent pathway.|
|Murph MM, Scaccia LA, Volpicelli LA, Radhakrishna H.|
|J Cell Sci. 2003 May 15;116(Pt 10):1969-80. Epub 2003 Mar 26.|
|Frequent mutations of lysophosphatidic acid receptor-1 gene in rat liver tumors.|
|Obo Y, Yamada T, Furukawa M, Hotta M, Honoki K, Fukushima N, Tsujiuchi T.|
|Mutat Res. 2009 Jan 15;660(1-2):47-50. Epub 2008 Oct 21.|
|The role of LPA1 in formation of synapses among cultured hippocampal neurons.|
|Pilpel Y, Segal M.|
|J Neurochem. 2006 Jun;97(5):1379-92. Epub 2006 Apr 21.|
|Lysophosphatidic acid and renal fibrosis.|
|Pradere JP, Gonzalez J, Klein J, Valet P, Gres S, Salant D, Bascands JL, Saulnier-Blache JS, Schanstra JP.|
|Biochim Biophys Acta. 2008 Sep;1781(9):582-7. Epub 2008 Apr 11. (REVIEW)|
|Neurochemical changes in LPA1 receptor deficient mice--a putative model of schizophrenia.|
|Roberts C, Winter P, Shilliam CS, Hughes ZA, Langmead C, Maycox PR, Dawson LA.|
|Neurochem Res. 2005 Mar;30(3):371-7.|
|Different mechanisms regulate lysophosphatidic acid (LPA)-dependent versus phorbol ester-dependent internalization of the LPA1 receptor.|
|Urs NM, Kowalczyk AP, Radhakrishna H.|
|J Biol Chem. 2008 Feb 29;283(9):5249-57. Epub 2007 Dec 18.|
|A single amino acid determines lysophospholipid specificity of the S1P1 (EDG1) and LPA1 (EDG2) phospholipid growth factor receptors.|
|Wang DA, Lorincz Z, Bautista DL, Liliom K, Tigyi G, Parrill AL.|
|J Biol Chem. 2001 Dec 28;276(52):49213-20. Epub 2001 Oct 16.|
|Integrin signalling regulates the nuclear localization and function of the lysophosphatidic acid receptor-1 (LPA1) in mammalian cells.|
|Waters CM, Saatian B, Moughal NA, Zhao Y, Tigyi G, Natarajan V, Pyne S, Pyne NJ.|
|Biochem J. 2006 Aug 15;398(1):55-62.|
|Functional proteomics approach to investigate the biological activities of cDNAs implicated in breast cancer.|
|Witt AE, Hines LM, Collins NL, Hu Y, Gunawardane RN, Moreira D, Raphael J, Jepson D, Koundinya M, Rolfs A, Taron B, Isakoff SJ, Brugge JS, LaBaer J.|
|J Proteome Res. 2006 Mar;5(3):599-610.|
|Mutations of lysophosphatidic acid receptor-1 gene during progression of lung tumors in rats.|
|Yamada T, Obo Y, Furukawa M, Hotta M, Yamasaki A, Honoki K, Fukushima N, Tsujiuchi T.|
|Biochem Biophys Res Commun. 2009 Jan 16;378(3):424-7. Epub 2008 Nov 21.|
|Physical and functional interactions of the lysophosphatidic acid receptors with PDZ domain-containing Rho guanine nucleotide exchange factors (RhoGEFs).|
|Yamada T, Ohoka Y, Kogo M, Inagaki S.|
|J Biol Chem. 2005 May 13;280(19):19358-63. Epub 2005 Mar 8.|
|Lysophosphatidic acid receptors determine tumorigenicity and aggressiveness of ovarian cancer cells.|
|Yu S, Murph MM, Lu Y, Liu S, Hall HS, Liu J, Stephens C, Fang X, Mills GB.|
|J Natl Cancer Inst. 2008 Nov 19;100(22):1630-42. Epub 2008 Nov 11.|
|This paper should be referenced as such :|
|Murph, MM ; Radhakrishna, H|
|LPAR1 (lysophosphatidic acid receptor 1)|
|Atlas Genet Cytogenet Oncol Haematol. 2010;14(3):289-292.|
|Free journal version : [ pdf ] [ DOI ]|
|On line version : http://atlasgeneticsoncology.usal.es/classic/Genes/LPAR1ID40405ch9q31.html|
|Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 3 ]|
8. External links
|REVIEW articles||automatic search in PubMed|
|Last year publications||automatic search in PubMed|
|© Atlas of Genetics and Cytogenetics in Oncology and Haematology||indexed on : Thu Jan 17 18:59:38 CET 2019|
For comments and suggestions or contributions, please contact us firstname.lastname@example.org.