Asymmetrical Macromolecular Complex Formation of Lysophosphatidic Acid Receptor 2 (LPA2) Mediates Gradient Sensing in Fibroblasts

Ren, Aiming; Moon, Changsuk; Zhang, Weiqiang; Sinha, Chandrima; Yarlagadda, Sunitha; Arora, Kavisha; Wang, Xusheng; Yue, Junming; Parthasarathi, Kaushik; Heil-Chapdelaine, Rick; Tigyi, Gábor; Naren, Anjaparavanda P.

doi:10.1074/jbc.m114.595512

Cited by 8 publications

(9 citation statements)

References 64 publications

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“…Interestingly, it has been observed that β-arrestin is not required for PMA-induced LPA 1 receptor internalization [ 64 ], which further emphasizes the differences between LPA-mediated processes and those induced by pharmacological activation of PKC. Agonist-triggered internalization of LPA 2 receptors has also been studied [ 60 , 65 ]. In one of these works clear agonist-induced receptor internalization was observed [ 60 ] whereas in the other, internalization was slow and very limited in magnitude [ 65 ]; marked differences in the experimental conditions (i. e., cell types, conditions for LPA exposure and in the detection of membrane receptors) might explain the disparate results.…”

Section: Discussionmentioning

confidence: 99%

“…Agonist-triggered internalization of LPA 2 receptors has also been studied [ 60 , 65 ]. In one of these works clear agonist-induced receptor internalization was observed [ 60 ] whereas in the other, internalization was slow and very limited in magnitude [ 65 ]; marked differences in the experimental conditions (i. e., cell types, conditions for LPA exposure and in the detection of membrane receptors) might explain the disparate results. Interestingly, LPA 2 receptors are key elements in the formation of the macromolecular complexes that mediate LPA gradient sensing in fibroblasts [ 65 ].…”

Section: Discussionmentioning

confidence: 99%

“…In one of these works clear agonist-induced receptor internalization was observed [ 60 ] whereas in the other, internalization was slow and very limited in magnitude [ 65 ]; marked differences in the experimental conditions (i. e., cell types, conditions for LPA exposure and in the detection of membrane receptors) might explain the disparate results. Interestingly, LPA 2 receptors are key elements in the formation of the macromolecular complexes that mediate LPA gradient sensing in fibroblasts [ 65 ]. In our work, we consistently observed that LPA- and PMA-induced LPA 2 receptor internalizations were of lesser magnitude than those observed with the remaining subtypes studied.…”

Section: Discussionmentioning

confidence: 99%

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Phosphorylation and Internalization of Lysophosphatidic Acid Receptors LPA1, LPA2, and LPA3

et al. 2015

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ResultsThe lysophosphatidic acid receptors LPA1, LPA2, and LPA3 were individually expressed in C9 cells and their signaling and regulation were studied. Agonist-activation increases intracellular calcium concentration in a concentration-dependent fashion. Phorbol myristate acetate markedly inhibited LPA1- and LPA3-mediated effect, whereas that mediated by LPA2 was only partially diminished; the actions of the phorbol ester were inhibited by bisindolylmaleimide I and by overnight incubation with the protein kinase C activator, which leads to down regulation of this protein kinase. Homologous desensitization was also observed for the three LPA receptors studied, with that of LPA2 receptors being consistently of lesser magnitude; neither inhibition nor down-regulation of protein kinase C exerted any effect on homologous desensitization. Activation of LPA1–3 receptors induced ERK 1/2 phosphorylation; this effect was markedly attenuated by inhibition of epidermal growth factor receptor tyrosine kinase activity, suggesting growth factor receptor transactivation in this effect. Lysophosphatidic acid and phorbol myristate acetate were able to induce LPA1–3 phosphorylation, in time- and concentration-dependent fashions. It was also clearly observed that agonists and protein kinase C activation induced internalization of these receptors. Phosphorylation of the LPA2 subtype required larger concentrations of these agents and its internalization was less intense than that of the other subtypes.ConclusionOur data show that these three LPA receptors are phosphoproteins whose phosphorylation state is modulated by agonist-stimulation and protein kinase C-activation and that differences in regulation and cellular localization exist, among the subtypes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Phosphorylation and Internalization of Lysophosphatidic Acid Receptors LPA1, LPA2, and LPA3

et al. 2015

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“…CD4+ T cells in mice lacking LPA2 ( Lpar2 −/− ) display a severe defect in cell motility during the early homing process at the lymph nodes (Knowlden et al, 2014 ). LPA2 is also required for gradient sensing during the chemotaxis of fibroblasts (Ren et al, 2014 ). In an in vivo model of collective cell migration, LPA2 induces cell-cell dissociation and promotes a partial epithelial-mesenchymal transition (EMT) in Xenopus neural crest (NC) cells by down-regulating cell-cell adhesions (Kuriyama et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Lpar2b Controls Lateral Line Tissue Size by Regulating Yap1 Activity in Zebrafish

Wang

Hou

Song

et al. 2018

Front. Mol. Neurosci.

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LPA signaling plays important roles during cell migration and proliferation in normal and pathological conditions. However, its role during sensory organ development remains unknown. Here we show a LPA receptor Lpar2b is expressed in the posterior lateral line primordium (pLLP) and mechanosensory organs called neuromasts (NMs) in zebrafish embryos. Lpar2b loss-of-function significantly reduces the number of NMs and hair cells in the posterior lateral line (pLL). Further analysis reveals that Lpar2b regulates the patterning and tissue size of the pLLP. Interestingly, we show that knocking down a Hippo effector Yap1 phenocopies the result of Lpar2b depletion, and Lpar2b regulates the phosphorylation and activity of Yap1 in the pLLP. Importantly, a phosphorylation-resistant Yap1 rescues pLLP size and NM number in Lpar2b-depleted embryos. Our results indicate Lpar2b controls primordium size and NM number by regulating Yap1 activity in the lateral line system.

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“…MAGI-3 had a negative regulatory effect on LPA 2 mediated cell function [17]. Studies have shown that spatial organization of PDZ motif-mediated LPA 2 receptor macromolecular complex assembly mediates LPA gradient sensing in fibroblasts [18]. LPA mediates anti-apoptosis of cells through LPA 2 receptor, and the damage repair effect of LPA 2 receptor on DNA can protect cells from radiation to some extent [19].…”

Section: Lpar2mentioning

confidence: 99%

Lysophosphatidic Acid Receptors: Biochemical and Clinical Implications in Different Diseases

Xiang¹,

Lü²,

Shao³

et al. 2020

J. Cancer

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Lysophosphatidic acid (LPA, 1-acyl-2-hemolytic-sn-glycerol-3-phosphate) extracted from membrane phospholipid is a kind of simple bioactive glycophospholipid, which has many biological functions such as stimulating cell multiplication, cytoskeleton recombination, cell survival, drug-fast, synthesis of DNA and ion transport. Current studies have shown that six G-coupled protein receptors (LPAR1-6) can be activated by LPA. They stimulate a variety of signal transduction pathways through heterotrimeric G-proteins (such as Gα12/13, Gαq/11, Gαi/o and GαS). LPA and its receptors play vital roles in cancers, nervous system diseases, cardiovascular diseases, liver diseases, metabolic diseases, etc. In this article, we discussed the structure of LPA receptors and elucidated their functions in various diseases, in order to better understand them and point out new therapeutic schemes for them.

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Asymmetrical Macromolecular Complex Formation of Lysophosphatidic Acid Receptor 2 (LPA2) Mediates Gradient Sensing in Fibroblasts

Cited by 8 publications

References 64 publications

Phosphorylation and Internalization of Lysophosphatidic Acid Receptors LPA1, LPA2, and LPA3

Phosphorylation and Internalization of Lysophosphatidic Acid Receptors LPA1, LPA2, and LPA3

Lpar2b Controls Lateral Line Tissue Size by Regulating Yap1 Activity in Zebrafish

Lysophosphatidic Acid Receptors: Biochemical and Clinical Implications in Different Diseases

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