G-Protein-Coupled Lysophosphatidic Acid Receptors and Their Regulation of AKT Signaling

Riaz, Anjum; Huang, Ying; Johansson, Staffan

doi:10.3390/ijms17020215

Cited by 55 publications

(62 citation statements)

References 107 publications

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“…We used 0, 0.1, 1, and 10 µM of LPA as the working concentrations and 24 h as the treatment duration for the following studies. The working concentration of LPA is close to the concentration that we detected in CSF (2.64–5.87 µM) and what was previously reported in LF tissues (2.42–2.71 µM) [10] and serum (10 µM) [5]. …”

Section: Resultssupporting

confidence: 89%

“…The highest concentration of LPA is found in the serum (∼10 µM) and in other body fluids like cerebrospinal fluid [5]. LPA is primarily synthesized by activated platelets [6].…”

Section: Introductionmentioning

confidence: 99%

“…The biological functions of LPA are mediated by six cell membrane receptors. The genes encoding these receptor proteins are designated LPAR1–6 in humans and Lparl–6 in mice [5]. Among them, LPAR1 is highly expressed in the central nervous system (CNS) and vascular endothelium [7, 8].…”

Section: Introductionmentioning

confidence: 99%

“…LPA activates the LPAR1 downstream signaling cascades via the G(i)/G(o), G(12)/G(13), and G(q) families of heteromeric G proteins. These play a role in cell migration, proliferation, and the response to tissue damage and infectious agents [5, 9]. …”

Section: Introductionmentioning

confidence: 99%

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Lysophosphatidic Acid Induces Ligamentum Flavum Hypertrophy Through the LPAR1/Akt Pathway

Zhou

Chen

et al. 2018

Cell Physiol Biochem

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Background/Aims: Hypertrophic ligamentum flavum (LF) is a major cause of lumbar spinal stenosis. Our previous work showed that high levels of lysophosphatidic acid (LPA) expression are positively correlated with LF hypertrophy. This study aimed to further unveil how LPA regulates LF hypertrophy Methods: We studied LPAR1 expression in human LF cells using PCR and western blotting. Cell viability cell cycle, apoptosis rate and molecular mechanisms were assayed in LPAR1 knockdown or overexpression LF cells. LF hypertrophy and the molecular mechanism was confirmed in human samples and in in vivo studies. Results: The expression of LPA and its receptor LPAR1 is significantly higher in tissues or cells harvested from hypertrophic LF compared to healthy controls. Moreover, LPA promoted LF cell proliferation by interacting with LPAR1. This conclusion is supported by the fact that depletion or overexpression of LPAR1 changed the effect of LPA on LF cell proliferation. LPA also inhibits apoptosis in LF cells through the receptor LPAR1. Importantly, we demonstrated that the LPA-LPAR1 interaction initiated Akt phosphorylation and determined cell proliferation and apoptosis. Our in vitro findings were supported by our in vivo evidence that lyophilized LPA significantly induced LF hypertrophy via the LPAR1-Akt signaling pathway. More importantly, targeted inhibition of LPAR1 by Ki16425 with a gel sponge implant effectively reduced LPA-associated LF hypertrophy. Taken together, these data indicate that LPA binds to the receptor LPAR1 to induce LF cell proliferation and inhibit apoptosis by activating AKT signaling cascades. Targeting this signaling cascade with Ki16425 is a potential therapeutic strategy for preventing LF hypertrophy. Conclusion: LPA-LPAR1-Akt activation is positively correlated with the proliferation and survival of LF cells. LPAR1 could be a target for new drugs and the development of new therapeutic methods for treating LF hypertrophy.

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Section: Resultssupporting

confidence: 89%

“…The highest concentration of LPA is found in the serum (∼10 µM) and in other body fluids like cerebrospinal fluid [5]. LPA is primarily synthesized by activated platelets [6].…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Lysophosphatidic Acid Induces Ligamentum Flavum Hypertrophy Through the LPAR1/Akt Pathway

Zhou

Chen

et al. 2018

Cell Physiol Biochem

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“…Inducible PM Targeting of GRK2ct-KERE Inhibits LPA-dependent Phosphorylation of Akt-To demonstrate that the inducible system can functionally inhibit ␤␥ at the PM, we assayed phosphorylation of Akt in response to LPA stimulation, a ␤␥-dependent signaling function in MDA-MB-231 cells (28). LPA agonist treatment promotes rapid phosphorylation of Akt, as measured by immunoblotting with a phospho-specific antibody to detect phosphorylation at serine 473, with maximal intensity ϳ10 min post-stimulation (Fig.…”

Section: A Lipid-binding Region Of Grk2 C Terminus Is Necessary Formentioning

confidence: 99%

Inducible Inhibition of Gβγ Reveals Localization-dependent Functions at the Plasma Membrane and Golgi

Klayman

Wedegaertner

2017

Journal of Biological Chemistry

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Edited by Henrik G. DohlmanHeterotrimeric G proteins signal at a variety of endomembrane locations, in addition to their canonical function at the cytoplasmic surface of the plasma membrane (PM), where they are activated by cell surface G protein-coupled receptors. Here we focus on ␤␥ signaling at the Golgi, where ␤␥ activates a signaling cascade, ultimately resulting in vesicle fission from the trans-Golgi network (TGN). To develop a novel molecular tool for inhibiting endogenous ␤␥ in a spatial-temporal manner, we take advantage of a lipid association mutant of the widely used ␤␥ inhibitor GRK2ct (GRK2ct-KERE) and the FRB/FKBP heterodimerization system. We show that GRK2ct-KERE cannot inhibit ␤␥ function when expressed in cells, but recruitment to a specific membrane location recovers the ability of GRK2ct-KERE to inhibit ␤␥ signaling. PM-recruited GRK2ct-KERE inhibits lysophosphatidic acid-induced phosphorylation of Akt, whereas Golgi-recruited GRK2ct-KERE inhibits cargo transport from the TGN to the PM. Moreover, we show that Golgi-recruited GRK2ct-KERE inhibits model basolaterally targeted but not apically targeted cargo delivery, for both PM-destined and secretory cargo, providing the first evidence of selectivity in terms of cargo transport regulated by ␤␥. Last, we show that Golgi fragmentation induced by ilimaquinone and nocodazole is blocked by ␤␥ inhibition, demonstrating that ␤␥ is a key regulator of multiple pathways that impact Golgi morphology. Thus, we have developed a new molecular tool, recruitable GRK2ct-KERE, to modulate ␤␥ signaling at specific subcellular locations, and we demonstrate novel cargo selectivity for ␤␥ regulation of TGN to PM transport and a novel role for ␤␥ in mediating Golgi fragmentation.

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BRET analysis reveals interaction between the lysophosphatidic acid receptor LPA2 and the lysophosphatidylinositol receptor GPR55 in live cells

Bang

Ghil

2021

FEBS Letters

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Lysophosphatidic acid (LPA) and lysophosphatidylinositol bind to the G protein-coupled receptors (GPCRs) LPA and GPR55, respectively. LPA 2 , a type 2 LPA receptor, and GPR55 are highly expressed in colon cancer and involved in cancer progression. However, crosstalk between the two receptors and potential effects on cellular physiology are not fully understood. Here, using BRET analysis, we found that LPA 2 and GPR55 interact in live cells. In the presence of both receptors, LPA 2 and/or GPR55 activation facilitated co-internalization, and activation of GPR55, uncoupled with Ga i , induced reduction of intracellular cAMP. Notably, co-activation of receptors synergistically triggered further decline in the cAMP level, promoted cell proliferation, and increased the expression of cancer progression-related genes, suggesting that physical and functional crosstalk between LPA 2 and GRR55 is involved in cancer progression.

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G-Protein-Coupled Lysophosphatidic Acid Receptors and Their Regulation of AKT Signaling

Cited by 55 publications

References 107 publications

Lysophosphatidic Acid Induces Ligamentum Flavum Hypertrophy Through the LPAR1/Akt Pathway

Lysophosphatidic Acid Induces Ligamentum Flavum Hypertrophy Through the LPAR1/Akt Pathway

Inducible Inhibition of Gβγ Reveals Localization-dependent Functions at the Plasma Membrane and Golgi

BRET analysis reveals interaction between the lysophosphatidic acid receptor LPA2 and the lysophosphatidylinositol receptor GPR55 in live cells

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