G-Protein-Coupled Receptor Cell Signaling Pathways Mediating Embryonic Chick Retinal Growth Cone Collapse Induced by Lysophosphatidic Acid and Sphingosine-1-Phosphate

AbstractLysophosphatidylserine (LysoPS) is an emerging lysophospholipid (LPL) mediator, which acts through G protein-coupled receptors, like lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P). LysoPS is detected in various tissues and cells and thought to be produced mainly by the deacylation of phosphatidylserine. LysoPS has been known to stimulate degranulation of mast cells. Recently, four LysoPS-specific G protein-coupled receptors (GPCRs) were identified. These GPCRs belong to the P2Y family which covers receptors for nucleotides and LPLs and are predominantly expressed in immune cells such as lymphocytes and macrophages. Studies on knockout mice of these GPCRs have revealed that LysoPS has immune-modulatory functions. Up-regulation of a LysoPS-producing enzyme, PS-specific phospholipase A1, was frequently observed in situations where the immune system is activated including autoimmune diseases and organ transplantations. Therefore, modulation of LysoPS signaling appears to be a promising method for providing therapies for the treatment of immune diseases. In this review, we summarize the biology of LysoPS-producing enzymes and receptors, recent developments in LysoPS signal modulators, and prospects for future therapeutic applications.

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Activation of RhoA by Lysophosphatidic Acid and Gα12/13 Subunits in Neuronal Cells: Induction of Neurite Retraction

Molecular Biology of the Cell ◽

10.1091/mbc.10.6.1851 ◽

1999 ◽

Vol 10 (6) ◽

pp. 1851-1857 ◽

Cited By ~ 208

Author(s):

Onno Kranenburg ◽

Mieke Poland ◽

Francis P. G. van Horck ◽

David Drechsel ◽

Alan Hall ◽

...

Keyword(s):

Tyrosine Kinase ◽

G Protein ◽

Lysophosphatidic Acid ◽

Growth Cone ◽

Kinase Inhibitors ◽

Specific Binding ◽

Neuronal Cells ◽

Growth Cone Collapse ◽

Neurite Retraction ◽

Activation Assay

Neuronal cells undergo rapid growth cone collapse, neurite retraction, and cell rounding in response to certain G protein–coupled receptor agonists such as lysophosphatidic acid (LPA). These shape changes are driven by Rho-mediated contraction of the actomyosin-based cytoskeleton. To date, however, detection of Rho activation has been hampered by the lack of a suitable assay. Furthermore, the nature of the G protein(s) mediating LPA-induced neurite retraction remains unknown. We have developed a Rho activation assay that is based on the specific binding of active RhoA to its downstream effector Rho-kinase (ROK). A fusion protein of GST and the Rho-binding domain of ROK pulls down activated but not inactive RhoA from cell lysates. Using GST-ROK, we show that in N1E-115 neuronal cells LPA activates endogenous RhoA within 30 s, concomitant with growth cone collapse. Maximal activation occurs after 3 min when neurite retraction is complete and the actin cytoskeleton is fully contracted. LPA-induced RhoA activation is completely inhibited by tyrosine kinase inhibitors (tyrphostin 47 and genistein). Activated Gα12 and Gα13 subunits mimic LPA both in activating RhoA and in inducing RhoA-mediated cytoskeletal contraction, thereby preventing neurite outgrowth. We conclude that in neuronal cells, LPA activates RhoA to induce growth cone collapse and neurite retraction through a G12/13-initiated pathway that involves protein-tyrosine kinase activity.

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Lysophosphatidic Acid and Sphingosine-1-Phosphate Activation of G-Protein-Coupled Receptors

Handbook of Cell Signaling ◽

10.1016/b978-0-12-374145-5.00147-9 ◽

2010 ◽

pp. 1191-1200

Author(s):

Tetsuji Mutoh ◽

Jerold Chun

Keyword(s):

G Protein ◽

Lysophosphatidic Acid ◽

G Protein Coupled Receptors ◽

Sphingosine 1 Phosphate ◽

G Protein Coupled

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Signaling mechanisms and molecular characteristics of G protein-coupled receptors for lysophosphatidic acid and sphingosine 1-phosphate

Journal of Cellular Biochemistry ◽

10.1002/(sici)1097-4644(1998)72:30/31+<147::aid-jcb19>3.0.co;2-f ◽

1998 ◽

Vol 72 (S30-31) ◽

pp. 147-157 ◽

Cited By ~ 91

Author(s):

Songzhu An ◽

Edward J. Goetzl ◽

Hsinyu Lee

Keyword(s):

G Protein ◽

Lysophosphatidic Acid ◽

G Protein Coupled Receptors ◽

Molecular Characteristics ◽

Signaling Mechanisms ◽

Sphingosine 1 Phosphate ◽

G Protein Coupled

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Modulating Sphingosine-1-Phosphate receptors to improve chemotherapy delivery to Ewing sarcoma

10.1101/805655 ◽

2019 ◽

Author(s):

Enrica Marmonti ◽

Hannah Savage ◽

Aiqian Zhang ◽

Claudia Alvarez ◽

Miriam Morrell ◽

...

Keyword(s):

G Protein ◽

Ewing Sarcoma ◽

Tyrosine Kinases ◽

Tumor Vasculature ◽

Cell Junction ◽

Tumor Vessels ◽

S1p Receptors ◽

Vessel Permeability ◽

Sphingosine 1 Phosphate ◽

G Protein Coupled

ABSTRACTTumor vasculature is innately dysfunctional. Poorly functional tumor vessels inefficiently deliver chemotherapy to tumor cells; vessel hyper-permeability promotes chemotherapy delivery primarily to a tumor’s periphery. Here we identify a method for enhancing chemotherapy delivery and efficacy in Ewing sarcoma (ES) in mice by modulating tumor vessel permeability. Vessel permeability is partially controlled by the G protein-coupled Sphinosine-1-phosphate receptors 1 and 2 (S1PR1 and S1PR2) on endothelial cells. S1PR1 promotes endothelial cell junction integrity while S1PR2 destabilizes it. We hypothesize that an imbalance of S1PR1:S1PR2 is partially responsible for the dysfunctional vascular phenotype characteristic of ES and that by altering the balance in favor of S1PR1, ES vessel hyper-permeability can be reversed. In this study, we demonstrate that pharmacologic activation of S1PR1 by SEW2871 or inhibition of S1PR2 by JTE-013 caused more organized, mature, and functional tumor vessels. Importantly, S1PR1 activation or S1PR2 inhibition improved chemotherapy delivery to the tumor and anti-tumor efficacy. Our data suggests that pharmacologic targeting of S1PR1 and S1PR2 may be a useful adjuvant to standard chemotherapy for ES patients.NOVELTY AND IMPACTThis study demonstrates that Sphingosine-1-Phosphate (S1P) receptors are potential novel targets for tumor vasculature remodeling and adjuvant therapy for the treatment of Ewing Sarcoma. Unlike receptor tyrosine kinases that have already been extensively evaluated for use as vascular normalizing agents in oncology, S1P receptors are G protein-coupled receptors, which have not been well studied in tumor endothelium. Pharmacologic activators and inhibitors of S1P receptors are currently in clinical trials for treatment of auto-immune and cardiovascular diseases, indicating potential for clinical translation of this work.

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