scholarly journals Autotaxin, a Secreted Lysophospholipase D, Is Essential for Blood Vessel Formation during Development

2006 ◽  
Vol 26 (13) ◽  
pp. 5015-5022 ◽  
Author(s):  
Laurens A. van Meeteren ◽  
Paula Ruurs ◽  
Catelijne Stortelers ◽  
Peter Bouwman ◽  
Marga A. van Rooijen ◽  
...  
Keyword(s):  
Lysophosphatidic Acid ◽  
Critical Role ◽  
G Protein Coupled Receptors ◽  
Blood Vessel Formation ◽  
Lysophospholipase D ◽  
Motility Factor ◽  
Nucleotide Pyrophosphatase ◽  
G Protein Coupled ◽  
Deficient Mice

ABSTRACT Autotaxin (ATX), or nucleotide pyrophosphatase-phosphodiesterase 2, is a secreted lysophospholipase D that promotes cell migration, metastasis, and angiogenesis. ATX generates lysophosphatidic acid (LPA), a lipid mitogen and motility factor that acts on several G protein-coupled receptors. Here we report that ATX-deficient mice die at embryonic day 9.5 (E9.5) with profound vascular defects in yolk sac and embryo resembling the Gα13 knockout phenotype. Furthermore, at E8.5, ATX-deficient embryos showed allantois malformation, neural tube defects, and asymmetric headfolds. The onset of these abnormalities coincided with increased expression of ATX and LPA receptors in normal embryos. ATX heterozygous mice appear healthy but show half-normal ATX activity and plasma LPA levels. Our results reveal a critical role for ATX in vascular development, indicate that ATX is the major LPA-producing enzyme in vivo, and suggest that the vascular defects in ATX-deficient embryos may be explained by loss of LPA signaling through Gα13.

Lysophosphatidic acid: mitogen and motility factor

2003 ◽  
Vol 31 (6) ◽  
pp. 1209-1212 ◽  
Author(s):  
F.N. van Leeuwen ◽  
B.N.G. Giepmans ◽  
L.A. van Meeteren ◽  
W.H. Moolenaar
Keyword(s):  
G Proteins ◽  
Lysophosphatidic Acid ◽  
Recent Progress ◽  
Small Gtpases ◽  
G Protein Coupled Receptors ◽  
Signal Transduction Pathways ◽  
Potent Inducer ◽  
Motility Factor ◽  
Lpa Receptors ◽  
G Protein Coupled

LPA (lysophosphatidic acid), the simplest of al glycerophospholipids, is a potent inducer of cell proliferation, migration and survival. It does so by activating its cognate G-protein-coupled receptors, four of which have been identified. LPA receptors couple to at least three distinct G-proteins and thereby activate multiple signal transduction pathways, particularly those initiated by the small GTPases Ras, Rho and Rac. Our recent work has shown that LPA signals Rac activation via the Tiam1 GDP/GTP exchange factor and thereby stimulates cell migration. Here we discuss recent progress in our understanding of LPA action.

scholarly journals The LUBAC participates in Lysophosphatidic Acid-induced NF-κB Activation

2020 ◽  
Author(s):  
Tiphaine Douanne ◽  
Sarah Chapelier ◽  
Robert Rottapel ◽  
Julie Gavard ◽  
Nicolas Bidère
Keyword(s):  
Transcription Factors ◽  
Cell Surface ◽  
Lysophosphatidic Acid ◽  
Critical Role ◽  
G Protein Coupled Receptors ◽  
Antigen Receptors ◽  
Embryonic Fibroblasts ◽  
Optimal Production ◽  
Guanine Exchange Factor ◽  
G Protein Coupled

AbstractThe natural bioactive glycerophospholipid lysophosphatidic acid (LPA) binds to its cognate G protein-coupled receptors (GPCRs) on the cell surface to promote the activation of several transcription factors, including NF-κB. LPA-mediated activation of NF-κB relies on the formation of a signalosome that contains the scaffold CARMA3, the adaptor BCL10 and the paracaspase MALT1 (CBM complex). The CBM has been extensively studied in lymphocytes, where it links antigen receptors to NF-κB activation via the recruitment of the linear ubiquitin assembly complex (LUBAC), a tripartite complex of HOIP, HOIL1 and SHARPIN. Moreover, MALT1 cleaves the LUBAC subunit HOIL1 to further enhance NF-κB activation. However, the contribution of the LUBAC downstream of GPCRs has not been investigated. By using murine embryonic fibroblasts from mice deficient for HOIP, HOIL1 and SHARPIN, we report that the LUBAC is crucial for the activation of NF-κB in response to LPA. Further echoing the situation in lymphocytes, LPA unbridles the protease activity of MALT1, which cleaves HOIL1 at the Arginine 165. The expression of a MALT1-insensitive version of HOIL1 reveals that this processing is required for the optimal production of the NF-κB target cytokine interleukin-6. Lastly, we provide evidence that the guanine exchange factor GEF-H1 activated by LPA favors MALT1-mediated cleavage of HOIL1 and NF-κB signaling. Together, our results unveil a critical role for the LUBAC as a positive regulator of NF-κB signaling downstream of GPCRs.

Deletion of the p110β isoform of phosphoinositide 3-kinase in platelets reveals its central role in Akt activation and thrombus formation in vitro and in vivo

Blood ◽  
2010 ◽  
Vol 115 (10) ◽  
pp. 2008-2013 ◽  
Author(s):  
Valérie Martin ◽  
Julie Guillermet-Guibert ◽  
Gaétan Chicanne ◽  
Cendrine Cabou ◽  
Martine Jandrot-Perrus ◽  
...  
Keyword(s):  
G Protein ◽  
Platelet Activation ◽  
Critical Role ◽  
G Protein Coupled Receptors ◽  
In Vivo Studies ◽  
Null Mouse ◽  
Functional Responses ◽  
Activation Motif ◽  
G Protein Coupled

Abstract During platelet activation, phosphoinositide 3-kinases (PI3Ks) produce lipid second messengers participating in the regulation of functional responses. Here, we generated a megakaryocyte-restricted p110β null mouse model and demonstrated a critical role of PI3Kβ in platelet activation via an immunoreceptor tyrosine-based activation motif, the glyco-protein VI-Fc receptor γ-chain complex, and its contribution in response to G-protein–coupled receptors. Interestingly, the production of phosphatidylinositol 3,4,5-trisphosphate and the activation of protein kinase B/Akt were strongly inhibited in p110β null platelets stimulated either via immunoreceptor tyrosine-based activation motif or G-protein–coupled receptors. Functional studies showed an important delay in fibrin clot retraction and an almost complete inability of these platelets to adhere onto fibrinogen under flow condition, suggesting that PI3Kβ is also acting downstream of αIIbβ3. In vivo studies showed that these mice have a normal bleeding time and are not protected from acute pulmonary thromboembolism but are resistant to thrombosis after FeCl3 injury of the carotid, suggesting that PI3Kβ is a potential target for antithrombotic drugs.

scholarly journals Essential role of IPS-1 in innate immune responses against RNA viruses

2006 ◽  
Vol 203 (7) ◽  
pp. 1795-1803 ◽  
Author(s):  
Himanshu Kumar ◽  
Taro Kawai ◽  
Hiroki Kato ◽  
Shintaro Sato ◽  
Ken Takahashi ◽  
...  
Keyword(s):  
Rna Viruses ◽  
Rna Virus ◽  
Critical Role ◽  
Nuclear Factor Κb ◽  
Type I ◽  
Innate Immune Responses ◽  
Antiviral Responses ◽  
Deficient Mice

IFN-β promoter stimulator (IPS)-1 was recently identified as an adapter for retinoic acid–inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (Mda5), which recognize distinct RNA viruses. Here we show the critical role of IPS-1 in antiviral responses in vivo. IPS-1–deficient mice showed severe defects in both RIG-I– and Mda5-mediated induction of type I interferon and inflammatory cytokines and were susceptible to RNA virus infection. RNA virus–induced interferon regulatory factor-3 and nuclear factor κB activation was also impaired in IPS-1–deficient cells. IPS-1, however, was not essential for the responses to either DNA virus or double-stranded B-DNA. Thus, IPS-1 is the sole adapter in both RIG-I and Mda5 signaling that mediates effective responses against a variety of RNA viruses.

scholarly journals Adhesion G Protein–Coupled Receptors: From In Vitro Pharmacology to In Vivo Mechanisms

2015 ◽  
Vol 88 (3) ◽  
pp. 617-623 ◽  
Author(s):  
Kelly R. Monk ◽  
Jörg Hamann ◽  
Tobias Langenhan ◽  
Saskia Nijmeijer ◽  
Torsten Schöneberg ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
In Vitro Pharmacology ◽  
G Protein Coupled

Selective recruitment of arrestin-3 to clathrin coated pits upon stimulation of G protein-coupled receptors

2000 ◽  
Vol 113 (13) ◽  
pp. 2463-2470 ◽  
Author(s):  
F. Santini ◽  
R.B. Penn ◽  
A.W. Gagnon ◽  
J.L. Benovic ◽  
J.H. Keen
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Coated Pits ◽  
Over Expression ◽  
Physiological Conditions ◽  
A Cell ◽  
G Protein Coupled ◽  
Comparable Magnitude

Non-visual arrestins (arrestin-2 and arrestin-3) play critical roles in the desensitization and internalization of many G protein-coupled receptors. In vitro experiments have shown that both non-visual arrestins bind with high and approximately comparable affinities to activated, phosphorylated forms of receptors. They also exhibit high affinity binding, again of comparable magnitude, to clathrin. Further, agonist-promoted internalization of many receptors has been found to be stimulated by exogenous over-expression of either arrestin2 or arrestin3. The existence of multiple arrestins raises the question whether stimulated receptors are selective for a specific endogenous arrestin under more physiological conditions. Here we address this question in RBL-2H3 cells, a cell line that expresses comparable levels of endogenous arrestin-2 and arrestin-3. When (beta)(2)-adrenergic receptors are stably expressed in these cells the receptors internalize efficiently following agonist stimulation. However, by immunofluorescence microscopy we determine that only arrestin-3, but not arrestin-2, is rapidly recruited to clathrin coated pits upon receptor stimulation. Similarly, in RBL-2H3 cells that stably express physiological levels of m1AChR, the addition of carbachol selectively induces the localization of arrestin-3, but not arrestin-2, to coated pits. Thus, this work demonstrates coupling of G protein-coupled receptors to a specific non-visual arrestin in an in vivo setting.

G-protein-coupled-receptor activation of the smooth muscle calponin gene

2001 ◽  
Vol 357 (2) ◽  
pp. 587-592 ◽  
Author(s):  
Nickolai O. DULIN ◽  
Sergei N. ORLOV ◽  
Chad M. KITCHEN ◽  
Tatyana A. VOYNO-YASENETSKAYA ◽  
Joseph M. MIANO
Keyword(s):  
Smooth Muscle ◽  
Protein Kinase ◽  
G Protein ◽  
Transcriptional Activation ◽  
Fold Increase ◽  
Receptor Activation ◽  
G Protein Coupled Receptors ◽  
Mitogen Activated Protein Kinase ◽  
G Protein Coupled

A hallmark of cultured smooth muscle cells (SMCs) is the rapid down-regulation of several lineage-restricted genes that define their in vivo differentiated phenotype. Identifying factors that maintain an SMC differentiated phenotype has important implications in understanding the molecular underpinnings governing SMC differentiation and their subversion to an altered phenotype in various disease settings. Here, we show that several G-protein coupled receptors [α-thrombin, lysophosphatidic acid and angiotensin II (AII)] increase the expression of smooth muscle calponin (SM-Calp) in rat and human SMC. The increase in SM-Calp protein appears to be selective for G-protein-coupled receptors as epidermal growth factor was without effect. Studies using AII showed a 30-fold increase in SM-Calp protein, which was dose- and time-dependent and mediated by the angiotensin receptor-1 (AT1 receptor). The increase in SM-Calp protein with AII was attributable to transcriptional activation of SM-Calp based on increases in steady-state SM-Calp mRNA, increases in SM-Calp promoter activity and complete abrogation of protein induction with actinomycin D. To examine the potential role of extracellular signal-regulated kinase (Erk1/2), protein kinase B, p38 mitogen-activated protein kinase and protein kinase C in AII-induced SM-Calp, inhibitors to each of the signalling pathways were used. None of these signalling molecules appears to be crucial for AII-induced SM-Calp expression, although Erk1/2 may be partially involved. These results identify SM-Calp as a target of AII-mediated signalling, and suggest that the SMC response to AII may incorporate a novel activity of SM-Calp.

scholarly journals Prospects for use of peptides and their derivatives, structurally corresponding to the G protein-coupled receptors, in medicine

2015 ◽  
Vol 61 (1) ◽  
pp. 19-29 ◽  
Author(s):  
A.O. Shpakov ◽  
E.A. Shpakova
Keyword(s):  
G Protein ◽  
Intracellular Signaling ◽  
High Efficiency ◽  
Clinical Medicine ◽  
Inflammatory Diseases ◽  
G Protein Coupled Receptors ◽  
Signaling Cascades ◽  
G Protein Coupled

The regulation of signaling pathways involved in the control of many physiological functions is carried out via the heterotrimeric G protein-coupled receptors (GPCR). The search of effective and selective regulators of GPCR and intracellular signaling cascades coupled with them is one of the important problems of modern fundamental and clinical medicine. Recently data suggest that synthetic peptides and their derivatives, structurally corresponding to the intracellular and transmembrane regions of GPCR, can interact with high efficiency and selectivity with homologous receptors and influence, thus, the functional activity of intracellular signaling cascades and fundamental cellular processes controlled by them. GPCR-peptides are active in both in vitro and in vivo. They regulate hematopoiesis, angiogenesis and cell proliferation, inhibit tumor growth and metastasis, and prevent the inflammatory diseases and septic shock. These data show greatest prospects in the development of the new generations of drugs based on GPCR-derived peptides, capable of regulating the important functions of the organism.

scholarly journals Rescue of defective G protein–coupled receptor function in vivo by intermolecular cooperation

2010 ◽  
Vol 107 (5) ◽  
pp. 2319-2324 ◽  
Author(s):  
Adolfo Rivero-Müller ◽  
Yen-Yin Chou ◽  
Inhae Ji ◽  
Svetlana Lajic ◽  
Aylin C. Hanyaloglu ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Luteinizing Hormone Receptor ◽  
Wild Type ◽  
Gpcr Signaling ◽  
Physiological Relevance ◽  
Biosynthesis Activation ◽  
Mutant Receptors ◽  
G Protein Coupled

G protein–coupled receptors (GPCRs) are ubiquitous mediators of signaling of hormones, neurotransmitters, and sensing. The old dogma is that a one ligand/one receptor complex constitutes the functional unit of GPCR signaling. However, there is mounting evidence that some GPCRs form dimers or oligomers during their biosynthesis, activation, inactivation, and/or internalization. This evidence has been obtained exclusively from cell culture experiments, and proof for the physiological significance of GPCR di/oligomerization in vivo is still missing. Using the mouse luteinizing hormone receptor (LHR) as a model GPCR, we demonstrate that transgenic mice coexpressing binding-deficient and signaling-deficient forms of LHR can reestablish normal LH actions through intermolecular functional complementation of the mutant receptors in the absence of functional wild-type receptors. These results provide compelling in vivo evidence for the physiological relevance of intermolecular cooperation in GPCR signaling.

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