scholarly journals Multifunctional role of GPCR signaling in epithelial tube formation

2022 ◽  
Author(s):  
Vishakha Vishwakarma ◽  
Thao Phuong Le ◽  
SeYeon Chung
Keyword(s):  
Rho Kinase ◽  
Tube Formation ◽  
Dependent Manner ◽  
Cortical Actin ◽  
Apical Constriction ◽  
Gpcr Signaling ◽  
Epithelial Tube ◽  
Cellular Forces ◽  
G Protein Coupled

Epithelial tube formation requires Rho1-dependent actomyosin contractility to generate the cellular forces that drive cell shape changes and rearrangement. Rho1 signaling is activated by G protein-coupled receptor (GPCR) signaling at the cell surface. During Drosophila embryonic salivary gland (SG) invagination, the GPCR ligand Folded gastrulation (Fog) activates Rho1 signaling to drive apical constriction. The SG receptor that transduces the Fog signal into Rho1-dependent myosin activation has not been identified. Here, we reveal that the Smog GPCR transduces Fog signal to regulate Rho kinase accumulation and myosin activation in the apicomedial region of cells to control apical constriction during SG invagination. We also report on unexpected Fog-independent roles for Smog in maintaining epithelial integrity and organizing cortical actin. Our data supports a model wherein Smog regulates distinct myosin pools and actin cytoskeleton in a ligand-dependent manner during epithelial tube formation.

scholarly journals Regulation of apical constriction via microtubule- and Rab11-dependent apical transport during tissue invagination

2021 ◽  
Vol 32 (10) ◽  
pp. 1033-1047
Author(s):  
Thao Phuong Le ◽  
SeYeon Chung
Keyword(s):  
Salivary Gland ◽  
Tube Formation ◽  
Apical Constriction ◽  
Epithelial Tube ◽  
Cellular Forces

During tissue invagination, contractile actomyosin structures generate the cellular forces that drive apical constriction. Using the Drosophila embryonic salivary gland as a model for epithelial tube formation, we show that microtubule- and Rab11-dependent apical transport is critical for regulating actomyosin networks during invagination.

scholarly journals Activation of the GPR35 pathway drives angiogenesis in the tumour microenvironment

Gut ◽  
2021 ◽  
pp. gutjnl-2020-323363
Author(s):  
Ester Pagano ◽  
Joshua E Elias ◽  
Georg Schneditz ◽  
Svetlana Saveljeva ◽  
Lorraine M Holland ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Tumour Growth ◽  
Tumour Microenvironment ◽  
Tube Formation ◽  
Tissue Remodelling ◽  
Colon Cancers ◽  
Inflammatory Bowel ◽  
Ion Pumping ◽  
G Protein Coupled

ObjectivePrimary sclerosing cholangitis (PSC) is in 70% of cases associated with inflammatory bowel disease. The hypermorphic T108M variant of the orphan G protein-coupled receptor GPR35 increases risk for PSC and ulcerative colitis (UC), conditions strongly predisposing for inflammation-associated liver and colon cancer. Lack of GPR35 reduces tumour numbers in mouse models of spontaneous and colitis associated cancer. The tumour microenvironment substantially determines tumour growth, and tumour-associated macrophages are crucial for neovascularisation. We aim to understand the role of the GPR35 pathway in the tumour microenvironment of spontaneous and colitis-associated colon cancers.DesignMice lacking GPR35 on their macrophages underwent models of spontaneous colon cancer or colitis-associated cancer. The role of tumour-associated macrophages was then assessed in biochemical and functional assays.ResultsHere, we show that GPR35 on macrophages is a potent amplifier of tumour growth by stimulating neoangiogenesis and tumour tissue remodelling. Deletion of Gpr35 in macrophages profoundly reduces tumour growth in inflammation-associated and spontaneous tumour models caused by mutant tumour suppressor adenomatous polyposis coli. Neoangiogenesis and matrix metalloproteinase activity is promoted by GPR35 via Na/K-ATPase-dependent ion pumping and Src activation, and is selectively inhibited by a GPR35-specific pepducin. Supernatants from human inducible-pluripotent-stem-cell derived macrophages carrying the UC and PSC risk variant stimulate tube formation by enhancing the release of angiogenic factors.ConclusionsActivation of the GPR35 pathway promotes tumour growth via two separate routes, by directly augmenting proliferation in epithelial cells that express the receptor, and by coordinating macrophages’ ability to create a tumour-permissive environment.

scholarly journals Functional modulation of PTH1R activation and signalling by RAMP2

2021 ◽  
Author(s):  
Katarina Nemec ◽  
Hannes Schihada ◽  
Gunnar Kleinau ◽  
Ulrike Zabel ◽  
Eugene O. Grushevskyi ◽  
...  
Keyword(s):  
Homology Modelling ◽  
Critical Role ◽  
Ion Homeostasis ◽  
Optical Biosensors ◽  
Dependent Manner ◽  
Activated State ◽  
Class B ◽  
Receptor Activity Modifying Proteins ◽  
G Protein Coupled

Receptor-activity-modifying proteins (RAMPs) are ubiquitously expressed membrane proteins that associate with different G protein-coupled receptors (GPCRs) including the parathyroid hormone 1 receptor (PTH1R), a class B GPCR, and an important modulator of mineral ion homeostasis and bone metabolism. However, it is unknown whether and how RAMP proteins may affect PTH1R function. Using different optical biosensors to measure the activation of PTH1R and its downstream signalling, we describe here that RAMP2 acts as a specific allosteric modulator of PTH1R, shifting PTH1R to a unique pre-activated state that permits faster activation in a ligand-specific manner. Moreover, RAMP2 modulates PTH1R downstream signalling in an agonist-dependent manner, most notably increasing the PTH-mediated Gi3 signalling sensitivity. Additionally, RAMP2 increases both PTH- and PTHrP-triggered β-arrestin2 recruitment to PTH1R. Employing homology modelling we describe the putative structural molecular basis underlying our functional findings. These data uncover a critical role of RAMPs in the activation and signalling of a GPCR that may provide a new venue for highly specific modulation of GPCR function and advanced drug design.

scholarly journals Sphingosine 1-phosphate-regulated transcriptomes in heterogenous arterial and lymphatic endothelium of the aorta

2019 ◽  
Author(s):  
Eric Engelbrecht ◽  
Michel V. Levesque ◽  
Liqun He ◽  
Michael Vanlandewijck ◽  
Anja Nitzsche ◽  
...  
Keyword(s):  
Cellular Heterogeneity ◽  
Dependent Manner ◽  
Branch Points ◽  
Transcriptional Responses ◽  
Gpcr Signaling ◽  
Aortic Endothelial Cells ◽  
Sphingosine 1 Phosphate ◽  
G Protein Coupled

AbstractDespite the medical importance of G protein-coupled receptors (GPCRs), in vivo cellular heterogeneity of GPCR signaling and downstream transcriptional responses are not understood. We report the comprehensive characterization of transcriptomes (bulk and single-cell) and chromatin domains regulated by sphingosine 1-phosphate receptor-1 (S1PR1) in adult mouse aortic endothelial cells. First, S1PR1 regulates NFkB and nuclear glucocorticoid receptor pathways to suppress inflammation-related mRNAs. Second, spatially distinct S1PR1 signaling in the aorta is associated with heterogenous endothelial cell (EC) subtypes. For example, a transcriptomically distinct arterial EC population at vascular branch points (aEC1) exhibits ligand- independent S1PR1/ß-arrestin coupling. In contrast, circulatory S1P-dependent S1PR1/ß-arrestin coupling was observed in non-branch point aEC2 cells that exhibit an inflammatory signature. Moreover, an adventitial lymphatic EC (LEC) population shows suppression of lymphangiogenic and inflammation-related transcripts in a S1P/S1PR1-dependent manner. These insights add resolution to existing concepts of GPCR signaling and S1P biology.

Rho kinase contributes to basal vascular tone in humans: role of endothelium-derived nitric oxide

2007 ◽  
Vol 293 (1) ◽  
pp. H541-H547 ◽  
Author(s):  
E. Büssemaker ◽  
Frank Pistrosch ◽  
Sarah Förster ◽  
Kay Herbrig ◽  
Peter Gross ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Vascular Tone ◽  
Rho Kinase ◽  
Calcium Sensitivity ◽  
Venous Occlusion ◽  
Dependent Manner ◽  
Endothelin 1 ◽  
Mlc Phosphorylation ◽  
Constrictor Response

Our objective was to determine the role of the Rho-associated kinase (ROK) for the regulation of FBF (FBF) and to unmask a potential role of ROK for the regulation of endothelium-derived nitric oxide (NO). Moreover, the effect of fasudil on the constrictor response to endothelin-1 was recorded. Regarding background, phosphorylation of the myosin light chain (MLC) determines the calcium sensitivity of the contractile apparatus. MLC phosphorylation depends on the activity of the MLC kinase and the MLC phosphatase. The latter enzyme is inhibited through phosphorylation by ROK. ROK has been suggested to inhibit NO generation, possibly via the inhibition of the Akt pathway. In this study, the effect of intra-arterial infusion of the ROK inhibitor fasudil on FBF in 12 healthy volunteers was examined by venous occlusion plethysmography. To unmask the role of NO, fasudil was infused during NO clamp. As a result, fasudil markedly increased FBF in a dose-dependent manner from 2.34 ± 0.21 to 6.96 ± 0.93 ml/100 ml forearm volume at 80 μg/min ( P < 0.001). At 1,600 μg/min, fasudil reduced systolic, diastolic, and mean arterial pressure while increasing heart rate. Fasudil abolished the vasoconstrictor effect of endothelin-1. The vascular response to fasudil (80 μmol/min) was blunted during NO clamp (104 ± 18% vs. 244 ± 48% for NO clamp + fasudil vs. fasudil alone; data as ratio between infused and noninfused arm with baseline = 0%, P < 0.05). In conclusion, 1) basal peripheral and systemic vascular tone depends on ROK; 2) a significant portion of fasudil-induced vasodilation is mediated by NO, suggesting that vascular bioavailable NO is negatively regulated by ROK; and 3) the constrictor response to endothelin involves the activation of ROK.

scholarly journals Loss of Gα12/13 exacerbates apical area dependence of actomyosin contractility

2016 ◽  
Vol 27 (22) ◽  
pp. 3526-3536 ◽  
Author(s):  
Shicong Xie ◽  
Frank M. Mason ◽  
Adam C. Martin
Keyword(s):  
Cell Shape ◽  
Rho Kinase ◽  
Dependent Manner ◽  
Timely Initiation ◽  
Apical Constriction ◽  
Size Dependent ◽  
Actin Cortex ◽  
Ventral Furrow ◽  
Delayed Initiation ◽  
Apical Area

During development, coordinated cell shape changes alter tissue shape. In the Drosophila ventral furrow and other epithelia, apical constriction of hundreds of epithelial cells folds the tissue. Genes in the Gα12/13 pathway coordinate collective apical constriction, but the mechanism of coordination is poorly understood. Coupling live-cell imaging with a computational approach to identify contractile events, we discovered that differences in constriction behavior are biased by initial cell shape. Disrupting Gα12/13 exacerbates this relationship. Larger apical area is associated with delayed initiation of contractile pulses, lower apical E-cadherin and F-actin levels, and aberrantly mobile Rho-kinase structures. Our results suggest that loss of Gα12/13 disrupts apical actin cortex organization and pulse initiation in a size-dependent manner. We propose that Gα12/13 robustly organizes the apical cortex despite variation in apical area to ensure the timely initiation of contractile pulses in a tissue with heterogeneity in starting cell shape.

scholarly journals GPR158/179 regulate G protein signaling by controlling localization and activity of the RGS7 complexes

2012 ◽  
Vol 197 (6) ◽  
pp. 711-719 ◽  
Author(s):  
Cesare Orlandi ◽  
Ekaterina Posokhova ◽  
Ikuo Masuho ◽  
Thomas A. Ray ◽  
Nazarul Hasan ◽  
...  
Keyword(s):  
G Protein ◽  
Night Vision ◽  
G Protein Signaling ◽  
Rgs Proteins ◽  
Protein Signaling ◽  
Gpcr Signaling ◽  
Signaling Specificity ◽  
Orphan Gpcrs ◽  
G Protein Coupled

The extent and temporal characteristics of G protein–coupled receptor (GPCR) signaling are shaped by the regulator of G protein signaling (RGS) proteins, which promote G protein deactivation. With hundreds of GPCRs and dozens of RGS proteins, compartmentalization plays a key role in establishing signaling specificity. However, the molecular details and mechanisms of this process are poorly understood. In this paper, we report that the R7 group of RGS regulators is controlled by interaction with two previously uncharacterized orphan GPCRs: GPR158 and GPR179. We show that GPR158/179 recruited RGS complexes to the plasma membrane and augmented their ability to regulate GPCR signaling. The loss of GPR179 in a mouse model of night blindness prevented targeting of RGS to the postsynaptic compartment of bipolar neurons in the retina, illuminating the role of GPR179 in night vision. We propose that the interaction of RGS proteins with orphan GPCRs promotes signaling selectivity in G protein pathways.

scholarly journals Dephosphorylation by protein phosphatase 2A regulates visual pigment regeneration and the dark adaptation of mammalian photoreceptors

2017 ◽  
Vol 114 (45) ◽  
pp. E9675-E9684 ◽  
Author(s):  
Alexander V. Kolesnikov ◽  
Tivadar Orban ◽  
Hui Jin ◽  
Celine Brooks ◽  
Lukas Hofmann ◽  
...  
Keyword(s):  
Protein Phosphatase ◽  
Dark Adaptation ◽  
Visual Pigment ◽  
Protein Phosphatase 2A ◽  
Gpcr Signaling ◽  
Rods And Cones ◽  
Retinal Rod ◽  
Phosphatase 2A ◽  
G Protein Coupled

Resetting of G-protein–coupled receptors (GPCRs) from their active state back to their biologically inert ground state is an integral part of GPCR signaling. This “on–off” GPCR cycle is regulated by reversible phosphorylation. Retinal rod and cone photoreceptors arguably represent the best-understood example of such GPCR signaling. Their visual pigments (opsins) are activated by light, transduce the signal, and are then inactivated by a GPCR kinase and arrestin. Although pigment inactivation by phosphorylation is well understood, the enzyme(s) responsible for pigment dephosphorylation and the functional significance of this reaction remain unknown. Here, we show that protein phosphatase 2A (PP2A) acts as opsin phosphatase in both rods and cones. Elimination of PP2A substantially slows pigment dephosphorylation, visual chromophore recycling, and ultimately photoreceptor dark adaptation. These findings demonstrate that visual pigment dephosphorylation regulates the dark adaptation of photoreceptors and provide insights into the role of this reaction in GPCR signaling.

scholarly journals Immunity-longevity tradeoff neurally controlled by GABAergic transcription factor PITX1/UNC-30

2021 ◽  
Author(s):  
Benson Otarigho ◽  
Alejandro Aballay
Keyword(s):  
Nervous System ◽  
Transcription Factor ◽  
Caenorhabditis Elegans ◽  
G Protein ◽  
Neural Control ◽  
Dependent Manner ◽  
G Protein Coupled ◽  
Y Receptors ◽  
Neuropeptide Y Receptors

A body of evidence indicates that metazoan immune and aging pathways are largely interconnected, but the mechanisms involved in their homeostatic control remain unclear. In this study, we found that the PITX (paired like homeodomain) transcription factor UNC-30 controls the tradeoff between immunity and longevity from the nervous system in Caenorhabditis elegans. PITX/UNC-30 functional loss enhanced immunity in a GATA/ELT-2- and p38 MAPK/PMK-1-dependent manner and reduced longevity by activating the MXD/MDL-1 and PQM-1 pathways. The immune inhibitory and longevity stimulatory functions of PITX/UNC-30 required the sensory neuron ASG and a neurotransmitter signaling pathway controlled by NPR-1, which is a G protein-coupled receptor related to mammalian neuropeptide Y receptors. Our findings uncovered a suppressive role of GABAergic signaling in the neural control of a biological tradeoff where energy is allocated towards immunity at the expense of longevity.

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