scholarly journals Formation of polarized contractile interfaces by self-organized Toll-8/Cirl GPCR asymmetry

2020 ◽  
Author(s):  
Jules Lavalou ◽  
Qiyan Mao ◽  
Stefan Harmansa ◽  
Stephen Kerridge ◽  
Annemarie C. Lellouch ◽  
...  
Keyword(s):  
Myosin Ii ◽  
Surface Protein ◽  
Cell Behaviors ◽  
Binding Partner ◽  
Self Organized ◽  
Toll Receptor ◽  
Axis Extension ◽  
Local Cell ◽  
Adhesion Gpcr ◽  
G Protein Coupled

SummaryDuring development, interfaces between cells with distinct genetic identities elicit signals to organize local cell behaviors driving tissue morphogenesis. The Drosophila embryonic axis extension requires planar polarized enrichment of Myosin-II powering oriented cell intercalations. Myosin-II levels are quantitatively controlled by G protein-coupled receptor (GPCR) signaling whereas Myosin-II polarity requires patterned expression of several Toll receptors. How Toll receptors polarizes Myosin-II, and how this involves GPCRs, remain unknown. Here we report that differential expression of a single Toll receptor, Toll-8, polarizes Myosin-II via a novel binding partner, the adhesion GPCR Cirl/Latrophilin. Asymmetric expression of Cirl is sufficient to enrich Myosin-II and Cirl localization is asymmetric at Toll-8 expression boundaries. Exploring the process dynamically, we reveal that Toll-8 and Cirl exhibit mutually dependent planar polarity in response to quantitative differences in Toll-8 expression between neighboring cells. Collectively, we propose that a novel cell surface protein complex Toll-8/Cirl self-organizes to generate local asymmetric interfaces essential for planar polarization of contractile interfaces.

Progress in demystification of adhesion G protein-coupled receptors

2013 ◽  
Vol 394 (8) ◽  
pp. 937-950 ◽  
Author(s):  
Ines Liebscher ◽  
Torsten Schöneberg ◽  
Simone Prömel
Keyword(s):  
G Protein ◽  
Usher Syndrome ◽  
G Protein Coupled Receptors ◽  
Dual Function ◽  
Cell Matrix ◽  
Proteolytic Site ◽  
Functional Features ◽  
Cell Matrix Interactions ◽  
Adhesion Gpcr ◽  
G Protein Coupled

Abstract Adhesion G protein-coupled receptors (aGPCR) form the second largest class of GPCR. They are phylogenetically old and have been highly conserved during evolution. Mutations in representatives of this class are associated with severe diseases such as Usher Syndrome, a combined congenital deaf-blindness, or bifrontal parietal polymicrogyria. The main characteristics of aGPCR are their enormous size and the complexity of their N termini. They contain a highly conserved GPCR proteolytic site (GPS) and several functional domains that have been implicated in cell-cell and cell-matrix interactions. Adhesion GPCR have been proposed to serve a dual function as adhesion molecules and as classical receptors. However, until recently there was no proof that aGPCR indeed couple to G proteins or even function as classical receptors. In this review, we have summarized and discussed recent evidence that aGPCR present many functional features of classical GPCR, including multiple G protein-coupling abilities, G protein-independent signaling and oligomerization, but also specific signaling properties only found in aGPCR.

scholarly journals Myosin II governs intracellular pressure and traction by distinct tropomyosin-dependent mechanisms

2019 ◽  
Vol 30 (10) ◽  
pp. 1170-1181 ◽  
Author(s):  
Kimheak Sao ◽  
Tia M. Jones ◽  
Andrew D. Doyle ◽  
Debonil Maity ◽  
Galina Schevzov ◽  
...  
Keyword(s):  
Myosin Ii ◽  
Three Dimensional ◽  
Traction Force ◽  
Negative Regulator ◽  
Cell Behaviors ◽  
Substrate Rigidity ◽  
Molecular Machinery ◽  
3D Environments ◽  
Cellular Forces ◽  
Intracellular Pressure

Two-dimensional (2D) substrate rigidity promotes myosin II activity to increase traction force in a process negatively regulated by tropomyosin (Tpm) 2.1. We recently discovered that actomyosin contractility can increase intracellular pressure and switch tumor cells from low-pressure lamellipodia to high-pressure lobopodial protrusions during three-dimensional (3D) migration. However, it remains unclear whether these myosin II–generated cellular forces are produced simultaneously, and by the same molecular machinery. Here we identify Tpm 1.6 as a positive regulator of intracellular pressure and confirm that Tpm 2.1 is a negative regulator of traction force. We find that Tpm 1.6 and 2.1 can control intracellular pressure and traction independently, suggesting these myosin II–dependent forces are generated by distinct mechanisms. Further, these tropomyosin-regulated mechanisms can be integrated to control complex cell behaviors on 2D and in 3D environments.

scholarly journals Antinociceptive modulation by the adhesion-GPCR CIRL promotes mechanosensory signal discrimination

2020 ◽  
Author(s):  
Sven Dannhäuser ◽  
Thomas J. Lux ◽  
Chun Hu ◽  
Mareike Selcho ◽  
Jeremy Tsung-Chieh Chen ◽  
...  
Keyword(s):  
Developmental Disorders ◽  
High Threshold ◽  
Mechanical Stimuli ◽  
Physiological Processes ◽  
Signal Discrimination ◽  
Low Threshold ◽  
Sensory Responses ◽  
Adhesion Gpcr ◽  
G Protein Coupled

ABSTRACTAdhesion-type G protein-coupled receptors (aGPCRs) participate in a vast range of physiological processes. Correspondingly, these receptors are associated with diverse human diseases, such as developmental disorders, defects of the nervous system, allergies and cancer. Several aGPCRs have recently been linked to mechanosensitive functions suggesting that processing of mechanical stimuli may be a common feature of this receptor family. CIRL (ADGRL/Latrophilin, LPHN), one of the oldest members of the aGPCR family, sensitizes sensory responses of larval Drosophila to gentle touch and sound by amplifying mechanosensory signal transduction in low-threshold mechanoreceptors (Scholz et al., 2015; 2017). In the present study, we show that Cirl is also expressed in high-threshold mechanical nociceptors where it adjusts nocifensive behaviour under physiological and pathophysiological conditions. Optogenetic in vivo experiments indicate that CIRL quenches cAMP levels in both mechanosensory submodalities. However, contrasting its effect in touch sensitive neurons, CIRL dampens the response of nociceptors to mechanical stimulation. Consistent with this finding, rat nociceptors display a drop in Cirl1 expression during allodynia. Taken together, these results demonstrate that CIRL exerts opposing modulatory functions in low-threshold mechanosensors and high-threshold nociceptors. This intriguing bipolar action likely facilitates the separation of mechanosensory signals carrying different physiological information.

scholarly journals Lysophosphatidic acid provokes fibroblast chemotaxis through combinatorial regulation of myosin II

2018 ◽  
Author(s):  
Sreeja B. Asokan ◽  
Heath E. Johnson ◽  
John Sondek ◽  
Maria S. Shutova ◽  
Tatyana M. Svitkina ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Myosin Ii ◽  
Leading Edge ◽  
Biologically Active ◽  
Combinatorial Regulation ◽  
Local Inhibition ◽  
3D Environments ◽  
And Migration ◽  
Microfluidic Chambers ◽  
G Protein Coupled

SUMMARYLysophophatidic acid (LPA), a biologically active phospholipid that is ubiquitously present in tissues and organs, provokes cellular responses such as proliferation, apoptosis, differentiation and migration via activation of G-protein coupled receptors. These receptors activate a broad range of intracellular signaling cascades to mediate these responses. Using microfluidic chambers that generate and maintain stable gradients, we observed that chemotaxis of fibroblasts to LPA has higher directional fidelity than chemotaxis provoked by the receptor tyrosine kinase (RTK) ligand platelet-derived growth factor (PDGF). Unlike fast moving amoeboid cells, mesenchymal cells such as fibroblasts do not require PI3K for chemotaxis to a GPCR ligand. In addition, the Arp2/3 complex is not required for fibroblast GPCR-based chemotaxis in either 2D or 3D environments. Our data indicate that combinatorial regulation of myosin II involving global activation by RhoA/ROCK and local inhibition of myosin II at the leading edge by PKC results in highly efficient chemotaxis of fibroblasts to LPA. Based on these observations, we develop a simple mathematical model to explain how dual regulation of myosin II is responsible for enhanced chemotaxis in LPA gradients relative to PDGF. Using pharmacological approaches, we test predictions of this model and modulate the fidelity of LPA and PDGF chemotaxis.

scholarly journals Dissociation of the intramolecularly cleaved N- and C-terminal fragments of the adhesion G protein-coupled receptor GPR133 (ADGRD1) increases canonical signaling

2020 ◽  
Author(s):  
Joshua D. Frenster ◽  
Gabriele Stephan ◽  
Niklas Ravn-Boess ◽  
Devin Bready ◽  
Jordan Wilcox ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
G Protein ◽  
Receptor Activation ◽  
List Type ◽  
G Protein Coupled Receptor ◽  
Major Mechanism ◽  
N Terminus ◽  
Adhesion Gpcr ◽  
G Protein Coupled

SUMMARYGPR133 (ADGRD1), an adhesion G protein-coupled receptor (GPCR), is necessary for growth of glioblastoma (GBM), a brain malignancy. The extracellular N-terminus of GPR133 is thought to be autoproteolytically cleaved into an N-terminal and a C-terminal fragment (NTF and CTF). Nevertheless, the role of this cleavage in receptor activation remains unclear. Here, we show that the wild-type (WT) receptor is cleaved after protein synthesis and generates significantly more canonical signaling than an uncleavable point mutant (H543R) in patient-derived GBM cultures and HEK293T cells. However, the resulting NTF and CTF remain non-covalently bound until the receptor is trafficked to the plasma membrane, where we find NTF-CTF dissociation. Using a fusion of the hPAR1 receptor N-terminus and the CTF of GPR133, we demonstrate that thrombin-induced cleavage and shedding of the hPAR1 NTF increases receptor signaling. This study supports a model where dissociation of the NTF at the plasma membrane promotes GPR133 activation.Highlights-GPR133 is intramolecularly cleaved in patient-derived GBM cultures-Cleaved GPR133 signals at higher efficacy than the uncleavable GPR133 H543R mutant-The N- and C-terminal fragments (NTF and CTF) of GPR133 dissociate at the plasma membrane-Acute thrombin-induced cleavage of the human PAR1 NTF from the GPR133 CTF increases signalingeTOC BlurbFrenster et al. demonstrate intramolecular cleavage of the adhesion GPCR GPR133 in glioblastoma and HEK293T cells. The resulting N- and C-terminal fragments dissociate at the plasma membrane to increase canonical signaling. The findings suggest dissociation of GPR133’s N-terminus at the plasma membrane represents a major mechanism of receptor activation.

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