Ligation of the adhesion‐GPCR EMR2 regulates human neutrophil function

Yona, Simon; Lin, Hsi‐Hsien; Dri, Pietro; Davies, John Q.; Hayhoe, Richard; Lewis, Stephanie J.; Heinsbroek, Sigrid E. M.; Brown, K A; Perretti, Mauro; Hamann, Jörg; Treacher, David; Gordon, Siamon; Stacey, Martin

doi:10.1096/fj.07-9435com

Cited by 88 publications

(96 citation statements)

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“…The only protein that is known to enhance GPR56-mediated signaling is an anti-GPR56 antibody that binds to the N terminus of the receptor (5). Similarly, N-terminal antibodies have been shown to activate the adhesion GPCR EMR2 (35), and an N-terminal-binding toxin (latrotoxin) has been shown to activate the adhesion GPCR latrophilin 1 (36). Despite the artificial nature of these antibody and toxin treatments, these studies are of significant interest in that they reveal the importance of N-terminal binding partners for receptor activation.…”

Section: Discussionmentioning

confidence: 99%

The N Terminus of the Adhesion G Protein-coupled Receptor GPR56 Controls Receptor Signaling Activity

Paavola

Stephenson

Ritter

et al. 2011

Journal of Biological Chemistry

160

205

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GPR56 is an adhesion G protein-coupled receptor that plays a key role in cortical development. Mutations to GPR56 in humans cause malformations of the cerebral cortex, but little is known about the normal function of the receptor. We found that the large N terminus (NT) of GPR56 is cleaved from the rest of the receptor during processing but remains non-covalently associated with the seven-transmembrane region of the receptor, as indicated by coimmunoprecipitation of the two GPR56 fragments from both transfected cells and native tissue. We also found that truncation of the GPR56 NT results in constitutive activation of receptor signaling, as revealed by increased GPR56-stimulated signaling upon transfection of HEK-293 cells with truncated GPR56, greatly enhanced binding of ␤-arrestins by truncated GPR56 relative to the full-length receptor, extensive ubiquitination of truncated GPR56, and cytotoxicity induced by truncated GPR56 that could be rescued by cotransfection of cells with ␤-arrestin 2. Furthermore, we found that the GPR56 NT is capable of homophilic trans-trans interactions that enhance receptor signaling activity. On the basis of these findings, we suggest a model of receptor activation in which the large N terminus of GPR56 constrains receptor activity but N-terminal interactions (GPR56 NT with an extracellular ligand and/or GPR56 NT homophilic trans-trans associations) can remove this inhibitory influence of the N terminus to activate receptor signaling.During the development of the cerebral cortex, neuronal precursors proliferate in the ventricular and subventricular zones that line the cerebral cavity and then migrate outward to make connections with other neurons. Given the billions of cells involved and the requirements for temporal and spatial precision, it is perhaps not surprising that many different types of problems can arise during this process. Abnormalities in cortical development can lead to a range of distinct neurodevelopmental disorders, some of which are caused by mutations to a single gene. For example, bilateral frontoparietal polymicrogyria is a condition in which patients exhibit profound cognitive abnormalities and seizures because of disordered cortical connectivity in the frontoparietal area. Bilateral frontoparietal polymicrogyria is an autosomal recessive syndrome that results from mutations in the orphan receptor GPR56 (1). Thus, insights into the natural function of GPR56 might shed light on the specific pathology underlying bilateral frontoparietal polymicrogyria and also lead to new insights about the fundamental mechanisms controlling cortical development.GPR56 is a member of the adhesion family of G proteincoupled receptors (GPCRs) 2 , which are characterized by extremely large extracellular N termini (NT) exhibiting homology to adhesion proteins (2). There are approximately 30 adhesion GPCRs, all of which are still considered to be orphan receptors. Almost all members of the adhesion GPCR family possess an N-terminal region known as a "GPCR proteolytic site" or GPS dom...

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Section: Discussionmentioning

confidence: 99%

The N Terminus of the Adhesion G Protein-coupled Receptor GPR56 Controls Receptor Signaling Activity

Paavola

Stephenson

Ritter

et al. 2011

Journal of Biological Chemistry

160

205

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“…CD97-deficient mice have increased numbers of granulocytes [28,36], which is due to a higher granulopoietic activity in the BM (Veninga et al, submitted for publication). Use of antibodies has demonstrated a role for EMR2 in neutrophil migration and cellular activation and shown its upregulation in patients suffering from systemic inflammation [37]. Overall, data from genetic models favour a role of F4/80 and CD97 in cell and/or Figure 6.…”

Section: Functionmentioning

confidence: 97%

F4/80 and the related adhesion‐GPCRs

et al. 2011

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The F4/80 monoclonal antibody was first reported in this journal 30 years ago (Eur. J. Immunol. 1981. 11: 805–815). F4/80 has become a widely used marker for monocytes and many, but not all, tissue macrophages in the mouse. F4/80 is a member of the EGF‐TM7 family of leukocyte plasma membrane heptahelical molecules, which includes CD97 and EMR2. This Viewpoint summarises current knowledge of the expression, structure and functions of the EGF‐TM7 family, as part of a larger family of tissue adhesion‐GPCRs.

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“…Adhesion GPCR are characterized by long extracellular N termini, which are composed of multiple functional domains, a seven-transmembrane spanning (7TM) domain, and a cytoplasmic tail. Adhesion GPCR are believed to play a role in immune functions (3,4), angiogenesis (5), cell polarity (6,7), and development (8,9). Mutations in some members of the protein family were identified as the cause of inherited developmental defects in humans such as Usher syndrome (VLGR1) (10) and bilateral frontoparietal polymicrogyria (GPR56) (11).…”

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confidence: 99%

Cell Adhesion Receptor GPR133 Couples to Gs Protein

Bohnekamp

Schöneberg

2011

Journal of Biological Chemistry

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Adhesion G protein-coupled receptors (GPCR), with their very large and complex N termini, are thought to participate in cell-cell and cell-matrix interactions and appear to be highly relevant in several developmental processes. Their intracellular signaling is still poorly understood. Here we demonstrate that GPR133, a member of the adhesion GPCR subfamily, activates the G s protein/adenylyl cyclase pathway. The presence of the N terminus and the cleavage at the GPCR proteolysis site are not required for G protein signaling. G s protein coupling was verified by G␣ s knockdown with siRNA, overexpression of G␣ s , coexpression of the chimeric Gq s4 protein that routes GPR133 activity to the phospholipase C/inositol phosphate pathway, and missense mutation within the transmembrane domain that abolished receptor activity without changing cell surface expression. It is likely that not only GPR133 but also other adhesion GPCR signal via classical receptor/G protein-interaction.Adhesion receptors comprise the second largest subfamily of putatively G protein-coupled receptors (GPCR) 2 with more than 30 members in vertebrates (1, 2). Adhesion GPCR are characterized by long extracellular N termini, which are composed of multiple functional domains, a seven-transmembrane spanning (7TM) domain, and a cytoplasmic tail. Adhesion GPCR are believed to play a role in immune functions (3, 4), angiogenesis (5), cell polarity (6, 7), and development (8, 9). Mutations in some members of the protein family were identified as the cause of inherited developmental defects in humans such as Usher syndrome (VLGR1) (10) and bilateral frontoparietal polymicrogyria (GPR56) (11). Although there is consensus on the fact that this receptor class mediates essential cellcell and cell-matrix interactions (1, 12), the molecular mechanism of intracellular signal transduction of adhesion GPCR remains obscure.There are only a few studies on intracellular signaling mechanisms of adhesion GPCR. Latrophilin 1, the prototype of adhesion GPCR, induces intracellular Ca 2ϩ signaling upon interaction with the exogenous ligand ␣-latrotoxin (13, 14). GPR56 appears to activate the G 12/13 protein/Rho pathway after stimulation with an antibody against the ectodomain (15). BAI1 recognizes phosphatidylserine and can directly recruit a Racguanine nucleotide exchange factor (Rac-GEF) complex to mediate the uptake of apoptotic cells (16). The cytoplasmic domain of BAI2 interacts with GA-binding protein ␥, and GAbinding protein-␣/␥ or GA-binding protein-␣/␤ work as transcriptional repressors of VEGF (17). However, clear evidence of intracellular signaling for most adhesion GPCR via G proteins is still missing (12).Genetic variations in the GPR133 gene, also a member of the adhesion GPCR family, were associated with adult height (18) and the RR interval duration in electrocardiograms (19). GPR133 is expressed in CNS (20) and other tissues; its endogenous agonists and the signal transduction are unknown. Here we demonstrate that GPR133 is coupled to the G s protein/adeny...

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Ligation of the adhesion‐GPCR EMR2 regulates human neutrophil function

Cited by 88 publications

References 61 publications

The N Terminus of the Adhesion G Protein-coupled Receptor GPR56 Controls Receptor Signaling Activity

The N Terminus of the Adhesion G Protein-coupled Receptor GPR56 Controls Receptor Signaling Activity

F4/80 and the related adhesion‐GPCRs

Cell Adhesion Receptor GPR133 Couples to Gs Protein

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