Cells

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0 pages, 2223 KiB

Open AccessArticle

The Posttraumatic Increase of the Adhesion GPCR EMR2/ADGRE2 on Circulating Neutrophils Is Not Related to Injury Severity

by Leyu Zheng, Moujie Rang, Carolin Fuchs, Annette Keß, Mandy Wunsch, Julia Hentschel, Cheng-Chih Hsiao, Christian Kleber, Georg Osterhoff and Gabriela Aust

Cells 2023, 12(22), 2657; https://doi.org/10.3390/cells12222657 - 20 Nov 2023

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Abstract

Trauma triggers a rapid innate immune response to aid the clearance of damaged/necrotic cells and their released damage-associated molecular pattern (DAMP). Here, we monitored the expression of EMR2/ADGRE2, involved in the functional regulation of innate immune cells, on circulating neutrophils in [...] Read more.

Trauma triggers a rapid innate immune response to aid the clearance of damaged/necrotic cells and their released damage-associated molecular pattern (DAMP). Here, we monitored the expression of EMR2/ADGRE2, involved in the functional regulation of innate immune cells, on circulating neutrophils in very severely and moderately/severely injured patients up to 240 h after trauma. Notably, neutrophilic EMR2 showed a uniform, injury severity- and type of injury-independent posttraumatic course in all patients. The percentage of EMR2⁺ neutrophils and their EMR2 level increased and peaked 48 h after trauma. Afterwards, they declined and normalized in some, but not all, patients. Circulating EMR2⁺ compared to EMR2⁻ neutrophils express less CD62L and more CD11c, a sign of activation. Neutrophilic EMR2 regulation was verified in vitro. Remarkably, it increased, depending on extracellular calcium, in controls as well. Cytokines, enhanced in patients immediately after trauma, and sera of patients did not further affect this neutrophilic EMR2 increase, whereas apoptosis induction disrupted it. Likely the damaged/necrotic cells/DAMPs, unavoidable during neutrophil culture, stimulate the neutrophilic EMR2 increase. In summary, the rapidly increased absolute number of neutrophils, especially present in very severely injured patients, together with upregulated neutrophilic EMR2, may expand our in vivo capacity to react to and finally clear damaged/necrotic cells/DAMPs after trauma. Full article

(This article belongs to the Special Issue Structures, Regulation, Signaling, and Physiological Functions of Adhesion G-Protein Coupled Receptors)

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19 pages, 3494 KiB

Open AccessArticle

Adhesion GPCR Gpr126 (Adgrg6) Expression Profiling in Zebrafish, Mouse, and Human Kidney

by Salvador Cazorla-Vázquez, Peter Kösters, Simone Bertz, Frederick Pfister, Christoph Daniel, Mark Dedden, Sebastian Zundler, Tilman Jobst-Schwan, Kerstin Amann and Felix B. Engel

Cells 2023, 12(15), 1988; https://doi.org/10.3390/cells12151988 - 02 Aug 2023

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Abstract

Adhesion G protein-coupled receptors (aGPCRs) comprise the second-largest class of GPCRs, the most common target for approved pharmacological therapies. aGPCRs play an important role in development and disease and have recently been associated with the kidney. Several aGPCRs are expressed in the kidney [...] Read more.

Adhesion G protein-coupled receptors (aGPCRs) comprise the second-largest class of GPCRs, the most common target for approved pharmacological therapies. aGPCRs play an important role in development and disease and have recently been associated with the kidney. Several aGPCRs are expressed in the kidney and some aGPCRs are either required for kidney development or their expression level is altered in diseased kidneys. Yet, general aGPCR function and their physiological role in the kidney are poorly understood. Here, we characterize in detail Gpr126 (Adgrg6) expression based on RNAscope^® technology in zebrafish, mice, and humans during kidney development in adults. Gpr126 expression is enriched in the epithelial linage during nephrogenesis and persists in the adult kidney in parietal epithelial cells, collecting ducts, and urothelium. Single-cell RNAseq analysis shows that gpr126 expression is detected in zebrafish in a distinct ionocyte sub-population. It is co-detected selectively with slc9a3.2, slc4a4a, and trpv6, known to be involved in apical acid secretion, buffering blood or intracellular pH, and to maintain high cytoplasmic Ca²⁺ concentration, respectively. Furthermore, gpr126-expressing cells were enriched in the expression of potassium transporter kcnj1a.1 and gcm2, which regulate the expression of a calcium sensor receptor. Notably, the expression patterns of Trpv6, Kcnj1a.1, and Gpr126 in mouse kidneys are highly similar. Collectively, our approach permits a detailed insight into the spatio-temporal expression of Gpr126 and provides a basis to elucidate a possible role of Gpr126 in kidney physiology. Full article

(This article belongs to the Special Issue Structures, Regulation, Signaling, and Physiological Functions of Adhesion G-Protein Coupled Receptors)

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9 pages, 1625 KiB

Open AccessCommunication

Collagen VI Is a Gi-Biased Ligand of the Adhesion GPCR GPR126/ADGRG6

by Caroline Wilde, Paulomi Mehta Chaudhry, Rong Luo, Kay-Uwe Simon, Xianhua Piao and Ines Liebscher

Cells 2023, 12(11), 1551; https://doi.org/10.3390/cells12111551 - 05 Jun 2023

Cited by 2 | Viewed by 2405

Abstract

GPR126/ADGRG6, a member of the adhesion G-protein-coupled receptor family, balances cell differentiation and proliferation through fine-tuning of intracellular cAMP levels, which is achieved through coupling to Gs and Gi proteins. While GPR126-mediated cAMP increase has been proven to be essential for differentiation of [...] Read more.

GPR126/ADGRG6, a member of the adhesion G-protein-coupled receptor family, balances cell differentiation and proliferation through fine-tuning of intracellular cAMP levels, which is achieved through coupling to Gs and Gi proteins. While GPR126-mediated cAMP increase has been proven to be essential for differentiation of Schwann cells, adipocytes and osteoblasts, Gi-signaling of the receptor was found to propagate breast cancer cell proliferation. Extracellular ligands or mechanical forces can modulate GPR126 activity but require an intact encrypted agonist sequence, coined the Stachel. Even though coupling to Gi can be seen for constitutively active truncated receptor versions of GPR126 as well as with a peptide agonist derived from the Stachel sequence, all known N-terminal modulators have so far only been shown to modulate Gs coupling. Here, we identified collagen VI as the first extracellular matrix ligand of GPR126 that induces Gi signaling at the receptor, which shows that N-terminal binding partners can mediate selective G protein signaling cascades that are masked by fully active truncated receptor variants. Full article

(This article belongs to the Special Issue Structures, Regulation, Signaling, and Physiological Functions of Adhesion G-Protein Coupled Receptors)

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15 pages, 3690 KiB

Open AccessArticle

The Adhesion G-Protein-Coupled Receptor GPR115/ADGRF4 Regulates Epidermal Differentiation and Associates with Cytoskeletal KRT1

by Romy Winkler, Marianne Quaas, Stefan Glasmacher, Uwe Wolfrum, Torsten Thalheim, Jörg Galle, Knut Krohn, Thomas M. Magin and Gabriela Aust

Cells 2022, 11(19), 3151; https://doi.org/10.3390/cells11193151 - 07 Oct 2022

Cited by 2 | Viewed by 2121 | Correction

Abstract

Among the 33 human adhesion G-protein-coupled receptors (aGPCRs), a unique subfamily of GPCRs, only ADGRF4, encoding GPR115, shows an obvious skin-dominated transcriptomic profile, but its expression and function in skin is largely unknown. Here, we report that GPR115 is present in a [...] Read more.

Among the 33 human adhesion G-protein-coupled receptors (aGPCRs), a unique subfamily of GPCRs, only ADGRF4, encoding GPR115, shows an obvious skin-dominated transcriptomic profile, but its expression and function in skin is largely unknown. Here, we report that GPR115 is present in a small subset of basal and in most suprabasal, noncornified keratinocytes of the stratified epidermis, supporting epidermal transcriptomic data. In psoriatic skin, characterized by hyperproliferation and delayed differentiation, the expression of GPR115 and KRT1/10, the fundamental suprabasal keratin dimer, is delayed. The deletion of ADGRF4 in HaCaT keratinocytes grown in an organotypic mode abrogates KRT1 and reduces keratinocyte stratification, indicating a role of GPR115 in epidermal differentiation. Unexpectedly, endogenous GPR115, which is not glycosylated and is likely not proteolytically processed, localizes intracellularly along KRT1/10-positive keratin filaments in a regular pattern. Our data demonstrate a hitherto unknown function of GPR115 in the regulation of epidermal differentiation and KRT1. Full article

(This article belongs to the Special Issue Structures, Regulation, Signaling, and Physiological Functions of Adhesion G-Protein Coupled Receptors)

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20 pages, 2587 KiB

Open AccessArticle

The Adhesion GPCR VLGR1/ADGRV1 Regulates the Ca²⁺ Homeostasis at Mitochondria-Associated ER Membranes

by Jacek Krzysko, Filip Maciag, Anna Mertens, Baran Enes Güler, Joshua Linnert, Karsten Boldt, Marius Ueffing, Kerstin Nagel-Wolfrum, Martin Heine and Uwe Wolfrum

Cells 2022, 11(18), 2790; https://doi.org/10.3390/cells11182790 - 07 Sep 2022

Cited by 7 | Viewed by 2489

Abstract

The very large G protein-coupled receptor (VLGR1, ADGRV1) is the largest member of the adhesion GPCR family. Mutations in VLGR1 have been associated with the human Usher syndrome (USH), the most common form of inherited deaf-blindness as well as childhood absence epilepsy. VLGR1 [...] Read more.

The very large G protein-coupled receptor (VLGR1, ADGRV1) is the largest member of the adhesion GPCR family. Mutations in VLGR1 have been associated with the human Usher syndrome (USH), the most common form of inherited deaf-blindness as well as childhood absence epilepsy. VLGR1 was previously found as membrane–membrane adhesion complexes and focal adhesions. Affinity proteomics revealed that in the interactome of VLGR1, molecules are enriched that are associated with both the ER and mitochondria, as well as mitochondria-associated ER membranes (MAMs), a compartment at the contact sites of both organelles. We confirmed the interaction of VLGR1 with key proteins of MAMs by pull-down assays in vitro complemented by in situ proximity ligation assays in cells. Immunocytochemistry by light and electron microscopy demonstrated the localization of VLGR1 in MAMs. The absence of VLGR1 in tissues and cells derived from VLGR1-deficient mouse models resulted in alterations in the MAM architecture and in the dysregulation of the Ca²⁺ transient from ER to mitochondria. Our data demonstrate the molecular and functional interaction of VLGR1 with components in MAMs and point to an essential role of VLGR1 in the regulation of Ca²⁺ homeostasis, one of the key functions of MAMs. Full article

(This article belongs to the Special Issue Structures, Regulation, Signaling, and Physiological Functions of Adhesion G-Protein Coupled Receptors)

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24 pages, 12188 KiB

Open AccessArticle

Thwarting of Lphn3 Functions in Cell Motility and Signaling by Cancer-Related GAIN Domain Somatic Mutations

by Monserrat Avila-Zozaya, Brenda Rodríguez-Hernández, Feliciano Monterrubio-Ledezma, Bulmaro Cisneros and Antony A. Boucard

Cells 2022, 11(12), 1913; https://doi.org/10.3390/cells11121913 - 13 Jun 2022

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Abstract

Cancer progression relies on cellular transition states accompanied by changes in the functionality of adhesion molecules. The gene for adhesion G protein-coupled receptor latrophilin-3 (aGPCR Lphn3 or ADGRL3) is targeted by tumor-specific somatic mutations predominantly affecting the conserved GAIN domain where most aGPCRs [...] Read more.

Cancer progression relies on cellular transition states accompanied by changes in the functionality of adhesion molecules. The gene for adhesion G protein-coupled receptor latrophilin-3 (aGPCR Lphn3 or ADGRL3) is targeted by tumor-specific somatic mutations predominantly affecting the conserved GAIN domain where most aGPCRs are cleaved. However, it is unclear how these GAIN domain-altering mutations impact Lphn3 function. Here, we studied Lphn3 cancer-related mutations as a proxy for revealing unknown GAIN domain functions. We found that while intra-GAIN cleavage efficiency was unaltered, most mutations produced a ligand-specific impairment of Lphn3 intercellular adhesion profile paralleled by an increase in cell-matrix actin-dependent contact structures for cells expressing the select S810L mutation. Aberrant remodeling of the intermediate filament vimentin, which was found to coincide with Lphn3-induced modification of nuclear morphology, had less impact on the nuclei of S810L expressing cells. Notoriously, receptor signaling through G13 protein was deficient for all variants bearing non-homologous amino acid substitutions, including the S810L variant. Analysis of cell migration paradigms revealed a non-cell-autonomous impairment in collective cell migration indistinctly of Lphn3 or its cancer-related variants expression, while cell-autonomous motility was potentiated in the presence of Lphn3, but this effect was abolished in S810L GAIN mutant-expressing cells. These data identify the GAIN domain as an important regulator of Lphn3-dependent cell motility, thus furthering our understanding of cellular and molecular events linking Lphn3 genetic somatic mutations to cancer-relevant pathogenesis mechanisms. Full article

(This article belongs to the Special Issue Structures, Regulation, Signaling, and Physiological Functions of Adhesion G-Protein Coupled Receptors)

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14 pages, 5403 KiB

Open AccessArticle

Adhesion GPCR GPR56 Expression Profiling in Human Tissues

by Fyn Kaiser, Markus Morawski, Knut Krohn, Nada Rayes, Cheng-Chih Hsiao, Marianne Quaas and Gabriela Aust

Cells 2021, 10(12), 3557; https://doi.org/10.3390/cells10123557 - 16 Dec 2021

Cited by 4 | Viewed by 3552

Abstract

Despite the immense functional relevance of GPR56 (gene ADGRG1) in highly diverse (patho)physiological processes such as tumorigenesis, immune regulation, and brain development, little is known about its exact tissue localization. Here, we validated antibodies for GPR56-specific binding using cells with tagged GPR56 [...] Read more.

Despite the immense functional relevance of GPR56 (gene ADGRG1) in highly diverse (patho)physiological processes such as tumorigenesis, immune regulation, and brain development, little is known about its exact tissue localization. Here, we validated antibodies for GPR56-specific binding using cells with tagged GPR56 or eliminated ADGRG1 in immunotechniques. Using the most suitable antibody, we then established the human GPR56 tissue expression profile. Overall, ADGRG1 RNA-sequencing data of human tissues and GPR56 protein expression correlate very well. In the adult brain especially, microglia are GPR56-positive. Outside the central nervous system, GPR56 is frequently expressed in cuboidal or highly prismatic secreting epithelia. High ADGRG1 mRNA, present in the thyroid, kidney, and placenta is related to elevated GPR56 in thyrocytes, kidney tubules, and the syncytiotrophoblast, respectively. GPR56 often appears in association with secreted proteins such as pepsinogen A in gastric chief cells and insulin in islet β-cells. In summary, GPR56 shows a broad, not cell-type restricted expression in humans. Full article

(This article belongs to the Special Issue Structures, Regulation, Signaling, and Physiological Functions of Adhesion G-Protein Coupled Receptors)

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Review

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16 pages, 1683 KiB

Open AccessReview

To Detach, Migrate, Adhere, and Metastasize: CD97/ADGRE5 in Cancer

by Gabriela Aust, Leyu Zheng and Marianne Quaas

Cells 2022, 11(9), 1538; https://doi.org/10.3390/cells11091538 - 04 May 2022

Cited by 10 | Viewed by 3526

Abstract

Tumorigenesis is a multistep process, during which cells acquire a series of mutations that lead to unrestrained cell growth and proliferation, inhibition of cell differentiation, and evasion of cell death. Growing tumors stimulate angiogenesis, providing them with nutrients and oxygen. Ultimately, tumor cells [...] Read more.

Tumorigenesis is a multistep process, during which cells acquire a series of mutations that lead to unrestrained cell growth and proliferation, inhibition of cell differentiation, and evasion of cell death. Growing tumors stimulate angiogenesis, providing them with nutrients and oxygen. Ultimately, tumor cells invade the surrounding tissue and metastasize; a process responsible for about 90% of cancer-related deaths. Adhesion G protein-coupled receptors (aGPCRs) modulate the cellular processes closely related to tumor cell biology, such as adhesion and detachment, migration, polarity, and guidance. Soon after first being described, individual human aGPCRs were found to be involved in tumorigenesis. Twenty-five years ago, CD97/ADGRE5 was discovered to be induced in one of the most severe tumors, dedifferentiated anaplastic thyroid carcinoma. After decades of research, the time has come to review our knowledge of the presence and function of CD97 in cancer. In summary, CD97 is obviously induced or altered in many tumor entities; this has been shown consistently in nearly one hundred published studies. However, its high expression at circulating and tumor-infiltrating immune cells renders the systemic targeting of CD97 in tumors difficult. Full article

(This article belongs to the Special Issue Structures, Regulation, Signaling, and Physiological Functions of Adhesion G-Protein Coupled Receptors)

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6 pages, 3593 KiB

Open AccessCorrection

Correction: Winkler et al. The Adhesion G-Protein-Coupled Receptor GPR115/ADGRF4 Regulates Epidermal Differentiation and Associates with Cytoskeletal KRT1. Cells 2022, 11, 3151

by Romy Winkler, Marianne Quaas, Stefan Glasmacher, Uwe Wolfrum, Torsten Thalheim, Jörg Galle, Knut Krohn, Thomas M. Magin and Gabriela Aust

Cells 2023, 12(13), 1677; https://doi.org/10.3390/cells12131677 - 21 Jun 2023

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Abstract

In the original publication [...] Full article

(This article belongs to the Special Issue Structures, Regulation, Signaling, and Physiological Functions of Adhesion G-Protein Coupled Receptors)

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