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Xianhua Piao - One of the best experts on this subject based on the ideXlab platform.
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GPR56 adgrg1 is a platelet collagen responsive gpcr and hemostatic sensor of shear force
Proceedings of the National Academy of Sciences of the United States of America, 2020Co-Authors: Jennifer Yeung, Rong Luo, Xianhua Piao, Hannah M. Stoveken, Reheman Adili, Emily N. Stringham, Alexander Vizurraga, Luciana K Rossellimurai, Michael HolinstatAbstract:Circulating platelets roll along exposed collagen at vessel injury sites and respond with filipodia protrusion, shape change, and surface area expansion to facilitate platelet adhesion and plug formation. Various glycoproteins were considered to be both collagen responders and mediators of platelet adhesion, yet the signaling kinetics emanating from these receptors do not fully account for the rapid platelet cytoskeletal changes that occur in blood flow. We found the free N-terminal fragment of the adhesion G protein-coupled receptor (GPCR) GPR56 in human plasma and report that GPR56 is the platelet receptor that transduces signals from collagen and blood flow-induced shear force to activate G protein 13 signaling for platelet shape change. GPR56−/− mice have prolonged bleeding, defective platelet plug formation, and delayed thrombotic occlusion. Human and mouse blood perfusion studies demonstrated GPR56 and shear-force dependence of platelet adhesion to immobilized collagen. Our work places GPR56 as an initial collagen responder and shear-force transducer that is essential for platelet shape change during hemostasis.
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GPR56/ADGRG1 is a platelet collagen-responsive GPCR and hemostatic sensor of shear force.
Proceedings of the National Academy of Sciences of the United States of America, 2020Co-Authors: Jennifer Yeung, Rong Luo, Xianhua Piao, Hannah M. Stoveken, Reheman Adili, Emily N. Stringham, Alexander Vizurraga, Luciana K. Rosselli-murai, Michael HolinstatAbstract:Circulating platelets roll along exposed collagen at vessel injury sites and respond with filipodia protrusion, shape change, and surface area expansion to facilitate platelet adhesion and plug formation. Various glycoproteins were considered to be both collagen responders and mediators of platelet adhesion, yet the signaling kinetics emanating from these receptors do not fully account for the rapid platelet cytoskeletal changes that occur in blood flow. We found the free N-terminal fragment of the adhesion G protein-coupled receptor (GPCR) GPR56 in human plasma and report that GPR56 is the platelet receptor that transduces signals from collagen and blood flow-induced shear force to activate G protein 13 signaling for platelet shape change. GPR56-/- mice have prolonged bleeding, defective platelet plug formation, and delayed thrombotic occlusion. Human and mouse blood perfusion studies demonstrated GPR56 and shear-force dependence of platelet adhesion to immobilized collagen. Our work places GPR56 as an initial collagen responder and shear-force transducer that is essential for platelet shape change during hemostasis.
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Unexpected redundancy of GPR56 and Gpr97 during hematopoietic cell development and differentiation
2020Co-Authors: Antonio Maglitto, Xianhua Piao, Samanta A. Mariani, E. De Pater, Carmen Rodriguez-seoane, Chris S. Vink, M.-l. Lukke, Elaine DzierzakAbstract:Abstract Integrated molecular signals regulate cell fate during embryonic hematopoietic stem cell (HSC) generation. The G-protein coupled receptor 56 (GPR56) is the most highly-upregulated receptor gene in cells that take on hematopoietic fate and it is expressed by adult bone marrow HSCs. Although GPR56 is required for hematopoietic stem/progenitor cell (HS/PC) generation in zebrafish embryos, its function in mammalian hematopoiesis remains unclear. Here we examine the role of GPR56 in HS/PC development in GPR56 conditional knockout (cKO) mouse embryos and Gpr knockout (KO) embryonic stem cell (ESC) hematopoietic differentiation cultures. Our results show a myeloid bias of GPR56 cKO fetal liver HSCs and an increased definitive myeloid progenitor cell frequency in GPR56KO ESC differentiation cultures. Surprisingly, we find that mouse Gpr97 rescues GPR56 morphant zebrafish hematopoietic generation, and that Gpr97 expression is upregulated in mouse GPR56 deletion models. When both GPR56 and Gpr97 are deleted in ESCs, no/few HS/PCs are generated upon ESC differentiation. Together, our results reveal novel and redundant functions for these two G-protein coupled receptors in normal mammalian hematopoietic cell development and differentiation.
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gain domain mediated cleavage is required for activation of g protein coupled receptor 56 GPR56 by its natural ligands and a small molecule agonist
Journal of Biological Chemistry, 2019Co-Authors: Tao Li, Stefanie Giera, Kelly R. Monk, Brian K Shoichet, Xianhua PiaoAbstract:: Adhesion G protein-coupled receptors (aGPCRs) represent a distinct family of GPCRs that regulate several developmental and physiological processes. Most aGPCRs undergo GPCR autoproteolysis-inducing domain-mediated protein cleavage, which produces a cryptic tethered agonist (termed Stachel (stinger)), and cleavage-dependent and -independent aGPCR signaling mechanisms have been described. aGPCR G1 (ADGRG1 or G protein-coupled receptor 56 (GPR56)) has pleiotropic functions in the development of multiple organ systems, which has broad implications for human diseases. To date, two natural GPR56 ligands, collagen III and tissue transglutaminase (TG2), and one small-molecule agonist, 3-α-acetoxydihydrodeoxygedunin (3-α-DOG), have been identified, in addition to a synthetic peptide, P19, that contains seven amino acids of the native Stachel sequence. However, the mechanisms by which these natural and small-molecule agonists signal through GPR56 remain unknown. Here we engineered a noncleavable receptor variant that retains signaling competence via the P19 peptide. We demonstrate that both natural and small-molecule agonists can activate only cleaved GPR56. Interestingly, TG2 required both receptor cleavage and the presence of a matrix protein, laminin, to activate GPR56, whereas collagen III and 3-α-DOG signaled without any cofactors. On the other hand, both TG2/laminin and collagen III activate the receptor by dissociating the N-terminal fragment from its C-terminal fragment, enabling activation by the Stachel sequence, whereas P19 and 3-α-DOG initiate downstream signaling without disengaging the N-terminal fragment from its C-terminal fragment. These findings deepen our understanding of how GPR56 signals via natural ligands, and a small-molecule agonist may be broadly applicable to other aGPCR family members.
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GAIN domain–mediated cleavage is required for activation of G protein–coupled receptor 56 (GPR56) by its natural ligands and a small-molecule agonist
The Journal of biological chemistry, 2019Co-Authors: Beika Zhu, Stefanie Giera, Rong Luo, Kelly R. Monk, Hayeon C Oak, Brian K Shoichet, Peng Jin, Parnian Lak, Xianhua PiaoAbstract:Adhesion G protein-coupled receptors (aGPCRs) represent a distinct family of GPCRs that regulate several developmental and physiological processes. Most aGPCRs undergo GPCR autoproteolysis-inducing domain-mediated protein cleavage, which produces a cryptic tethered agonist (termed Stachel (stinger)), and cleavage-dependent and -independent aGPCR signaling mechanisms have been described. aGPCR G1 (ADGRG1 or G protein-coupled receptor 56 (GPR56)) has pleiotropic functions in the development of multiple organ systems, which has broad implications for human diseases. To date, two natural GPR56 ligands, collagen III and tissue transglutaminase (TG2), and one small-molecule agonist, 3-α-acetoxydihydrodeoxygedunin (3-α-DOG), have been identified, in addition to a synthetic peptide, P19, that contains seven amino acids of the native Stachel sequence. However, the mechanisms by which these natural and small-molecule agonists signal through GPR56 remain unknown. Here we engineered a noncleavable receptor variant that retains signaling competence via the P19 peptide. We demonstrate that both natural and small-molecule agonists can activate only cleaved GPR56. Interestingly, TG2 required both receptor cleavage and the presence of a matrix protein, laminin, to activate GPR56, whereas collagen III and 3-α-DOG signaled without any cofactors. On the other hand, both TG2/laminin and collagen III activate the receptor by dissociating the N-terminal fragment from its C-terminal fragment, enabling activation by the Stachel sequence, whereas P19 and 3-α-DOG initiate downstream signaling without disengaging the N-terminal fragment from its C-terminal fragment. These findings deepen our understanding of how GPR56 signals via natural ligands, and a small-molecule agonist may be broadly applicable to other aGPCR family members.
Hsi Hsien Lin - One of the best experts on this subject based on the ideXlab platform.
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the activation and signaling mechanisms of GPR56 adgrg1 in melanoma cell
Frontiers in Oncology, 2018Co-Authors: Kuan-yeh Huang, Hsi Hsien LinAbstract:Adhesion G protein-coupled receptors (aGPCRs) constitute the second largest GPCR subfamily. GPR56/ADGRG1 is a member of the ADGRG subgroup of aGPCRs. Although GPR56 is best known for its pivotal role in the cerebral cortical development, it is also important for tumor progression. Numerous studies have revealed that GPR56 is expressed in various cancer types with a role in cancer cell adhesion, migration and metastasis. In a recent study, we found that the immobilized GPR56-specific CG4 antibody enhanced IL-6 production and migration ability of melanoma cells. In this review, we will summarize the current understanding of GPR56 function and discuss the activation and signaling mechanisms of GPR56 in melanoma cells.
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High levels of soluble GPR56/ADGRG1 are associated with positive rheumatoid factor and elevated tumor necrosis factor in patients with rheumatoid arthritis
Journal of microbiology immunology and infection = Wei mian yu gan ran za zhi, 2017Co-Authors: Wen-yi Tseng, Nien Yi Chiang, Gin Wen Chang, Tai-yun Yang, Wen-pin Tsai, Siamon Gordon, Chang-fu Kuo, Shue-fen Luo, Hsi Hsien LinAbstract:Abstract Background GPR56/ADGRG1 is a member of the adhesion-class G protein-coupled receptor (aGPCR) family important in brain development, oncogenesis and tumor metastasis. Like other aGPCRs, GPR56 is cleaved at the GPCR proteolysis site (GPS) motif into an N-terminal fragment (NTF) and a C-terminal fragment (CTF). Existence of soluble GPR56 (sGPR56) has been shown in vitro , however the underlying mechanism and its pathophysiologic role remains undetermined. Objective To assess the presence of sGPR56 in human serum using ELISA assay and compare the serum sGPR56 levels among patients of various chronic inflammatory diseases and healthy subjects. Patients and methods In this study, serum samples from patients with systemic lupus erythematosus (SLE) (n = 57), rheumatoid arthritis (RA) (n = 95), Sjogren's syndrome (SS) (n = 29), ankylosing spondylitis (AS) (n = 51), and normal controls (n = 81) were analyzed using sGPR56-specific ELISA. Result We show that serum sGPR56 levels are increased in patients of RA, but not in those with SLE, SS and AS. Intriguingly, serum sGPR56 levels in RA patients correlated with positive rheumatoid factor, a marker of bone erosion and poor outcome. In addition, an elevated sGPR56 level is also noted in RA patients with higher tumor necrosis factor level. Conclusion we conclude that sGPR56 is present in vivo and sGPR56 level is elevated in certain chronic inflammatory diseases such as RA. Hence, sGPR56 might be considered a potential biomarker for RA disease progression.
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GPR56 adgrg1 activation promotes melanoma cell migration via ntf dissociation and ctf mediated gα12 13 rhoa signaling
Journal of Investigative Dermatology, 2017Co-Authors: Nien Yi Chiang, Hsiao Lin Pan, Gin Wen Chang, Yen-ming Peng, Horng-heng Juang, Tse-ching Chen, Hsi Hsien LinAbstract:GPR56/ADGRG1 is a versatile adhesion G protein-coupled receptor with diverse biological functions. GPR56 expression is variably detected in human melanoma cell lines and correlates inversely with the metastatic potential of melanoma lesions. GPR56 associates with the tetraspanins CD9 and CD81 on the melanoma cell surface. GPR56 activation by immobilized CG4 monoclonal antibody facilitates N-terminal fragment dissociation in a CD9/CD81-dependent manner specifically inducing IL-6 production, which promotes cell migration and invasion. Interestingly, expression of GPR56-C-terminal fragment alone recapitulates the antibody-induced receptor function, implicating a major role for the C-terminal fragment in GPR56 activation and signaling. Analysis of site-directed mutant receptors attests the importance of the conserved N-terminal residues of the C-terminal fragment for its self-activation. Finally, we show that the GPR56-induced signaling in melanoma cells is mediated by the Gα12/13/RhoA pathway. In summary, the expression and activation of GPR56 may modulate melanoma progression in part by inducing IL-6 production after N-terminal fragment dissociation and C-terminal fragment self-activation.
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GPR56/ADGRG1 Activation Promotes Melanoma Cell Migration via NTF Dissociation and CTF-Mediated Gα12/13/RhoA Signaling
Journal of Investigative Dermatology, 2017Co-Authors: Nien Yi Chiang, Hsiao Lin Pan, Gin Wen Chang, Yen-ming Peng, Horng-heng Juang, Tse-ching Chen, Hsi Hsien LinAbstract:GPR56/ADGRG1 is a versatile adhesion G protein-coupled receptor with diverse biological functions. GPR56 expression is variably detected in human melanoma cell lines and correlates inversely with the metastatic potential of melanoma lesions. GPR56 associates with the tetraspanins CD9 and CD81 on the melanoma cell surface. GPR56 activation by immobilized CG4 monoclonal antibody facilitates N-terminal fragment dissociation in a CD9/CD81-dependent manner specifically inducing IL-6 production, which promotes cell migration and invasion. Interestingly, expression of GPR56-C-terminal fragment alone recapitulates the antibody-induced receptor function, implicating a major role for the C-terminal fragment in GPR56 activation and signaling. Analysis of site-directed mutant receptors attests the importance of the conserved N-terminal residues of the C-terminal fragment for its self-activation. Finally, we show that the GPR56-induced signaling in melanoma cells is mediated by the Gα12/13/RhoA pathway. In summary, the expression and activation of GPR56 may modulate melanoma progression in part by inducing IL-6 production after N-terminal fragment dissociation and C-terminal fragment self-activation.
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Heparin interacts with the adhesion GPCR GPR56, reduces receptor shedding, and promotes cell adhesion and motility.
Journal of cell science, 2016Co-Authors: Nien Yi Chiang, Gin Wen Chang, Yen-ming Peng, Ming-ling Kuo, Cheng Chih Hsiao, Yi-shu Huang, Hsi Hsien LinAbstract:GPR56 is an adhesion-class G-protein-coupled receptor responsible for bilateral frontoparietal polymicrogyria (BFPP), a severe disorder of cortical formation. Additionally, GPR56 is involved in biological processes as diverse as hematopoietic stem cell generation and maintenance, myoblast fusion, muscle hypertrophy, immunoregulation and tumorigenesis. Collagen III and tissue transglutaminase 2 (TG2) have been revealed as the matricellular ligands of GPR56 involved in BFPP and melanoma development, respectively. In this study, we identify heparin as a glycosaminoglycan interacting partner of GPR56. Analyses of truncated and mutant GPR56 proteins reveal two basic-residue-rich clusters, R(26)GHREDFRFC(35) and L(190)KHPQKASRRP(200), as the major heparin-interacting motifs that overlap partially with the collagen III- and TG2-binding sites. Interestingly, the GPR56-heparin interaction is modulated by collagen III but not TG2, even though both ligands are also heparin-binding proteins. Finally, we show that the interaction with heparin reduces GPR56 receptor shedding, and enhances cell adhesion and motility. These results provide novel insights into the interaction of GPR56 with its multiple endogenous ligands and have functional implications in diseases such as BFPP and cancer.
Rong Luo - One of the best experts on this subject based on the ideXlab platform.
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GPR56 adgrg1 is a platelet collagen responsive gpcr and hemostatic sensor of shear force
Proceedings of the National Academy of Sciences of the United States of America, 2020Co-Authors: Jennifer Yeung, Rong Luo, Xianhua Piao, Hannah M. Stoveken, Reheman Adili, Emily N. Stringham, Alexander Vizurraga, Luciana K Rossellimurai, Michael HolinstatAbstract:Circulating platelets roll along exposed collagen at vessel injury sites and respond with filipodia protrusion, shape change, and surface area expansion to facilitate platelet adhesion and plug formation. Various glycoproteins were considered to be both collagen responders and mediators of platelet adhesion, yet the signaling kinetics emanating from these receptors do not fully account for the rapid platelet cytoskeletal changes that occur in blood flow. We found the free N-terminal fragment of the adhesion G protein-coupled receptor (GPCR) GPR56 in human plasma and report that GPR56 is the platelet receptor that transduces signals from collagen and blood flow-induced shear force to activate G protein 13 signaling for platelet shape change. GPR56−/− mice have prolonged bleeding, defective platelet plug formation, and delayed thrombotic occlusion. Human and mouse blood perfusion studies demonstrated GPR56 and shear-force dependence of platelet adhesion to immobilized collagen. Our work places GPR56 as an initial collagen responder and shear-force transducer that is essential for platelet shape change during hemostasis.
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GPR56/ADGRG1 is a platelet collagen-responsive GPCR and hemostatic sensor of shear force.
Proceedings of the National Academy of Sciences of the United States of America, 2020Co-Authors: Jennifer Yeung, Rong Luo, Xianhua Piao, Hannah M. Stoveken, Reheman Adili, Emily N. Stringham, Alexander Vizurraga, Luciana K. Rosselli-murai, Michael HolinstatAbstract:Circulating platelets roll along exposed collagen at vessel injury sites and respond with filipodia protrusion, shape change, and surface area expansion to facilitate platelet adhesion and plug formation. Various glycoproteins were considered to be both collagen responders and mediators of platelet adhesion, yet the signaling kinetics emanating from these receptors do not fully account for the rapid platelet cytoskeletal changes that occur in blood flow. We found the free N-terminal fragment of the adhesion G protein-coupled receptor (GPCR) GPR56 in human plasma and report that GPR56 is the platelet receptor that transduces signals from collagen and blood flow-induced shear force to activate G protein 13 signaling for platelet shape change. GPR56-/- mice have prolonged bleeding, defective platelet plug formation, and delayed thrombotic occlusion. Human and mouse blood perfusion studies demonstrated GPR56 and shear-force dependence of platelet adhesion to immobilized collagen. Our work places GPR56 as an initial collagen responder and shear-force transducer that is essential for platelet shape change during hemostasis.
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A splicing isoform of GPR56 mediates microglial synaptic refinement via phosphatidylserine binding
2020Co-Authors: Brian Chiou, Stefanie Giera, Rong Luo, Casey K Gilman, Tatsuhiro Koshi, Hayeon C Oak, Erin M. Johnson-venkatesh, Allie K. MuthukumarAbstract:Developmental synaptic remodeling is important for the formation of precise neural circuitry and its disruption has been linked to neurodevelopmental disorders such as autism and schizophrenia. Microglia prune synapses, but integration of this synapse pruning with overlapping and concurrent neurodevelopmental processes remains elusive. Adhesion G protein-coupled receptor ADGRG1/GPR56 controls multiple aspects of brain development in a cell type-specific manner: in neural progenitor cells, GPR56 regulates cortical lamination, whereas in oligodendrocyte progenitor cells, GPR56 controls developmental myelination and myelin repair. Here, we show that microglial GPR56 maintains appropriate synaptic numbers in several brain regions in a time- and circuit-dependent fashion. Phosphatidylserine (PS) on pre-synaptic elements binds GPR56 in a domain-specific manner, and microglia-specific deletion of GPR56 leads to increased synapses as a result of reduced microglial engulfment of PS+ pre-synaptic inputs. Remarkably, a particular alternatively spliced isoform of GPR56 is selectively required for microglia-mediated synaptic pruning. Our present data provide a ligand- and isoform-specific mechanism underlying microglial GPR56-mediated synapse pruning in the context of complex neurodevelopmental processes.
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GAIN domain–mediated cleavage is required for activation of G protein–coupled receptor 56 (GPR56) by its natural ligands and a small-molecule agonist
The Journal of biological chemistry, 2019Co-Authors: Beika Zhu, Stefanie Giera, Rong Luo, Kelly R. Monk, Hayeon C Oak, Brian K Shoichet, Peng Jin, Parnian Lak, Xianhua PiaoAbstract:Adhesion G protein-coupled receptors (aGPCRs) represent a distinct family of GPCRs that regulate several developmental and physiological processes. Most aGPCRs undergo GPCR autoproteolysis-inducing domain-mediated protein cleavage, which produces a cryptic tethered agonist (termed Stachel (stinger)), and cleavage-dependent and -independent aGPCR signaling mechanisms have been described. aGPCR G1 (ADGRG1 or G protein-coupled receptor 56 (GPR56)) has pleiotropic functions in the development of multiple organ systems, which has broad implications for human diseases. To date, two natural GPR56 ligands, collagen III and tissue transglutaminase (TG2), and one small-molecule agonist, 3-α-acetoxydihydrodeoxygedunin (3-α-DOG), have been identified, in addition to a synthetic peptide, P19, that contains seven amino acids of the native Stachel sequence. However, the mechanisms by which these natural and small-molecule agonists signal through GPR56 remain unknown. Here we engineered a noncleavable receptor variant that retains signaling competence via the P19 peptide. We demonstrate that both natural and small-molecule agonists can activate only cleaved GPR56. Interestingly, TG2 required both receptor cleavage and the presence of a matrix protein, laminin, to activate GPR56, whereas collagen III and 3-α-DOG signaled without any cofactors. On the other hand, both TG2/laminin and collagen III activate the receptor by dissociating the N-terminal fragment from its C-terminal fragment, enabling activation by the Stachel sequence, whereas P19 and 3-α-DOG initiate downstream signaling without disengaging the N-terminal fragment from its C-terminal fragment. These findings deepen our understanding of how GPR56 signals via natural ligands, and a small-molecule agonist may be broadly applicable to other aGPCR family members.
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GPR56 adgrg1 regulates development and maintenance of peripheral myelin
Journal of Experimental Medicine, 2018Co-Authors: Sarah D Ackerman, Rong Luo, Amit Mogha, Yannick Poitelon, Breanne L. Harty, Nicholas E. Sanchez, Asvin K. K. Lakkaraju, Paul Gamble, Mitchell Drozario, Matthew R MacewanAbstract:Myelin is a multilamellar sheath generated by specialized glia called Schwann cells (SCs) in the peripheral nervous system (PNS), which serves to protect and insulate axons for rapid neuronal signaling. In zebrafish and rodent models, we identify GPR56/ADGRG1 as a conserved regulator of PNS development and health. We demonstrate that, during SC development, GPR56-dependent RhoA signaling promotes timely radial sorting of axons. In the mature PNS, GPR56 is localized to distinct SC cytoplasmic domains, is required to establish proper myelin thickness, and facilitates organization of the myelin sheath. Furthermore, we define plectin-a scaffolding protein previously linked to SC domain organization, myelin maintenance, and a series of disorders termed "plectinopathies"-as a novel interacting partner of GPR56. Finally, we show that GPR56 mutants develop progressive neuropathy-like symptoms, suggesting an underlying mechanism for peripheral defects in some human patients with GPR56 mutations. In sum, we define GPR56 as a new regulator in the development and maintenance of peripheral myelin.
Nien Yi Chiang - One of the best experts on this subject based on the ideXlab platform.
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high levels of soluble GPR56 adgrg1 are associated with positive rheumatoid factor and elevated tumor necrosis factor in patients with rheumatoid arthritis
Journal of Microbiology Immunology and Infection, 2017Co-Authors: Nien Yi Chiang, Gin Wen Chang, Tai-yun Yang, Wen-yi Tseng, Wen-pin Tsai, Siamon Gordon, Chang-fu Kuo, Shue-fen LuoAbstract:Abstract Background GPR56/ADGRG1 is a member of the adhesion-class G protein-coupled receptor (aGPCR) family important in brain development, oncogenesis and tumor metastasis. Like other aGPCRs, GPR56 is cleaved at the GPCR proteolysis site (GPS) motif into an N-terminal fragment (NTF) and a C-terminal fragment (CTF). Existence of soluble GPR56 (sGPR56) has been shown in vitro , however the underlying mechanism and its pathophysiologic role remains undetermined. Objective To assess the presence of sGPR56 in human serum using ELISA assay and compare the serum sGPR56 levels among patients of various chronic inflammatory diseases and healthy subjects. Patients and methods In this study, serum samples from patients with systemic lupus erythematosus (SLE) (n = 57), rheumatoid arthritis (RA) (n = 95), Sjogren's syndrome (SS) (n = 29), ankylosing spondylitis (AS) (n = 51), and normal controls (n = 81) were analyzed using sGPR56-specific ELISA. Result We show that serum sGPR56 levels are increased in patients of RA, but not in those with SLE, SS and AS. Intriguingly, serum sGPR56 levels in RA patients correlated with positive rheumatoid factor, a marker of bone erosion and poor outcome. In addition, an elevated sGPR56 level is also noted in RA patients with higher tumor necrosis factor level. Conclusion we conclude that sGPR56 is present in vivo and sGPR56 level is elevated in certain chronic inflammatory diseases such as RA. Hence, sGPR56 might be considered a potential biomarker for RA disease progression.
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High levels of soluble GPR56/ADGRG1 are associated with positive rheumatoid factor and elevated tumor necrosis factor in patients with rheumatoid arthritis
Journal of microbiology immunology and infection = Wei mian yu gan ran za zhi, 2017Co-Authors: Wen-yi Tseng, Nien Yi Chiang, Gin Wen Chang, Tai-yun Yang, Wen-pin Tsai, Siamon Gordon, Chang-fu Kuo, Shue-fen Luo, Hsi Hsien LinAbstract:Abstract Background GPR56/ADGRG1 is a member of the adhesion-class G protein-coupled receptor (aGPCR) family important in brain development, oncogenesis and tumor metastasis. Like other aGPCRs, GPR56 is cleaved at the GPCR proteolysis site (GPS) motif into an N-terminal fragment (NTF) and a C-terminal fragment (CTF). Existence of soluble GPR56 (sGPR56) has been shown in vitro , however the underlying mechanism and its pathophysiologic role remains undetermined. Objective To assess the presence of sGPR56 in human serum using ELISA assay and compare the serum sGPR56 levels among patients of various chronic inflammatory diseases and healthy subjects. Patients and methods In this study, serum samples from patients with systemic lupus erythematosus (SLE) (n = 57), rheumatoid arthritis (RA) (n = 95), Sjogren's syndrome (SS) (n = 29), ankylosing spondylitis (AS) (n = 51), and normal controls (n = 81) were analyzed using sGPR56-specific ELISA. Result We show that serum sGPR56 levels are increased in patients of RA, but not in those with SLE, SS and AS. Intriguingly, serum sGPR56 levels in RA patients correlated with positive rheumatoid factor, a marker of bone erosion and poor outcome. In addition, an elevated sGPR56 level is also noted in RA patients with higher tumor necrosis factor level. Conclusion we conclude that sGPR56 is present in vivo and sGPR56 level is elevated in certain chronic inflammatory diseases such as RA. Hence, sGPR56 might be considered a potential biomarker for RA disease progression.
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GPR56 adgrg1 activation promotes melanoma cell migration via ntf dissociation and ctf mediated gα12 13 rhoa signaling
Journal of Investigative Dermatology, 2017Co-Authors: Nien Yi Chiang, Hsiao Lin Pan, Gin Wen Chang, Yen-ming Peng, Horng-heng Juang, Tse-ching Chen, Hsi Hsien LinAbstract:GPR56/ADGRG1 is a versatile adhesion G protein-coupled receptor with diverse biological functions. GPR56 expression is variably detected in human melanoma cell lines and correlates inversely with the metastatic potential of melanoma lesions. GPR56 associates with the tetraspanins CD9 and CD81 on the melanoma cell surface. GPR56 activation by immobilized CG4 monoclonal antibody facilitates N-terminal fragment dissociation in a CD9/CD81-dependent manner specifically inducing IL-6 production, which promotes cell migration and invasion. Interestingly, expression of GPR56-C-terminal fragment alone recapitulates the antibody-induced receptor function, implicating a major role for the C-terminal fragment in GPR56 activation and signaling. Analysis of site-directed mutant receptors attests the importance of the conserved N-terminal residues of the C-terminal fragment for its self-activation. Finally, we show that the GPR56-induced signaling in melanoma cells is mediated by the Gα12/13/RhoA pathway. In summary, the expression and activation of GPR56 may modulate melanoma progression in part by inducing IL-6 production after N-terminal fragment dissociation and C-terminal fragment self-activation.
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GPR56/ADGRG1 Activation Promotes Melanoma Cell Migration via NTF Dissociation and CTF-Mediated Gα12/13/RhoA Signaling
Journal of Investigative Dermatology, 2017Co-Authors: Nien Yi Chiang, Hsiao Lin Pan, Gin Wen Chang, Yen-ming Peng, Horng-heng Juang, Tse-ching Chen, Hsi Hsien LinAbstract:GPR56/ADGRG1 is a versatile adhesion G protein-coupled receptor with diverse biological functions. GPR56 expression is variably detected in human melanoma cell lines and correlates inversely with the metastatic potential of melanoma lesions. GPR56 associates with the tetraspanins CD9 and CD81 on the melanoma cell surface. GPR56 activation by immobilized CG4 monoclonal antibody facilitates N-terminal fragment dissociation in a CD9/CD81-dependent manner specifically inducing IL-6 production, which promotes cell migration and invasion. Interestingly, expression of GPR56-C-terminal fragment alone recapitulates the antibody-induced receptor function, implicating a major role for the C-terminal fragment in GPR56 activation and signaling. Analysis of site-directed mutant receptors attests the importance of the conserved N-terminal residues of the C-terminal fragment for its self-activation. Finally, we show that the GPR56-induced signaling in melanoma cells is mediated by the Gα12/13/RhoA pathway. In summary, the expression and activation of GPR56 may modulate melanoma progression in part by inducing IL-6 production after N-terminal fragment dissociation and C-terminal fragment self-activation.
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Heparin interacts with the adhesion GPCR GPR56, reduces receptor shedding, and promotes cell adhesion and motility.
Journal of cell science, 2016Co-Authors: Nien Yi Chiang, Gin Wen Chang, Yen-ming Peng, Ming-ling Kuo, Cheng Chih Hsiao, Yi-shu Huang, Hsi Hsien LinAbstract:GPR56 is an adhesion-class G-protein-coupled receptor responsible for bilateral frontoparietal polymicrogyria (BFPP), a severe disorder of cortical formation. Additionally, GPR56 is involved in biological processes as diverse as hematopoietic stem cell generation and maintenance, myoblast fusion, muscle hypertrophy, immunoregulation and tumorigenesis. Collagen III and tissue transglutaminase 2 (TG2) have been revealed as the matricellular ligands of GPR56 involved in BFPP and melanoma development, respectively. In this study, we identify heparin as a glycosaminoglycan interacting partner of GPR56. Analyses of truncated and mutant GPR56 proteins reveal two basic-residue-rich clusters, R(26)GHREDFRFC(35) and L(190)KHPQKASRRP(200), as the major heparin-interacting motifs that overlap partially with the collagen III- and TG2-binding sites. Interestingly, the GPR56-heparin interaction is modulated by collagen III but not TG2, even though both ligands are also heparin-binding proteins. Finally, we show that the interaction with heparin reduces GPR56 receptor shedding, and enhances cell adhesion and motility. These results provide novel insights into the interaction of GPR56 with its multiple endogenous ligands and have functional implications in diseases such as BFPP and cancer.
Gin Wen Chang - One of the best experts on this subject based on the ideXlab platform.
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high levels of soluble GPR56 adgrg1 are associated with positive rheumatoid factor and elevated tumor necrosis factor in patients with rheumatoid arthritis
Journal of Microbiology Immunology and Infection, 2017Co-Authors: Nien Yi Chiang, Gin Wen Chang, Tai-yun Yang, Wen-yi Tseng, Wen-pin Tsai, Siamon Gordon, Chang-fu Kuo, Shue-fen LuoAbstract:Abstract Background GPR56/ADGRG1 is a member of the adhesion-class G protein-coupled receptor (aGPCR) family important in brain development, oncogenesis and tumor metastasis. Like other aGPCRs, GPR56 is cleaved at the GPCR proteolysis site (GPS) motif into an N-terminal fragment (NTF) and a C-terminal fragment (CTF). Existence of soluble GPR56 (sGPR56) has been shown in vitro , however the underlying mechanism and its pathophysiologic role remains undetermined. Objective To assess the presence of sGPR56 in human serum using ELISA assay and compare the serum sGPR56 levels among patients of various chronic inflammatory diseases and healthy subjects. Patients and methods In this study, serum samples from patients with systemic lupus erythematosus (SLE) (n = 57), rheumatoid arthritis (RA) (n = 95), Sjogren's syndrome (SS) (n = 29), ankylosing spondylitis (AS) (n = 51), and normal controls (n = 81) were analyzed using sGPR56-specific ELISA. Result We show that serum sGPR56 levels are increased in patients of RA, but not in those with SLE, SS and AS. Intriguingly, serum sGPR56 levels in RA patients correlated with positive rheumatoid factor, a marker of bone erosion and poor outcome. In addition, an elevated sGPR56 level is also noted in RA patients with higher tumor necrosis factor level. Conclusion we conclude that sGPR56 is present in vivo and sGPR56 level is elevated in certain chronic inflammatory diseases such as RA. Hence, sGPR56 might be considered a potential biomarker for RA disease progression.
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High levels of soluble GPR56/ADGRG1 are associated with positive rheumatoid factor and elevated tumor necrosis factor in patients with rheumatoid arthritis
Journal of microbiology immunology and infection = Wei mian yu gan ran za zhi, 2017Co-Authors: Wen-yi Tseng, Nien Yi Chiang, Gin Wen Chang, Tai-yun Yang, Wen-pin Tsai, Siamon Gordon, Chang-fu Kuo, Shue-fen Luo, Hsi Hsien LinAbstract:Abstract Background GPR56/ADGRG1 is a member of the adhesion-class G protein-coupled receptor (aGPCR) family important in brain development, oncogenesis and tumor metastasis. Like other aGPCRs, GPR56 is cleaved at the GPCR proteolysis site (GPS) motif into an N-terminal fragment (NTF) and a C-terminal fragment (CTF). Existence of soluble GPR56 (sGPR56) has been shown in vitro , however the underlying mechanism and its pathophysiologic role remains undetermined. Objective To assess the presence of sGPR56 in human serum using ELISA assay and compare the serum sGPR56 levels among patients of various chronic inflammatory diseases and healthy subjects. Patients and methods In this study, serum samples from patients with systemic lupus erythematosus (SLE) (n = 57), rheumatoid arthritis (RA) (n = 95), Sjogren's syndrome (SS) (n = 29), ankylosing spondylitis (AS) (n = 51), and normal controls (n = 81) were analyzed using sGPR56-specific ELISA. Result We show that serum sGPR56 levels are increased in patients of RA, but not in those with SLE, SS and AS. Intriguingly, serum sGPR56 levels in RA patients correlated with positive rheumatoid factor, a marker of bone erosion and poor outcome. In addition, an elevated sGPR56 level is also noted in RA patients with higher tumor necrosis factor level. Conclusion we conclude that sGPR56 is present in vivo and sGPR56 level is elevated in certain chronic inflammatory diseases such as RA. Hence, sGPR56 might be considered a potential biomarker for RA disease progression.
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GPR56 adgrg1 activation promotes melanoma cell migration via ntf dissociation and ctf mediated gα12 13 rhoa signaling
Journal of Investigative Dermatology, 2017Co-Authors: Nien Yi Chiang, Hsiao Lin Pan, Gin Wen Chang, Yen-ming Peng, Horng-heng Juang, Tse-ching Chen, Hsi Hsien LinAbstract:GPR56/ADGRG1 is a versatile adhesion G protein-coupled receptor with diverse biological functions. GPR56 expression is variably detected in human melanoma cell lines and correlates inversely with the metastatic potential of melanoma lesions. GPR56 associates with the tetraspanins CD9 and CD81 on the melanoma cell surface. GPR56 activation by immobilized CG4 monoclonal antibody facilitates N-terminal fragment dissociation in a CD9/CD81-dependent manner specifically inducing IL-6 production, which promotes cell migration and invasion. Interestingly, expression of GPR56-C-terminal fragment alone recapitulates the antibody-induced receptor function, implicating a major role for the C-terminal fragment in GPR56 activation and signaling. Analysis of site-directed mutant receptors attests the importance of the conserved N-terminal residues of the C-terminal fragment for its self-activation. Finally, we show that the GPR56-induced signaling in melanoma cells is mediated by the Gα12/13/RhoA pathway. In summary, the expression and activation of GPR56 may modulate melanoma progression in part by inducing IL-6 production after N-terminal fragment dissociation and C-terminal fragment self-activation.
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GPR56/ADGRG1 Activation Promotes Melanoma Cell Migration via NTF Dissociation and CTF-Mediated Gα12/13/RhoA Signaling
Journal of Investigative Dermatology, 2017Co-Authors: Nien Yi Chiang, Hsiao Lin Pan, Gin Wen Chang, Yen-ming Peng, Horng-heng Juang, Tse-ching Chen, Hsi Hsien LinAbstract:GPR56/ADGRG1 is a versatile adhesion G protein-coupled receptor with diverse biological functions. GPR56 expression is variably detected in human melanoma cell lines and correlates inversely with the metastatic potential of melanoma lesions. GPR56 associates with the tetraspanins CD9 and CD81 on the melanoma cell surface. GPR56 activation by immobilized CG4 monoclonal antibody facilitates N-terminal fragment dissociation in a CD9/CD81-dependent manner specifically inducing IL-6 production, which promotes cell migration and invasion. Interestingly, expression of GPR56-C-terminal fragment alone recapitulates the antibody-induced receptor function, implicating a major role for the C-terminal fragment in GPR56 activation and signaling. Analysis of site-directed mutant receptors attests the importance of the conserved N-terminal residues of the C-terminal fragment for its self-activation. Finally, we show that the GPR56-induced signaling in melanoma cells is mediated by the Gα12/13/RhoA pathway. In summary, the expression and activation of GPR56 may modulate melanoma progression in part by inducing IL-6 production after N-terminal fragment dissociation and C-terminal fragment self-activation.
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the adhesion g protein coupled receptor GPR56 adgrg1 is an inhibitory receptor on human nk cells
Cell Reports, 2016Co-Authors: Gin Wen Chang, Yen-ming Peng, Cheng Chih Hsiao, Natasja A. M. Kragten, Ester B. M. Remmerswaal, Martijn D. B. Van De Garde, Rachel Straussberg, Gabriele M. König, Felipe Vieira A Braga, Evi KostenisAbstract:Natural killer (NK) cells possess potent cytotoxic mechanisms that need to be tightly controlled. Here, we explored the regulation and function of GPR56/ADGRG1, an adhesion G protein-coupled receptor implicated in developmental processes and expressed distinctively in mature NK cells. Expression of GPR56 was triggered by Hobit (a homolog of Blimp-1 in T cells) and declined upon cell activation. Through studying NK cells from polymicrogyria patients with disease-causing mutations in ADGRG1, encoding GPR56, and NK-92 cells ectopically expressing the receptor, we found that GPR56 negatively regulates immediate effector functions, including production of inflammatory cytokines and cytolytic proteins, degranulation, and target cell killing. GPR56 pursues this activity by associating with the tetraspanin CD81. We conclude that GPR56 inhibits natural cytotoxicity of human NK cells.
