Heparin interacts with adhesion-GPCR GPR56/ADGRG1, reduces receptor shedding, and promotes cell adhesion and motility

Chiang, Nien‐Yi; Chang, Gin-Wen; Huang, Yi-Shu; Peng, Yen-Ming; Hsiao, Cheng-Chih; Kuo, Ming‐Ling; Lin, Hsi‐Hsien

doi:10.1242/jcs.174458

Cited by 36 publications

(34 citation statements)

References 70 publications

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“…Preliminary studies have proposed that GPCR ECRs regulate receptor functions, likely including G-protein signaling, on binding to extracellular ligands (9,(23)(24)(25)(26)(27)(28)(29). Two complementary models for ligand-induced aGPCR activation have been proposed (Fig.…”

mentioning

confidence: 99%

Stachel -independent modulation of GPR56/ADGRG1 signaling by synthetic ligands directed to its extracellular region

Salzman

Zhang

Gupta

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

101

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Adhesion G protein-coupled receptors (aGPCRs) play critical roles in diverse biological processes, including neurodevelopment and cancer progression. aGPCRs are characterized by large and diverse extracellular regions (ECRs) that are autoproteolytically cleaved from their membrane-embedded signaling domains. Although ECRs regulate receptor function, it is not clear whether ECRs play a direct regulatory role in G-protein signaling or simply serve as a protective cap for the activating "Stachel" sequence. Here, we present a mechanistic analysis of ECR-mediated regulation of GPR56/ADGRG1, an aGPCR with two domains [pentraxin and laminin/neurexin/sex hormonebinding globulin-like (PLL) and G protein-coupled receptor autoproteolysis-inducing (GAIN)] in its ECR. We generated a panel of high-affinity monobodies directed to each of these domains, from which we identified activators and inhibitors of GPR56-mediated signaling. Surprisingly, these synthetic ligands modulated signaling of a GPR56 mutant defective in autoproteolysis and hence, in Stachel peptide exposure. These results provide compelling support for a ligandinduced and ECR-mediated mechanism that regulates aGPCR signaling in a transient and reversible manner, which occurs in addition to the Stachel-mediated activation.adhesion GPCR | allostery | cell signaling | monobody | protein engineering

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mentioning

confidence: 99%

Stachel -independent modulation of GPR56/ADGRG1 signaling by synthetic ligands directed to its extracellular region

Salzman

Zhang

Gupta

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

101

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“…GPR56 ligands comprise two general subtypes: (1) proteins from the surface of neighboring cells, and (2) extracellular matrix proteins. Known extracellular ligands of GPR56 include collagen III, transglumatinase 2, and heparin 23,27,28 . Following activation of the GPR56 receptor by its ligands, the extracellular and transmembrane domains dissociate to reveal a tetheredpeptide-agonist 11 .…”

Section: Discussionmentioning

confidence: 99%

GPR56/ADGRG1 is associated with response to antidepressant treatment

et al. 2020

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It remains unclear why many patients with depression do not respond to antidepressant treatment. In three cohorts of individuals with depression and treated with serotoninnorepinephrine reuptake inhibitor (N = 424) we show that responders, but not nonresponders, display an increase of GPR56 mRNA in the blood. In a small group of subjects we also show that GPR56 is downregulated in the PFC of individuals with depression that died by suicide. In mice, we show that chronic stress-induced Gpr56 downregulation in the blood and prefrontal cortex (PFC), which is accompanied by depression-like behavior, and can be reversed by antidepressant treatment. Gpr56 knockdown in mouse PFC is associated with depressive-like behaviors, executive dysfunction and poor response to antidepressant treatment. GPR56 peptide agonists have antidepressant-like effects and upregulated AKT/ GSK3/EIF4 pathways. Our findings uncover a potential role of GPR56 in antidepressant response.

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“…CHO-K1 and HEK293T cells were cultured in Ham’s F-12 and Dulbecco’s modified Eagle’s medium (DMEM), respectively. Transient transfection of expression constructs was performed using Lipofectamine TM (Invitrogen) reagent as described previously 38 . Cells were washed 6 hr post transfection and cultured with fresh medium for 2–3 days for subsequent analysis.…”

Section: Methodsmentioning

confidence: 99%

Membrane-association of EMR2/ADGRE2-NTF is regulated by site-specific N-glycosylation

Huang

Chiang

Chang

et al. 2018

Sci Rep

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The evolutionarily conserved adhesion G protein-coupled receptors (aGPCRs) play critical roles in biological processes as diverse as brain development, cell polarity and innate immune functions. A defining feature of aGPCRs is the GPCR autoproteolysis inducing (GAIN) domain capable of self-catalytic cleavage, resulting in the generation of an extracellular N-terminal fragment (NTF) and a seven-transmembrane C-terminal fragment (CTF) involved in the cellular adhesion and signaling functions, respectively. Interestingly, two different NTF subtypes have previously been identified, namely an NTF that couples non-covalently with the CTF and a membrane-associated NTF that tethers on cell surface independently. The two NTF subtypes are expected to regulate aGPCR signaling via distinct mechanisms however their molecular characteristics are largely unknown. Herein, the membrane-associated NTF of EMR2/ADGRE2 is investigated and found to be modified by differential N-glycosylation. The membrane association of EMR2-NTF occurs in post-ER compartments and site-specific N-glycosylation in the GAIN domain is involved in modulating its membrane-association ability. Finally, a unique amphipathic α-helix in the GAIN domain is identified as a putative membrane anchor of EMR2-NTF. These results provide novel insights into the complex interaction and activation mechanisms of aGPCRs.

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Heparin interacts with adhesion-GPCR GPR56/ADGRG1, reduces receptor shedding, and promotes cell adhesion and motility

Cited by 36 publications

References 70 publications

Stachel -independent modulation of GPR56/ADGRG1 signaling by synthetic ligands directed to its extracellular region

Stachel -independent modulation of GPR56/ADGRG1 signaling by synthetic ligands directed to its extracellular region

GPR56/ADGRG1 is associated with response to antidepressant treatment

Membrane-association of EMR2/ADGRE2-NTF is regulated by site-specific N-glycosylation

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