New functions and signaling mechanisms for the class of adhesion G protein–coupled receptors

Liebscher, Ines; Ackley, Brian D.; Araç, Demet; Ariestanti, Donna Maretta; Aust, Gabriela; Bae, Byoung-Il; Bista, Bigyan R.; Bridges, James P.; Duman, Joseph G.; Engel, Felix B.; Giera, Stefanie; Goffinet, André M.; Hall, Randy A.; Hamann, Jörg; Hartmann, Nicole; Lin, Horng‐Chyuan; Liu, Mingyao; Luo, Rong; Mogha, Amit; Monk, Kelly R.; Peeters, Miriam C.; Prömel, Simone; Ressl, Susanne; Schiöth, Helgi B.; Sigoillot, Séverine M.; Song, Helen; Talbot, William S.; Tall, Gregory G.; White, James P.; Wolfrum, Uwe; Xu, Lei; Piao, Xiangshu

doi:10.1111/nyas.12580

Cited by 27 publications

(29 citation statements)

References 98 publications

(250 reference statements)

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“…2, cell-matrix interactions, which regulate integrin "outside-in" and "inside-out" signaling, are singled out as one potential proteinase signaling target (mechanism 7). However, signaling via cell adhesion interactions is also now known to be regulated by a large superfamily of adhesion G protein-coupled receptors (aGPCRs) or ADGRs [recommended IUPHAR nomenclature (Hamann et al, 2015)], which are described in detail elsewhere (Yona et al, 2008;Arac et al, 2012b;Paavola and Hall, 2012;Langenhan et al, 2013;Liebscher et al, 2014a;Hamann et al, 2015). Surprisingly, ADGRs and the PARs share the tethered ligand paradigm of activation but via a very different ADGR autoproteolytic process.…”

Section: Proteinase-mediated Signaling and Inflammationmentioning

confidence: 99%

“…The key to the activation of ADGRs lies in a common GPCR-Autoproteolysis-INducing domain (acronym: GAIN domain; Fig. 7), that triggers receptor cleavage during the process of endosomal maturation and transport to the cell surface (Arac et al, 2012a,b;Promel et al, 2013;Liebscher et al, 2014a;Hamann et al, 2015). Thus these receptors possess intrinsic proteolytic activity that is integral to their signaling mechanism.…”

Section: Proteinase-mediated Signaling and Inflammationmentioning

confidence: 99%

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Proteinases, Their Extracellular Targets, and Inflammatory Signaling

Ramachandran¹,

Altier²,

Οικονομοπούλου³

et al. 2016

Pharmacol Rev

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Given that over 2% of the human genome codes for proteolytic enzymes and their inhibitors, it is not surprising that proteinases serve many physiologic-pathophysiological roles. In this context, we provide an overview of proteolytic mechanisms regulating inflammation, with a focus on cell signaling stimulated by the generation of inflammatory peptides; activation of the proteinase-activated receptor (PAR) family of G protein-coupled receptors (GPCR), with a mechanism in common with adhesion-triggered GPCRs (ADGRs); and by proteolytic ion channel regulation. These mechanisms are considered in the much wider context that proteolytic mechanisms serve, including the processing of growth factors and their receptors, the regulation of matrix-integrin signaling, and the generation and release of membrane-tethered receptor ligands. These signaling mechanisms are relevant for inflammatory, neurodegenerative, and cardiovascular diseases as well as for cancer. We propose that the inflammation-triggering proteinases and their proteolytically generated substrates represent attractive therapeutic targets and we discuss appropriate targeting strategies.

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Section: Proteinase-mediated Signaling and Inflammationmentioning

confidence: 99%

Section: Proteinase-mediated Signaling and Inflammationmentioning

confidence: 99%

Proteinases, Their Extracellular Targets, and Inflammatory Signaling

Ramachandran¹,

Altier²,

Οικονομοπούλου³

et al. 2016

Pharmacol Rev

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“…The activation mechanisms of aGPCRs have garnered much attention in recent years (31)(32)(33). Studies by several groups have delineated a model of activation termed the cryptic agonist model wherein dissociation of the NTF from the membrane-embedded CTF unveils the agonistic properties of the remaining extracellular stalk (also termed the "stachel") (9 -11, 34).…”

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confidence: 99%

Disease-associated extracellular loop mutations in the adhesion G protein-coupled receptor G1 (ADGRG1; GPR56) differentially regulate downstream signaling

Kishore

Hall

2017

Journal of Biological Chemistry

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Mutations to the adhesion G protein-coupled receptor ADGRG1 (G1; also known as GPR56) underlie the neurological disorder bilateral frontoparietal polymicrogyria. Disease-associated mutations in G1 studied to date are believed to induce complete loss of receptor function through disruption of either receptor trafficking or signaling activity. Given that N-terminal truncation of G1 and other adhesion G protein-coupled receptors has been shown to significantly increase the receptors' constitutive signaling, we examined two different bilateral frontoparietal polymicrogyria-inducing extracellular loop mutations (R565W and L640R) in the context of both full-length and N-terminally truncated (ΔNT) G1. Interestingly, we found that these mutations reduced surface expression of full-length G1 but not G1-ΔNT in HEK-293 cells. Moreover, the mutations ablated receptor-mediated activation of serum response factor luciferase, a classic measure of Gα-mediated signaling, but had no effect on G1-mediated signaling to nuclear factor of activated T cells (NFAT) luciferase. Given these differential signaling results, we sought to further elucidate the pathway by which G1 can activate NFAT luciferase. We found no evidence that ΔNT activation of NFAT is dependent on Gα-mediated or β-arrestin-mediated signaling but rather involves liberation of Gβγ subunits and activation of calcium channels. These findings reveal that disease-associated mutations to the extracellular loops of G1 differentially alter receptor trafficking, depending on the presence of the N terminus, and differentially alter signaling to distinct downstream pathways.

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“…With regard to CNS myelination and remyelination, we are only at the beginning of a better understanding of the role of GPRCs and their ligands. In particular, the lysophospholipid receptors, adhesion GPCRs and purinergic receptors are increasingly recognized to regulate OLG differentiation and myelination (Fumagalli et al, 2015b; Groves et al, 2013; Liebscher et al, 2014; Yung et al, 2015). Here we will focus on GPR17 and its extracellular ligands as they have been implicated to contribute to the pathology seen upon CNS injury (see below).…”

Section: Introductionmentioning

confidence: 99%

Extracellular cues influencing oligodendrocyte differentiation and (re)myelination

Wheeler

Fuss

2016

Experimental Neurology

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There is an increasing number of neurologic disorders found to be associated with loss and/or dysfunction of the CNS myelin sheath, ranging from the classic demyelinating disease, Multiple Sclerosis, through CNS injury, to neuropsychiatric diseases. The disabling burden of these diseases has sparked a growing interest in gaining a better understanding of the molecular mechanisms regulating the differentiation of the myelinating cells of the CNS, oligodendrocytes (OLGs), and the process of (re)myelination. In this context, the importance of the extracellular milieu is becoming increasingly recognized. Under pathological conditions, changes in inhibitory as well as permissive/promotional cues are thought to lead to an overall extracellular environment that is obstructive for the regeneration of the myelin sheath. Given the general view that remyelination is, even though limited in human, a natural response to demyelination, targeting pathologically ‘dysregulated’ extracellular cues and their downstream pathways is regarded as a promising approach toward the enhancement of remyelination by endogenous (or if necessary transplanted) OLG progenitor cells. In this review, we will introduce the extracellular cues that have been implicated in the modulation of (re)myelination. These cues can be soluble, part of the extracellular matrix (ECM) or mediators of cell-cell interactions. Their inhibitory and permissive/promotional roles with regard to remyelination as well as their potential for therapeutic intervention will be discussed.

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New functions and signaling mechanisms for the class of adhesion G protein–coupled receptors

Cited by 27 publications

References 98 publications

Proteinases, Their Extracellular Targets, and Inflammatory Signaling

Proteinases, Their Extracellular Targets, and Inflammatory Signaling

Disease-associated extracellular loop mutations in the adhesion G protein-coupled receptor G1 (ADGRG1; GPR56) differentially regulate downstream signaling

Extracellular cues influencing oligodendrocyte differentiation and (re)myelination

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