ADAMs as mediators of EGF receptor transactivation by G protein-coupled receptors

A disintegrin and metalloprotease (ADAM) is a membrane-anchored metalloprotease implicated in the ectodomain shedding of cell surface proteins, including the ligands for epidermal growth factor (EGF) receptors (EGFR)/ErbB. It has been well documented that the transactivation of the EGFR plays critical roles for many cellular functions, such as proliferation and migration mediated through multiple G protein-coupled receptors (GPCRs). Recent accumulating evidence has suggested that ADAMs are the key metalloproteases activated by several GPCR agonists to produce a mature EGFR ligand leading to the EGFR transactivation. In this review, we describe the current knowledge on ADAMs implicated in mediating EGFR transactivation. The major focus of the review will be on the possible upstream mechanisms of ADAM activation by GPCRs as well as downstream signal transduction and the pathophysiological significances of ADAM-dependent EGFR transactivation.

Download Full-text

The metalloprotease Kuzbanian (ADAM10) mediates the transactivation of EGF receptor by G protein–coupled receptors

The Journal of Cell Biology ◽

10.1083/jcb.200112026 ◽

2002 ◽

Vol 158 (2) ◽

pp. 221-226 ◽

Cited By ~ 218

Author(s):

Yibing Yan ◽

Kyoko Shirakabe ◽

Zena Werb

Keyword(s):

Signaling Pathways ◽

G Protein ◽

Egf Receptor ◽

Critical Role ◽

G Protein Coupled Receptors ◽

Heparin Binding ◽

Egf Receptors ◽

Gpcr Activation ◽

G Protein Coupled ◽

Stimulation Of

Communication between different signaling pathways enables cells to coordinate the responses to diverse environmental signals. Activation of the transmembrane growth factor precursors plays a critical role in this communication and often involves metalloprotease-mediated proteolysis. Stimulation of G protein–coupled receptors (GPCR) transactivates the EGF receptors (EGFRs), which occurs via a metalloprotease-dependent cleavage of heparin-binding EGF (HB-EGF). However, the metalloprotease mediating the transactivation remains elusive. We show that the integral membrane metalloprotease Kuzbanian (KUZ; ADAM10), which controls Notch signaling in Drosophila, stimulates GPCR transactivation of EGFR. Upon stimulation of the bombesin receptors, KUZ increases the docking and activation of adaptors Src homology 2 domain–containing protein and Gab1 on the EGFR, and activation of Ras and Erk. In contrast, transfection of a protease domain–deleted KUZ, or blocking endogenous KUZ by morpholino antisense oligonucleotides, suppresses the transactivation. The effect of KUZ on shedding of HB-EGF and consequent transactivation of the EGFR depends on its metalloprotease activity. GPCR activation enhances the association of KUZ and its substrate HB-EGF with tetraspanin CD9. Thus, KUZ regulates the relay between the GPCR and EGFR signaling pathways.

Download Full-text

The relevance of adhesion G protein-coupled receptors in metabolic functions

Biological Chemistry ◽

10.1515/hsz-2021-0146 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Isabell Kaczmarek ◽

Tomáš Suchý ◽

Simone Prömel ◽

Torsten Schöneberg ◽

Ines Liebscher ◽

...

Keyword(s):

G Protein ◽

Drug Targets ◽

Metabolic Diseases ◽

Current Knowledge ◽

G Protein Coupled Receptors ◽

Specific Expression ◽

Physiological Functions ◽

Metabolic Functions ◽

Central Nervous Systems ◽

G Protein Coupled

Abstract G protein-coupled receptors (GPCRs) modulate a variety of physiological functions and have been proven to be outstanding drug targets. However, approximately one-third of all non-olfactory GPCRs are still orphans in respect to their signal transduction and physiological functions. Receptors of the class of Adhesion GPCRs (aGPCRs) are among these orphan receptors. They are characterized by unique features in their structure and tissue-specific expression, which yields them interesting candidates for deorphanization and testing as potential therapeutic targets. Capable of G-protein coupling and non-G protein-mediated function, aGPCRs may extend our repertoire of influencing physiological function. Besides their described significance in the immune and central nervous systems, growing evidence indicates a high importance of these receptors in metabolic tissue. RNAseq analyses revealed high expression of several aGPCRs in pancreatic islets, adipose tissue, liver, and intestine but also in neurons governing food intake. In this review, we focus on aGPCRs and their function in regulating metabolic pathways. Based on current knowledge, this receptor class represents high potential for future pharmacological approaches addressing obesity and other metabolic diseases.

Download Full-text

Understudied G Protein-Coupled Receptors in the Kidney

Nephron ◽

10.1159/000517355 ◽

2021 ◽

pp. 1-4

Author(s):

Nathan A. Zaidman ◽

Jennifer L. Pluznick

Keyword(s):

Renal Function ◽

Cell Surface ◽

Gene Family ◽

G Protein ◽

External Environment ◽

G Protein Coupled Receptors ◽

Surface Proteins ◽

Cell Surface Proteins ◽

Large Subset ◽

G Protein Coupled

G protein-coupled receptors (GPCRs) are cell surface proteins which play a key role in allowing cells, tissues, and organs to respond to changes in the external environment in order to maintain homeostasis. Despite the fact that GPCRs are known to play key roles in a variety of tissues, there are a large subset of GPCRs that remain poorly studied. In this minireview, we will summarize what is known regarding the “understudied” GPCRs with respect to renal function, and in so doing will highlight the promise represented by studying this gene family.

Download Full-text

Atypical Chemokine Receptors in Cardiovascular Disease

Thrombosis and Haemostasis ◽

10.1055/s-0038-1676988 ◽

2019 ◽

Vol 119 (04) ◽

pp. 534-541 ◽

Cited By ~ 4

Author(s):

Selin Gencer ◽

Emiel van der Vorst ◽

Maria Aslani ◽

Christian Weber ◽

Yvonne Döring ◽

...

Keyword(s):

G Protein ◽

Chemokine Receptors ◽

Cellular Response ◽

Current Knowledge ◽

G Protein Coupled Receptors ◽

Signalling Pathways ◽

Atherosclerosis Development ◽

G Protein Coupled ◽

Precise Role

AbstractInflammation has been well recognized as one of the main drivers of atherosclerosis development and therefore cardiovascular diseases (CVDs). It has been shown that several chemokines, small 8 to 12 kDa cytokines with chemotactic properties, play a crucial role in the pathophysiology of atherosclerosis. Chemokines classically mediate their effects by binding to G-protein-coupled receptors called chemokine receptors. In addition, chemokines can also bind to atypical chemokine receptors (ACKRs). ACKRs fail to induce G-protein-dependent signalling pathways and thus subsequent cellular response, but instead are able to internalize, scavenge or transport chemokines. In this review, we will give an overview of the current knowledge about the involvement of ACKR1–4 in CVDs and especially in atherosclerosis development. In the recent years, several studies have highlighted the importance of ACKRs in CVDs, although there are still several controversies and unexplored aspects that have to be further elucidated. A better understanding of the precise role of these atypical receptors may pave the way towards novel and improved therapeutic strategies.

Download Full-text

Identification of the C3a Receptor (C3AR1) as the Target of the VGF-derived Peptide TLQP-21 in Rodent Cells

Journal of Biological Chemistry ◽

10.1074/jbc.m113.497214 ◽

2013 ◽

Vol 288 (38) ◽

pp. 27434-27443 ◽

Cited By ~ 59

Author(s):

Sebastien Hannedouche ◽

Valerie Beck ◽

Juliet Leighton-Davies ◽

Martin Beibel ◽

Guglielmo Roma ◽

...

Keyword(s):

G Protein ◽

Cellular Response ◽

G Protein Coupled Receptors ◽

Proteolytic Processing ◽

Rodent Models ◽

Cellular Functions ◽

Genome Wide ◽

Response To Stress ◽

G Protein Coupled ◽

Human Receptor

TLQP-21, a peptide derived from VGF (non-acronymic) by proteolytic processing, has been shown to modulate energy metabolism, differentiation, and cellular response to stress. Although extensively investigated, the receptor for this endogenous peptide has not previously been described. This study describes the use of a series of studies that show G protein-coupled receptor-mediated biological activity of TLQP-21 signaling in CHO-K1 cells. Unbiased genome-wide sequencing of the transcriptome from responsive CHO-K1 cells identified a prioritized list of possible G protein-coupled receptors bringing about this activity. Further experiments using a series of defined receptor antagonists and siRNAs led to the identification of complement C3a receptor-1 (C3AR1) as a target for TLQP-21 in rodents. We have not been able to demonstrate so far that this finding is translatable to the human receptor. Our results are in line with a large number of physiological observations in rodent models of food intake and metabolic control, where TLQP-21 shows activity. In addition, the sensitivity of TLQP-21 signaling to pertussis toxin is consistent with the known signaling pathway of C3AR1. The binding of TLQP-21 to C3AR1 not only has effects on signaling but also modulates cellular functions, as TLQP-21 was shown to have a role in directing migration of mouse RAW264.7 cells.

Download Full-text

Beyond the Flavour: The Potential Druggability of Chemosensory G Protein-Coupled Receptors

International Journal of Molecular Sciences ◽

10.3390/ijms20061402 ◽

2019 ◽

Vol 20 (6) ◽

pp. 1402 ◽

Cited By ~ 15

Author(s):

Antonella Di Pizio ◽

Maik Behrens ◽

Dietmar Krautwurst

Keyword(s):

G Protein ◽

Drug Targets ◽

Current Knowledge ◽

Chemical Space ◽

G Protein Coupled Receptors ◽

The Body ◽

Odorant Receptors ◽

Taste Receptors ◽

Umami Taste ◽

G Protein Coupled

G protein-coupled receptors (GPCRs) belong to the largest class of drug targets. Approximately half of the members of the human GPCR superfamily are chemosensory receptors, including odorant receptors (ORs), trace amine-associated receptors (TAARs), bitter taste receptors (TAS2Rs), sweet and umami taste receptors (TAS1Rs). Interestingly, these chemosensory GPCRs (csGPCRs) are expressed in several tissues of the body where they are supposed to play a role in biological functions other than chemosensation. Despite their abundance and physiological/pathological relevance, the druggability of csGPCRs has been suggested but not fully characterized. Here, we aim to explore the potential of targeting csGPCRs to treat diseases by reviewing the current knowledge of csGPCRs expressed throughout the body and by analysing the chemical space and the drug-likeness of flavour molecules.

Download Full-text

Synergy between proinflammatory ligands of G protein-coupled receptors in neutrophil activation and migration

Journal of Leukocyte Biology ◽

10.1189/jlb.1003479 ◽

2004 ◽

Vol 76 (1) ◽

pp. 185-194 ◽

Cited By ~ 79

Author(s):

Mieke Gouwy ◽

Sofie Struyf ◽

Julie Catusse ◽

Paul Proost ◽

Jo Van Damme

Keyword(s):

G Protein ◽

Neutrophil Activation ◽

G Protein Coupled Receptors ◽

And Migration ◽

G Protein Coupled

Download Full-text

Organized cannabinoid receptor distribution in neurons revealed by super-resolution fluorescence imaging

Nature Communications ◽

10.1038/s41467-020-19510-5 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Hui Li ◽

Jie Yang ◽

Cuiping Tian ◽

Min Diao ◽

Quan Wang ◽

...

Keyword(s):

G Protein ◽

Fluorescence Imaging ◽

Cannabinoid Receptor ◽

Super Resolution ◽

G Protein Coupled Receptors ◽

Cellular Functions ◽

Cannabinoid Receptor 1 ◽

Intracellular Organization ◽

Dynamic Movement ◽

G Protein Coupled

Abstract G-protein-coupled receptors (GPCRs) play important roles in cellular functions. However, their intracellular organization is largely unknown. Through investigation of the cannabinoid receptor 1 (CB1), we discovered periodically repeating clusters of CB1 hotspots within the axons of neurons. We observed these CB1 hotspots interact with the membrane-associated periodic skeleton (MPS) forming a complex crucial in the regulation of CB1 signaling. Furthermore, we found that CB1 hotspot periodicity increased upon CB1 agonist application, and these activated CB1 displayed less dynamic movement compared to non-activated CB1. Our results suggest that CB1 forms periodic hotspots organized by the MPS as a mechanism to increase signaling efficacy upon activation.

Download Full-text