Progress in demystification of adhesion G protein-coupled receptors

Abstract Adhesion G protein-coupled receptors (aGPCR) form the second largest class of GPCR. They are phylogenetically old and have been highly conserved during evolution. Mutations in representatives of this class are associated with severe diseases such as Usher Syndrome, a combined congenital deaf-blindness, or bifrontal parietal polymicrogyria. The main characteristics of aGPCR are their enormous size and the complexity of their N termini. They contain a highly conserved GPCR proteolytic site (GPS) and several functional domains that have been implicated in cell-cell and cell-matrix interactions. Adhesion GPCR have been proposed to serve a dual function as adhesion molecules and as classical receptors. However, until recently there was no proof that aGPCR indeed couple to G proteins or even function as classical receptors. In this review, we have summarized and discussed recent evidence that aGPCR present many functional features of classical GPCR, including multiple G protein-coupling abilities, G protein-independent signaling and oligomerization, but also specific signaling properties only found in aGPCR.

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Shedding of c-Met is regulated by crosstalk between a G-protein coupled receptor and the EGF receptor and is mediated by a TIMP-3 sensitive metalloproteinase

Journal of Cell Science ◽

10.1242/jcs.114.6.1213 ◽

2001 ◽

Vol 114 (6) ◽

pp. 1213-1220

Author(s):

D. Nath ◽

N.J. Williamson ◽

R. Jarvis ◽

G. Murphy

Keyword(s):

Growth Factor ◽

G Protein ◽

Egf Receptor ◽

Growth Factor Receptor ◽

Receptor Activation ◽

Ectodomain Shedding ◽

G Protein Coupled Receptor ◽

Cell Matrix ◽

Cell Matrix Interactions ◽

G Protein Coupled

A wide repertoire of transmembrane proteins are proteolytically released from the cell surface by a process known as ‘ectodomain shedding’, under both normal and pathophysiological conditions. Little is known about the physiological mechanisms that regulate this process. As a model system, we have investigated the metalloproteinase-mediated cleavage of the hepatocyte growth factor receptor, Met. We show that epidermal growth factor (EGF) receptor activation, either directly by EGF or indirectly via the G-protein coupled receptor (GPCR) agonist lysophosphatidic acid (LPA), induces cleavage of Met through activation of the Erk MAP kinase signalling cascade. The tyrosine kinase activity of the EGFR was a prerequisite for this stimulation, since treatment of cells with a synthetic inhibitor of this receptor, AG1478, completely abrogated shedding. The metalloproteinase mediating Met cleavage was specifically inhibited by the tissue inhibitor of metalloproteinases (TIMP)-3, but not by TIMP-1 or TIMP-2. Furthermore, the level of Met shedding could be modulated by different cell-matrix interactions. Our results indicate that ectodomain shedding is a highly regulated process that can be stimulated by EGFR signalling pathways and integrin ligation.

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The repertoire of Adhesion G protein-coupled receptors in adipocytes and their functional relevance

International Journal of Obesity ◽

10.1038/s41366-020-0570-2 ◽

2020 ◽

Vol 44 (10) ◽

pp. 2124-2136 ◽

Cited By ~ 1

Author(s):

Tomáš Suchý ◽

Christian Zieschang ◽

Yulia Popkova ◽

Isabell Kaczmarek ◽

Juliane Weiner ◽

...

Keyword(s):

G Protein ◽

Lipid Accumulation ◽

Adipocyte Differentiation ◽

G Protein Coupled Receptors ◽

Adipose Tissues ◽

Functional Relevance ◽

And Function ◽

Adhesion Gpcr ◽

The Impact ◽

G Protein Coupled

Abstract Background G protein-coupled receptors (GPCR) are well-characterized regulators of a plethora of physiological functions among them the modulation of adipogenesis and adipocyte function. The class of Adhesion GPCR (aGPCR) and their role in adipose tissue, however, is poorly studied. With respect to the demand for novel targets in obesity treatment, we present a comprehensive study on the expression and function of this enigmatic GPCR class during adipogenesis and in mature adipocytes. Methods The expression of all aGPCR representatives was determined by reanalyzing RNA-Seq data and by performing qPCR in different mouse and human adipose tissues under low- and high-fat conditions. The impact of aGPCR expression on adipocyte differentiation and lipid accumulation was studied by siRNA-mediated knockdown of all expressed members of this receptor class. The biological characteristics and function of mature adipocytes lacking selected aGPCR were analyzed by mass spectrometry and biochemical methods (lipolysis, glucose uptake, adiponectin secretion). Results More than ten aGPCR are significantly expressed in visceral and subcutaneous adipose tissues and several aGPCR are differentially regulated under high-caloric conditions in human and mouse. Receptor knockdown of six receptors resulted in an impaired adipogenesis indicating their expression is essential for proper adipogenesis. The altered lipid composition was studied in more detail for two representatives, ADGRG2/GPR64 and ADGRG6/GPR126. While GPR126 is mainly involved in adipocyte differentiation, GPR64 has an additional role in mature adipocytes by regulating metabolic processes. Conclusions Adhesion GPCR are significantly involved in qualitative and quantitative adipocyte lipid accumulation and can control lipolysis. Factors driving adipocyte formation and function are governed by signaling pathways induced by aGPCR yielding these receptors potential targets for treating obesity.

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G-protein-coupled receptors, cholesterol and palmitoylation: facts about fats

Journal of Molecular Endocrinology ◽

10.1677/jme-08-0114 ◽

2009 ◽

Vol 42 (5) ◽

pp. 371-379 ◽

Cited By ~ 87

Author(s):

Bice Chini ◽

Marco Parenti

Keyword(s):

Plasma Membrane ◽

G Protein ◽

G Protein Coupled Receptors ◽

Membrane Domains ◽

Functional Features ◽

Gpcr Structure ◽

Carboxyl Terminal ◽

The Impact ◽

G Protein Coupled ◽

Partner Proteins

G-protein-coupled receptors (GPCRs) are integral membrane proteins, hence it is not surprising that a number of their structural and functional features are modulated by both proteins and lipids. The impact of interacting proteins and lipids on the assembly and signalling of GPCRs has been extensively investigated over the last 20–30 years, and a further impetus has been given by the proposal that GPCRs and/or their immediate signalling partners (G proteins) can partition within plasma membrane domains, termed rafts and caveolae, enriched in glycosphingolipids and cholesterol. The high content of these specific lipids, in particular of cholesterol, in the vicinity of GPCR transmembranes can affect GPCR structure and/or function. In addition, most GPCRs are post-translationally modified with one or more palmitic acid(s), a 16-carbon saturated fatty acid, covalently bound to cysteine(s) localised in the carboxyl-terminal cytoplasmic tail. The insertion of palmitate into the cytoplasmic leaflet of the plasma membrane can create a fourth loop, thus profoundly affecting GPCR structure and hence the interactions with intracellular partner proteins. This review briefly highlights how lipids of the membrane and the receptor themselves can influence GPCR organisation and functioning.

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