Adhesion-GPCRs: emerging roles for novel receptors

doi:10.1016/j.tibs.2008.07.005

Trends in Biochemical Sciences

Volume 33, Issue 10, October 2008, Pages 491-500

https://doi.org/10.1016/j.tibs.2008.07.005 Get rights and content

The G protein-coupled receptor (GPCR) family comprises the largest class of cell surface receptors found in metazoan proteomes. Within the novel GPCR subfamily of adhesion-GPCRs, ∼150 distinct orthologues, from invertebrates to mammals, have been identified to date. All members of this family contain a large extracellular region, often containing common protein modules, coupled to a seven-transmembrane domain via a stalk region that seems to be crucial for functionality. Owing to their unique structure, restricted expression profile and involvement in several human diseases, adhesion-GPCRs have long been proposed to have vital dual roles in cellular adhesion and signalling. More recent studies have provided structural, evolutionary, developmental and immunological insights in relation to the adhesion-GPCR family.

Section snippets

GPCRs: an overview

The G protein-coupled receptor (GPCR) superfamily is the principal class of cell membrane receptor found in metazoans. Since the completion of the human genome project, >800 genes encoding GPCRs, subdivided into five categories, have been identified [1]. These receptors can sense a diverse array of stimuli (e.g. peptides, ions, lipid analogues, light and odour) in a discriminating fashion, and subsequently transduce a signal from the ligand–receptor complex into numerous cellular responses. The

The adhesion-GPCR: a family portrait

Through phylogenetic analysis of GPCRs, the GRAFS [1] classification system subdivides GPCRs into five discrete families: glutamate, rhodopsin, adhesion, frizzled/taste2 and secretin receptors. The adhesion-GPCR family can be further subdivided into eight groups [1]. Adhesion-GPCRs are defined by the existence of a large extracellular region linked to a TM7 moiety via a GPCR proteolytic site (GPS)-containing stalk region. The extended N terminus often contains common structural domains,

Adhesion-GPCR structure: a role in function and disease

Receptor dimerization, such as that occurring in tyrosine kinase receptors and the GABA_B1–B2 GPCRs [16], has long been recognized to modulate receptor biology [17]. Several adhesion-GPCRs have been reported to dimerize or form oligomers. Examples include ETL (EGF-like, latrophilin and TM7-domain-containing 1), which forms detergent-sensitive dimers in response to cell lysis [18], disulfide-linked GPR116 dimers formed through intermolecular covalent association in the extracellular domain [19]

Adhesion-GPCRs: a family history

Another characteristic of adhesion-GPCRs is their complex genomic structure. All family members are encoded by genes containing multiple exons that are presumed to have arisen through exon shuffling, gene duplication, deletion and conversion [34]. These mechanisms have led to the evolution of 33 mammalian adhesion-GPCRs, which are often found in distinct gene clusters within the genome. Although the genes encode highly complex chimaeric receptors, they are not confined to mammals and higher

Adhesion-GPCRs in immunology

Inflammation is characterized by the recruitment of blood-borne phagocytes to sites of injury or infection. This response is coordinated by an assortment of receptors, including lectins, TLRs, selectins, integrins and the Ig superfamily, found on leukocyte cell membranes [50]. Interestingly, the expression pattern of EGF-TM7 receptors, the first-described adhesion-GPCRs, is predominantly leukocyte restricted. The EGF-TM7 family members CD97, EMR1 (F4/80 receptor), EMR2, EMR3 and EMR4 all have

Adhesion-GPCRs in developmental biology

Embryogenesis involves the highly coordinated assembly of distinct cellular communities, orchestrating the formation of a defined body plan. One level of cellular organization that is essential for successful development is planar cell polarity (PCP), in which cells or parts of cells orient themselves specifically within a distinct layer. Planar polarity is evident in the vertebrate inner ear and in the organization of D. melanogaster back bristles, photoreceptors and wing hairs. Numerous cell

Adhesion-GPCRs in tumourigenesis

Tumour growth and dissemination is a highly complex, multistep process that involves angiogenesis, cellular migration, invasion and metastasis. The aberrant expression of several adhesion-GPCRs on cancer cells, and their involvement in many of these processes have now been demonstrated 5, 11, 43, 44, 78. GPR124 was originally identified as a tumour endothelial marker that is upregulated during tumour angiogenesis [79]. GPR124 is shed from endothelial cells [44], and further proteolytic

Concluding remarks

Adhesion-GPCRs are unusual owing to their unique structure, comprising a large and complex extracellular domain composed of various common protein modules (Figure 1). Adhesion-GPCR family members are expressed ubiquitously; however, the expression of each receptor is frequently highly regulated and restricted to specific cell types. For example, CELSR1–3 68, 69 and latrophilin1/3 25, 84, 85, 86 are highly expressed in the CNS and coordinate neuronal development and neurotransmitter release,

Acknowledgements

S.Y. is supported by the Edward P. Abraham Fund; H.H.L. is supported by the National Science Council (NSC 96–2320-B-182–005) and Chang Gung Memorial Hospital (CMRP330083), Taiwan; M.S. is supported by the Medical Research Council (UK).

Glossary

Apoptosis: or programmed cell death, is a form of cell death whereby the cell activates an internal cell-death program. Apoptosis contrasts with necrosis, death caused by external factors (e.g. phagocytosis of apoptotic cells results in non-inflammatory uptake by phagocytes, whereas phagocytosis of necrotic cells results in inflammation).
Immune tolerance: is the failure to respond to an antigen; the immune system is tolerant to self-antigens. The tolerance to self-antigens is a critical feature of

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Trends in Biochemical Sciences

ReviewAdhesion-GPCRs: emerging roles for novel receptors

Section snippets

GPCRs: an overview

The adhesion-GPCR: a family portrait

Adhesion-GPCR structure: a role in function and disease

Adhesion-GPCRs: a family history

Adhesion-GPCRs in immunology

Adhesion-GPCRs in developmental biology

Adhesion-GPCRs in tumourigenesis

Concluding remarks

Acknowledgements

Glossary

Blood

J. Biol. Chem.

J. Biol. Chem.

Am. J. Pathol.

Biochem. Biophys. Res. Commun.

Trends Biochem. Sci.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Neuron

J. Biol. Chem.

FEBS Lett.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Dev. Biol.

Cell

J. Biol. Chem.

Blood

J. Biol. Chem.

Genomics

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Neuroimmunol.

Genomics

Mol. Cell. Neurosci.

Mech. Dev.

Mech. Dev.

Dev. Cell

Curr. Biol.

Am. J. Hum. Genet.

Am. J. Pathol.

Exp. Cell Res.

J. Biol. Chem.

FEBS Lett.

J. Biol. Chem.

Brain Res. Mol. Brain Res.

FEBS Lett.

FEBS Lett.

FEBS Lett.

Mol. Cell. Neurosci.

Structural diversity of G protein-coupled receptors and significance for drug discovery

Nat. Rev. Drug Discov.

Heterotrimeric G protein activation by G-protein-coupled receptors

Nat. Rev. Mol. Cell Biol.

The seven-span transmembrane receptor CD97 has a cellular ligand (CD55, DAF)

J. Exp. Med.

GPR56 and TG2: possible roles in suppression of tumor growth by the microenvironment

Cell Cycle

BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module

Nature

Dynamic regulation of a GPCR-tetraspanin-G protein complex on intact cells: central role of CD81 in facilitating GPR56-Galpha q/11 association

Mol. Biol. Cell

Ligation of the adhesion-GPCR EMR2 regulates human neutrophil function

FASEB J.

The evolutionary history and tissue mapping of GPR123: specific CNS expression pattern predominantly in thalamic nuclei and regions containing large pyramidal cells

J. Neurochem.

Review
Adhesion-GPCRs: emerging roles for novel receptors