The role of GPR56/ADGRG1 in health and disease

Abstract

GPR56/ADGRG1 is a versatile adhesion G protein-coupled receptor important in the physiological functions of the central and peripheral nervous systems, reproductive system, muscle hypertrophy, immune regulation, and hematopoietic stem cell generation. By contrast, aberrant expression or deregulated functions of GPR56 have been implicated in diverse pathological processes, including bilateral frontoparietal polymicrogyria, depression, and tumorigenesis. In this review article, we summarize and discuss the current understandings of the role of GPR56 in health and disease.

Keywords: Adhesion GPCR; G protein; Ligand; Signaling.

Fig. 1

Organization of the GPR56 gene and receptor protein variants. (A) Schematic diagrams of the GPR56 gene (upper panel) and the encoding receptor protein (lower panel). The GPR56 gene consists of 14 exons, of which the exons 2–14 code for the receptor protein. The figure depicts the full-length GPR56 gene with a length of 2082 base pairs (Intron: line; Exon: solid bar; coding region: blue; non-coding region: red). The corresponding wild-type (WT) protein isoform is composed of 693 amino acids (Signal Peptide: red; PLL domain-β sheet A: yellow; PLL domain-β sheet B: green; GAIN-subdomain A: purple; GAIN-subdomain B: dark green; GPS region and Stachel peptide: pink; TM regions: orange; Intracellular and extracellular loops: cyan) [16,22]. (B) Schematic diagrams depicting the four GPR56 alternatively spliced isoforms, S1–S4. The corresponding protein structures are depicted below the gene structure [16,22,24]. (C) The schematic cartoon of the structural organization of GPR56 receptor protein. ICR: Intracellular Region.

Fig. 2

GPR56 signaling in physiological processes. (A) In a neuron cell, collagen III acts as a ligand of GPR56 [28]. During the inactive state, GPR56 is found in detergent-soluble non-lipid raft regions of the plasma membrane [102]. However, in the presence of collagen III, the NTF of GPR56 binds to the collagen III which subsequently leads to removal of NTF from the CTF [103]. The shedding of NTF exposes the tethered Stachel agonistic peptide within the CTF [33]. The removal of NTF is also followed by the translocation of CTF to lipid rafts [103]. The tethered Stachel sequence then binds to and induces the conformational changes in CTF to activate the Gα_12/13 protein [28]. Upon the GDP-GTP exchange, this heterotrimeric G-protein complex dissociates into Gα_12/13 and Gβγ subunits. The Gα_12/13 subunit then activates RhoA, which activates various downstream signaling molecules to finally result in the inhibition of migration of the neuron [28]. Some observations suggest a possible interaction of GPR56 with integrin α3β1 [43]. Laminin-511 is known to bind to the integrin α3β1. However, the details of this interaction of GPR56 with integrin remains elusive. (B) In the skeletal muscle cells, resistance exercises and apigenin, a natural flavone found in many edible plants, induces muscle hypertrophy [48,49]. Apigenin enters the cell and activates Prmt7, which then directly activates PGC-1α [49]. The PGC-1α is a transcriptional coactivator which enhances GPR56 and collagen III expression, thereby finally inducing muscle hypertrophy via the IGF-1-mTORC1 pathway [48,49]. (C) In an oligodendrocyte progenitor cell (OPC), the tripartite signaling complex formed of TG2 released by microglia, laminin-111 from ECM, and GPR56 on its cell surface induce the myelin formation and repair in CNS by promoting OPC proliferation and inhibiting its premature differentiation to oligodendrocytes via the Gα_12/13-RhoA signaling pathway [47,96]. (D) In a Schwann cell, GPR56 in association with other transmembrane and cytoskeletal linker proteins, like dystroglycan and plectin, induces proper PNS myelination by cytoskeletal remodeling via the RhoA pathway and physical interaction with plectin [29]. (E) Hobit is the primary driver of GPR56 expression in human cytotoxic NK cells [54]. GPR56 in association with CD81 inhibits the effector functions of cytotoxic NK cells during inactive state [19,54]. However, NK cell activation leads to the cleavage of a portion of GPR56 ECR and induces PKC-mediated internalization of the GPR56 receptor, thereby removing its inhibitory effector functions [54]. The solid lines represent direct interaction, whereas the dotted lines indicate indirect pathways with potential additional intermediate(s).

Fig. 3

GPR56 signaling in pathological processes. (A) In a colorectal cancer (CRC) cell, progastrin (PG) binds to GPR56 and promotes the epithelial-to-mesenchymal transition and metastasis by the PI3K/Akt pathway. Moreover, GPR56 also promotes drug resistance by promoting MDR1 expression via the RhoA pathway [[83], [84], [85]]. (B) GPR56 inhibits the metastasis and tumor survival in a melanoma cell by internalization and degradation of TG2-bound GPR56 thereby controlling the concentration of TG2 in ECM which is a major promoter of tumor survival [46,104]. An alternative mechanism observed in melanoma cells is the interaction of GPR56 with tetraspanins such as CD81, which recruit Gα_q/11(Gβγ) heterotrimer and finally inhibits VEGF secretion, and hence the angiogenesis, via the PKCα pathway [72,104]. (C) In the HT1080 cell line, heparin has been demonstrated to bind to the NTF of GPR56 [32,104]. One of the major heparin-binding sites of GPR56 overlaps with the collagen III-binding site, hence making heparin capable of modulating the binding and signaling by collagen III [32]. It is observed that the binding of heparin reduces NTF shedding and promotes cell motility and adhesion [32]. (D) In U87-MG cells, GPR56 inhibits cell migration via the Gα_q and Rho pathway [81]. Moreover, GPR56 also inhibits mesenchymal transition and radioresistance by inhibiting the NF-κB signaling pathway upstream of NEMO [82]. TNF activates the TNF receptor which promotes mesenchymal transition and radioresistance by activating NF-κB signaling pathway and downregulating GPR56 indirectly [82]. The solid lines represent direct interaction, whereas the dotted lines indicate indirect pathways with potential additional intermediate(s).