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Sticky Signaling—Adhesion Class G Protein–Coupled Receptors Take the Stage

Emerging insight on the structural and functional versatility of Adhesion-GPCRs draws a fascinating picture of the multiple signals these molecules transmit. Gloss Adhesion-type heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptors (Adhesion-GPCRs) comprise a class of noncanonical seven-transmembrane spanning (7TM) receptors present on almost any cell type. Despite their abundance, remarkable size, and intriguing two-unit structure facilitating cell-cell and cell-matrix contacts in various organ systems, Adhesion-GPCRs are by far the most poorly understood 7TM receptors. Data indicate that a juxtamembrane GPCR autoproteolysis-inducing domain containing the GPCR proteolysis site (GPS) figures prominently in the biological function of Adhesion-GPCRs. This review, which has five figures, five tables, and 216 references, discusses the currently available data regarding the major structural elements of Adhesion-GPCRs in the context of receptor function and signaling. Adhesion-type heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptors (Adhesion-GPCRs) comprise a class of widely distributed seven-transmembrane spanning (7TM) receptors with unusual layout and properties. The key to understanding the function of Adhesion-GPCRs appears to be their hybrid architecture: They have an extracellular domain containing an extended array of protein folds fit for interactions, and structural elements of GPCRs with a 7TM and an intracellular domain. If and how these distinct protein portions interact is currently under intense investigation. Intriguingly, all Adhesion-GPCRs have a juxtamembrane GPCR autoproteolysis-inducing domain that, in many homologs, facilitates the autocatalytic processing into an N-terminal fragment (NTF) and a C-terminal fragment (CTF), which subsequently remain attached at the cell surface. The NTF provides the ability for combinatorial engagement with cellular or matrix-associated molecules facilitating cell adhesion, orientation, and positioning during development, immune responses, and tumor growth. The CTF, like in canonical GPCRs, initiates interactions with different types of signaling molecules, including heterotrimeric G proteins, small guanosine triphosphatases, and transmembrane protein partners, yet the agonistic potential of most known Adhesion-GPCR ligands is uncertain. Studies with truncated receptors suggest that the NTF and CTF of Adhesion-GPCRs may function as autonomous adhesive and signaling units, respectively, but other studies in nonvertebrates demonstrating NTF-CTF interplay challenge this view. We discuss the available data concerning the main structural elements of Adhesion-GPCRs in the context of receptor function and signaling.