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GPCR Signaling and Trafficking: The Long and Short of It

2016; Elsevier BV; Volume: 28; Issue: 3 Linguagem: Inglês

10.1016/j.tem.2016.10.007

1879-3061

Nathan J. Pavlos, Peter A. Friedman,

Cellular transport and secretion

Some GPCRs mediate transient as well as sustained signaling following sequestration in endosomes. GPCRs displaying persistent signaling and accelerated recycling harbor a C-terminal recognition motif that facilitates release and exchange between PDZ proteins. Emerging evidence suggests that sustained signaling exerts distinct functional actions. Post-endocytic sorting machineries, assembled on the surface of endosomes, link GPCR signaling and trafficking. GPCRs are capable of following more than one endosomal trafficking itinerary back to the cell surface. Emerging findings disclose unexpected components of G protein-coupled receptor (GPCR) signaling and cell biology. Select GPCRs exhibit classical signaling, that is restricted to cell membranes, as well as newly described persistent signaling that depends on internalization of the GPCR bound to β-arrestins. Termination of non-canonical endosomal signaling requires intraluminal acidification and sophisticated protein trafficking machineries. Recent studies reveal the structural determinants of the trafficking chaperones. This review summarizes advances in GPCR signaling and trafficking with a focus on the parathyroid hormone receptor (PTHR) as a prototype, and on the actin–sorting nexin 27 (SNX27)–retromer tubule (ASRT) complex, an endosomal sorting hub responsible for recycling and preservation of cell surface receptors. The findings are integrated into a model of PTHR trafficking with implications for signal transduction, bone growth, and mineral ion metabolism. Emerging findings disclose unexpected components of G protein-coupled receptor (GPCR) signaling and cell biology. Select GPCRs exhibit classical signaling, that is restricted to cell membranes, as well as newly described persistent signaling that depends on internalization of the GPCR bound to β-arrestins. Termination of non-canonical endosomal signaling requires intraluminal acidification and sophisticated protein trafficking machineries. Recent studies reveal the structural determinants of the trafficking chaperones. This review summarizes advances in GPCR signaling and trafficking with a focus on the parathyroid hormone receptor (PTHR) as a prototype, and on the actin–sorting nexin 27 (SNX27)–retromer tubule (ASRT) complex, an endosomal sorting hub responsible for recycling and preservation of cell surface receptors. The findings are integrated into a model of PTHR trafficking with implications for signal transduction, bone growth, and mineral ion metabolism. a multiprotein trafficking complex composed of SNX27 and retromer that assembles tubules on endosomes, into which cargo proteins are sorted and then recycled back to the plasma membrane. It works in conjunction with actin via the WASH complex. in BRET the donor fluorophore of the FRET pair is replaced with a luciferase, which in the presence of a luciferin substrate excites the acceptor fluorophore as in FRET. evolutionarily conserved complexes that facilitate the biogenesis of multivesicular endosomes (MVEs) containing GPCRs, and other membrane proteins, through a process involving the sequential recruitment of ESCRT sub-complexes (ESCRT-0/I, -II, -III, and -IV) which mediate formation of intraluminal vesicles (ILVs), encapsulation of ubiquitinated cargo, deubiquitination, and finally scission of the ILVs. a nonfluorescent molecule but becomes highly fluorescent upon binding to a specific sequence consisting of a biarsenical-tetracysteine tag with the form CCXXCC. an optical technique that measures changes in intramolecular conformations or protein–protein interactions. It is based on the transfer of conserved energy between two fluorophores with overlapping excitation and emission spectra. the largest class of seven transmembrane domain receptors that transduce signals ranging from light to growth and hormone action. GPCRs are classified into four major families, designated A–D. Family B incorporates peptide hormone receptors including the parathyroid hormone receptor (PTHR). single-domain antibody fragments containing the structural and functional properties of heavy-chain dimers antibodies that naturally occur in llamas, dromedaries, and camels (Camelidae), and are devoid of light chains. a short linear motif that resides within the far C terminus of many transmembrane proteins including GPCRs. It interacts with PDZ domain-containing adaptor proteins containing compatible consensus sequences. a scaffolding module found in many cytoplasmic adaptor proteins. It serves as a platform for the recruitment and assembly of protein–protein complexes. an ancient evolutionarily conserved pentameric protein complex composed of the core vacuolar protein sorting (Vps) proteins Vps26/Vps29/Vps35 that interact with two Bin/amphiphysin/Rvs (BAR) domain-containing SNXs. It forms the major subcomplex of the ASRT trafficking complex. a unique PDZ domain-containing member of the SNX protein family that acts as a ‘cargo selector’ for the ASRT complex. It also possesses PX- and FERM-like domain(s) that link it to endosomal membranes and associated cargoes, respectively. a post-translational modification whereby ubiquitin is covalently added to protein substrates by the sequential actions of three ubiquitin enzymes: E1 (ubiquitin activation), E2 (ubiquitin carrying), E3 (ubiquitin ligase). The ubiquitinated substrates are targeted for proteosomal degradation. a multimeric protein complex composed of WASH1, strumpellin, SWIP, FAM21, and CCDC53 that activates the actin-related protein 2/3 (Arp2/3) complex which nucleates filamentous actin required to drive the elongation of ASRT-positive tubules from endosomes.