title: Cell-surface receptors transactivation mediated by g protein-coupled receptors.
abstract: G protein-coupled receptors (GPCRs) are seven transmembrane-spanning proteins belonging to a large family of cell-surface receptors involved in many intracellular signaling cascades. Despite GPCRs lack intrinsic tyrosine kinase activity, tyrosine phosphorylation of a tyrosine kinase receptor (RTK) occurs in response to binding of specific agonists of several such receptors, triggering intracellular mitogenic cascades. This suggests that the notion that GPCRs are associated with the regulation of post-mitotic cell functions is no longer believable. Crosstalk between GPCR and RTK may occur by different molecular mechanism such as the activation of metalloproteases, which can induce the metalloprotease-dependent release of RTK ligands, or in a ligand-independent manner involving membrane associated non-receptor tyrosine kinases, such as c-Src. Reactive oxygen species (ROS) are also implicated as signaling intermediates in RTKs transactivation. Intracellular concentration of ROS increases transiently in cells stimulated with GPCR agonists and their deliberated and regulated generation is mainly catalyzed by enzymes that belong to nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family. Oxidation and/or reduction of cysteine sulfhydryl groups of phosphatases tightly controls the activity of RTKs and ROS-mediated inhibition of cellular phosphatases results in an equilibrium shift from the non-phosphorylated to the phosphorylated state of RTKs. Many GPCR agonists activate phospholipase C, which catalyze the hydrolysis of phosphatidylinositol 4,5-bis-phosphate to produce inositol 1,4,5-triphosphate and diacylglicerol. The consequent mobilization of Ca2+ from endoplasmic reticulum leads to the activation of protein kinase C (PKC) isoforms. PKCα mediates feedback inhibition of RTK transactivation during GPCR stimulation. Recent data have expanded the coverage of transactivation to include Serine/Threonine kinase receptors and Toll-like receptors. Herein, we discuss the main mechanisms of GPCR-mediated cell-surface receptors transactivation and the pathways involved in intracellular responses induced by GPCR agonists. These studies may suggest the design of novel strategies for therapeutic interventions.
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, Naples 80131, Italy. fabio.cattaneo@unina.it.
authors.forename: Fabio
authors.initials: F
authors.lastname: Cattaneo
authors.affiliation: Department of Medicine and Health Sciences, University of Molise, Campobasso 86100, Italy. germano.guerra@unimol.it.
authors.forename: Germano
authors.initials: G
authors.lastname: Guerra
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, Naples 80131, Italy. melania.parisi@unina.it.
authors.forename: Melania
authors.initials: M
authors.lastname: Parisi
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, Naples 80131, Italy. mar.demarinis@studenti.unina.it.
authors.forename: Marta
authors.initials: M
authors.lastname: De Marinis
authors.affiliation: Department of Sport Science and Wellness, University of Naples Parthenope, Naples 80133, Italy. tafuri@uniparthenope.it.
authors.forename: Domenico
authors.initials: D
authors.lastname: Tafuri
authors.affiliation: Department of Public Health, School of Medicine, University of Naples Federico II, Naples 80131, Italy. mariapia.cinelli@unina.it.
authors.forename: Mariapia
authors.initials: M
authors.lastname: Cinelli
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, Naples 80131, Italy. rosario.ammendola@unina.it.
authors.forename: Rosario
authors.initials: R
authors.lastname: Ammendola
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism; D008666:Metalloendopeptidases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism; D015533:Transcriptional Activation; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D017382:Reactive Oxygen Species; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D051193:Toll-Like Receptors; D000071557:beta-Arrestins; D020794:Receptor Protein-Tyrosine Kinases; D008666:Metalloendopeptidases