title: The ubiquitin ligase Mdm2 controls oligodendrocyte maturation by intertwining mTOR with G protein-coupled receptor kinase 2 in the regulation of GPR17 receptor desensitization.
abstract: During oligodendrocyte precursor cell (OPC) differentiation, defective control of the membrane receptor GPR17 has been suggested to block cell maturation and impair remyelination under demyelinating conditions. After the immature oligodendrocyte stage, to enable cells to complete maturation, GPR17 is physiologically down-regulated via phosphorylation/desensitization by G protein-coupled receptor kinases (GRKs); conversely, GRKs are regulated by the "mammalian target of rapamycin" mTOR. However, how GRKs and mTOR are connected to each other in modulating GPR17 function and oligodendrogenesis has remained elusive. Here we show, for the first time, a role for Murine double minute 2 (Mdm2), a ligase previously involved in ubiquitination/degradation of the onco-suppressor p53 protein. In maturing OPCs, both rapamycin and Nutlin-3, a small molecule inhibitor of Mdm2-p53 interactions, increased GRK2 sequestration by Mdm2, leading to impaired GPR17 down-regulation and OPC maturation block. Thus, Mdm2 intertwines mTOR with GRK2 in regulating GPR17 and oligodendrogenesis and represents a novel actor in myelination.
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università Degli Studi Di Milano, Milan, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Fumagalli
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università Degli Studi Di Milano, Milan, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Bonfanti
authors.affiliation: Department of Pharmacy, University of Pisa, Pisa, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Daniele
authors.affiliation: Department of Pharmacy, University of Pisa, Pisa, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Zappelli
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università Degli Studi Di Milano, Milan, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Lecca
authors.affiliation: Department of Pharmacy, University of Pisa, Pisa, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Martini
authors.affiliation: Department of Pharmacy, University of Pisa, Pisa, Italy.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Trincavelli
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università Degli Studi Di Milano, Milan, Italy.
authors.forename: Maria P
authors.initials: MP
authors.lastname: Abbracchio
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002491:Central Nervous System Agents / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D002491:Central Nervous System Agents; C534979:GPR17 protein, mouse; C514731:GPR17 protein, rat; D007093:Imidazoles; D009419:Nerve Tissue Proteins; D010879:Piperazines; D043562:Receptors, G-Protein-Coupled; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; C497207:Mdm2 protein, mouse; C497208:Mdm2 protein, rat; D051736:Proto-Oncogene Proteins c-mdm2; C546843:mTOR protein, mouse; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; C496568:GRK2 protein, mouse; C496569:Grk2 protein, rat; D054769:G-Protein-Coupled Receptor Kinase 2; D020123:Sirolimus
keywords: GPR17 receptor; Nutlin-3; myelination; oligodendrocyte precursor cells; rapamycin