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The ubiquitin ligase M dm2 controls oligodendrocyte maturation by intertwining m TOR with G protein‐coupled receptor kinase 2 in the regulation of GPR 17 receptor desensitization
Author(s) -
Fumagalli Marta,
Bonfanti Elisabetta,
Daniele Simona,
Zappelli Elisa,
Lecca Davide,
Martini Claudia,
Trincavelli Maria L.,
Abbracchio Maria P.
Publication year - 2015
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.22896
Subject(s) - biology , ubiquitin ligase , microbiology and biotechnology , g protein coupled receptor kinase , pi3k/akt/mtor pathway , homologous desensitization , mdm2 , kinase , ubiquitin , neuroscience , receptor , signal transduction , g protein coupled receptor , desensitization (medicine) , biochemistry , gene
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. GLIA 2015;63:2327–2339