RGD Reference Report - The ubiquitin ligase Mdm2 controls oligodendrocyte maturation by intertwining mTOR with G protein-coupled receptor kinase 2 in the regulation of GPR17 receptor desensitization. - Rat Genome Database

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The ubiquitin ligase Mdm2 controls oligodendrocyte maturation by intertwining mTOR with G protein-coupled receptor kinase 2 in the regulation of GPR17 receptor desensitization.

Authors: Fumagalli, M  Bonfanti, E  Daniele, S  Zappelli, E  Lecca, D  Martini, C  Trincavelli, ML  Abbracchio, MP 
Citation: Fumagalli M, etal., Glia. 2015 Dec;63(12):2327-39. doi: 10.1002/glia.22896. Epub 2015 Jul 31.
RGD ID: 11076228
Pubmed: PMID:26228571   (View Abstract at PubMed)
DOI: DOI:10.1002/glia.22896   (Journal Full-text)

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.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Grk2Ratcellular response to rapamycin  IEP  RGD 

Molecular Function

  

Objects Annotated

Genes (Rattus norvegicus)
Gpr17  (G protein-coupled receptor 17)
Grk2  (G protein-coupled receptor kinase 2)
Mdm2  (MDM2 proto-oncogene)


Additional Information