GSK-3-mediated phosphorylation enhances Maf-transforming activity
Nathalie Rocques1, Nancy Abou Zeid, Karine Sii-Felice
1Institut Curie, Centre de Recherche, Orsay F-91405, France.
Molecular Cell
|November 29, 2007
Summary
Glycogen synthase kinase-3 (GSK-3) phosphorylation of Maf oncoproteins enhances their oncogenic activity. This process involves MafA ubiquitination and degradation, paradoxically increasing its transcriptional activity.
Area of Science:
- Molecular Biology
- Oncology
- Biochemistry
Background:
- Maf oncoproteins, AP-1 superfamily members, regulate development, metabolism, and tumorigenesis.
- Maf proteins are overexpressed in multiple myeloma, indicating their role in cancer progression.
Purpose of the Study:
- To investigate the role of GSK-3 dependent phosphorylation in controlling Maf oncoprotein activity.
- To identify downstream targets and mechanisms regulated by GSK-3 mediated Maf phosphorylation.
Main Methods:
- Microarray analysis to identify gene expression changes.
- Phosphorylation site mapping and analysis of ubiquitination and degradation pathways.
- Co-immunoprecipitation to study protein interactions.
Main Results:
- GSK-3 dependent phosphorylation increases Maf oncoprotein's oncogenic activity.
- GSK-3 mediated Maf phosphorylation regulates a gene-expression subprogram involved in extracellular matrix remodeling.
- GSK-3 triggers sequential phosphorylation of MafA, leading to ubiquitination and degradation.
- Phosphorylation paradoxically enhances MafA transcriptional activity by recruiting the coactivator P/CAF, which protects MafA from degradation.
Conclusions:
- GSK-3 plays a critical role in regulating Maf oncoprotein activity and oncogenic potential.
- The interplay between GSK-3, MafA, and P/CAF influences cancer progression through extracellular matrix remodeling.
- Understanding this regulatory mechanism offers potential therapeutic targets for multiple myeloma and other cancers.
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