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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
PubMed

Insights

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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