GSK-3-Mediated Phosphorylation Enhances Maf-Transforming Activity

• DOI: 10.1016/j.molcel.2007.11.009
• Publication Date: 2007-12-05T20:51:23Z
• Authors: Nathalie Rocques; Nancy Abou Zeid; Karine Sii-Felice; Laure Lecoin; Marie-Paule Felde...; Alain Eychène; Celio Pouponnot
• Keywords: 0303 health sciences; Maf Transcription Factors, Large; Transcription, Genetic; Molecular Sequence Data; Ubiquitination; Cell Biology; Cell Line; Rats; Glycogen Synthase Kinase 3; Phosphoserine; 03 medical and health sciences; Cell Transformation, Neoplastic; Phosphothreonine; COS Cells; Chlorocebus aethiops; Animals; Humans; p300-CBP Transcription Factors; Amino Acid Sequence; Phosphorylation; Molecular Biology; Chickens; Protein Processing, Post-Translational

The Maf oncoproteins are b-Zip transcription factors of the AP-1 superfamily. They are involved in developmental, metabolic, and tumorigenic processes. Maf proteins are overexpressed in about 50% of human multiple myelomas. Here, we show that Maf-transforming activity is controlled by GSK-3-dependent phosphorylation and that phosphorylation by GSK-3 can increase the oncogenic activity of a protein. Using microarray analysis, we identify a gene-expression subprogram regulated by GSK-3-mediated Maf phosphorylation involved in extracellular matrix remodeling and relevant to cancer progression. We also demonstrate that GSK-3 triggers MafA sequential phosphorylation on residues S61, T57, T53, and S49, inducing its ubiquitination and degradation. Paradoxically, this phosphorylation increases MafA-transcriptional activity through the recruitment of the coactivator P/CAF. We further demonstrate that P/CAF protects MafA from ubiquitination and degradation, suggesting that, upon the release of the coactivator complex, MafA becomes polyubiquitinated and degraded to allow the response to terminate.