GSK-3-mediated phosphorylation enhances Maf-transforming activity.
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.
Rocques
Nathalie
N
Institut Curie, Centre de Recherche, Orsay F-91405, France.
Abou Zeid
Nancy
N
Sii-Felice
Karine
K
Lecoin
Laure
L
Felder-Schmittbuhl
Marie-Paule
MP
Eychène
Alain
A
Pouponnot
Celio
C
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D002645:Chickens; D002522:Chlorocebus aethiops; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D006801:Humans; D051473:Maf Transcription Factors, Large / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D010769:Phosphothreonine / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D051381:Rats; D014158:Transcription, Genetic; D054875:Ubiquitination; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
D038362:Glycogen Synthase Kinase 3; D051473:Maf Transcription Factors, Large; D010768:Phosphoserine; D010769:Phosphothreonine; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor