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.
Institut Curie, Centre de Recherche, Orsay F-91405, France.
Nathalie
N
Rocques
Nancy
N
Abou Zeid
Karine
K
Sii-Felice
Laure
L
Lecoin
Marie-Paule
MP
Felder-Schmittbuhl
Alain
A
Eychène
Celio
C
Pouponnot
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