Identification of PCTA, a TGIF antagonist that promotes PML function in TGF-beta signalling.
The TGIF homoeodomain protein functions as an important negative regulator in the TGF-beta signalling pathway. The inhibitory function of TGIF is executed in part through its ability to sequester the tumour suppressor cytoplasmic promyelocytic leukaemia (cPML) in the nucleus, thereby preventing the phosphorylation of Smad2 by the activated TGF-beta type I receptor. Here, we report on the identification of PCTA (PML competitor for TGIF association), a TGIF antagonist that promotes TGF-beta-induced transcriptional and cytostatic responses. We provide evidence that PCTA functions in TGF-beta signalling by relieving the suppression of Smad2 phosphorylation by TGIF. Furthermore, we demonstrate that PCTA selectively competes with cPML for TGIF association, resulting in the accumulation of cPML in the cytoplasm, where it associates with SARA and coordinates the access of Smad2 for phosphorylation by the activated TGF-beta type I receptor. Thus, our findings on the mode of action of PCTA provide new and important insights into the molecular mechanism underlying the antagonistic interplay between TGIF and cPML in the TGF-beta signalling network.
Faresse
Nourdine
N
Laboratory of Cell Signaling and Carcinogenesis, INSERM U673, Paris, France.
Colland
Frédéric
F
Ferrand
Nathalie
N
Prunier
Céline
C
Bourgeade
Marie-Francoise
MF
Atfi
Azeddine
A
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D018076:DNA, Complementary; D004285:Dogs; D005260:Female; D015723:Gene Library; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D010920:Placenta / Q000378:metabolism; D000071156:Promyelocytic Leukemia Protein; D012097:Repressor Proteins / Q000037:antagonists & inhibitors*; D051899:Smad2 Protein / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D044767:Ubiquitin-Protein Ligases
D002352:Carrier Proteins; D018076:DNA, Complementary; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D012097:Repressor Proteins; C497782:SMAD2 protein, human; D051899:Smad2 Protein; C097504:TGIF1 protein, human; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; C475081:IRF2BP1 protein, human; D044767:Ubiquitin-Protein Ligases