Identification of PCTA, a TGIF antagonist that promotes PML function in TGF-β signalling
Open Access
- 29 May 2008
- journal article
- Published by Springer Science and Business Media LLC in The EMBO Journal
- Vol. 27 (13), 1804-1815
- https://doi.org/10.1038/emboj.2008.109
Abstract
The TGIF homoeodomain protein functions as an important negative regulator in the TGF‐β 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‐β type I receptor. Here, we report on the identification of PCTA (PML competitor for TGIF association), a TGIF antagonist that promotes TGF‐β‐induced transcriptional and cytostatic responses. We provide evidence that PCTA functions in TGF‐β 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‐β 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‐β signalling network.Keywords
This publication has 29 references indexed in Scilit:
- TGFβ–SMAD signal transduction: molecular specificity and functional flexibilityNature Reviews Molecular Cell Biology, 2007
- The disintegrin and metalloproteinase ADAM12 contributes to TGF-β signaling through interaction with the type II receptorThe Journal of cell biology, 2007
- Embryonic Fibroblasts from Mice Lacking Tgif Were Defective in Cell CyclingMolecular and Cellular Biology, 2006
- Cytoplasmic PML function in TGF-β signallingNature, 2004
- Functional Proteomics Mapping of a Human Signaling PathwayGenome Research, 2004
- Cytostatic and apoptotic actions of TGF-β in homeostasis and cancerNature Reviews Cancer, 2003
- Smad-dependent and Smad-independent pathways in TGF-β family signallingNature, 2003
- c-Jun NH2-Terminal Kinase Is Essential for the Regulation of AP-1 by Tumor Necrosis FactorMolecular and Cellular Biology, 2003
- Mechanism for Mutational Inactivation of the Tumor Suppressor Smad2Molecular and Cellular Biology, 2001
- Signal Transduction by the JNK Group of MAP KinasesCell, 2000