Desuppression Of Tgf-Beta Signaling Via Nuclear C-Abl-Mediated Phosphorylation Of Tif1 Gamma/Trim33 At Tyr-524,-610, And-1048

Protein-tyrosine kinases regulate a broad range of intracellular processes occurring primarily just beneath the plasma membrane. With the greatest care to prevent dephosphorylation, we have shown that nuclear tyrosine phosphorylation regulates global chromatin structural states. However, the roles for tyrosine phosphorylation in the nucleus are poorly understood. Here we identify transcriptional intermediary factor 1-gamma (TIF1 gamma/TRIM33/Ectodermin), which suppresses transforming growth factor-beta (TGF-beta) signaling through the association with Smad2/3 transcription factor, as a new nuclear substrate of c-Abl tyrosine kinase. Replacement of the three tyrosine residues Tyr-524, -610, and -1048 with phenylalanine (3YF) inhibits c-Abl-mediated phosphorylation of TIF1. and enhances TIF1 gamma's association with Smad3. Importantly, knockdown-rescue experiments show that 3YF strengthens TIF1 gamma's ability to suppress TGF-beta signaling. Intriguingly, activation of c-Abl by epidermal growth factor (EGF) induces desuppression of TGF-beta signaling via enhancing the tyrosine phosphorylation level of TIF1 gamma. TGF-beta together with EGF synergistically provokes desuppressive responses of epithelial-tomesenchymal transition through tyrosine phosphorylation of TIF1 gamma. These results suggest that nuclear c-Abl-mediated tyrosine phosphorylation of TIF1 gamma has a desuppressive role in TGF-beta-Smad2/3 signaling.