Nuclear Translocation of Type I Transforming Growth Factor β Receptor Confers a Novel Function in RNA Processing

Abstract

Signaling of transforming growth factor β (TGF-β) is redirected in cancer to promote malignancy, but how TGF-β function is altered in a transformed cell is not fully understood. Here we investigated TGF-β signaling by profiling proteins that differentially bound to type I TGF-β receptor (TβRI) in non-transformed, HER2-transformed, and HER2-negative breast cancer cells using immunoprecipitation followed by protein identification. Interestingly, several nuclear proteins implicated in post-transcriptional RNA processing were uniquely identified in the TβRI co-precipitants from HER2-transformed cells. Ligand-inducible nuclear translocation of TβRI was only observed in transformed cells, and the translocation required importin β1, nucleolin, and Smad2/3. This trafficking was dependent on the high Ran GTPase activity resulting from oncogenic transformation. In the nucleus, TβRI associated with purine-rich RNA sequences in a synergistic manner with the RNA-binding factor hnRNP A1. We further found that nuclear translocation of TβRI specifically induced EGFR transcript isoform c, which encodes a soluble EGFR protein, through alternative splicing or 3' -end processing. Our study reveals for the first time a cancer-specific nuclear translocation of TβRI and its potential function in regulating nuclear RNA processing, as well as a novel gain-of-function mechanism of TGF-β signaling in cancer.