Nuclear translocation of type I transforming growth factor ? receptor confers a novel function in RNA processing.

ABSTRACT: Signaling of transforming growth factor ? (TGF-?) is redirected in cancer to promote malignancy, but how TGF-? function is altered in a transformed cell is not fully understood. We investigated TGF-? signaling by profiling proteins that differentially bound to type I TGF-? receptor (T?RI) in nontransformed, HER2-transformed, and HER2-negative breast cancer cells using immunoprecipitation followed by protein identification. Interestingly, several nuclear proteins implicated in posttranscriptional RNA processing were uniquely identified in the T?RI coprecipitates from HER2-transformed cells. Ligand-inducible nuclear translocation of T?RI was observed only in transformed cells, and the translocation required importin ?1, nucleolin, and Smad2/3. This trafficking was dependent on the high Ran GTPase activity resulting from oncogenic transformation. In the nucleus, T?RI associated with purine-rich RNA sequences in a synergistic manner with the RNA-binding factor hnRNP A1. We further found that nuclear translocation of T?RI specifically induced epidermal growth factor receptor (EGFR) transcript isoform c, which encodes a soluble EGFR protein, through alternative splicing or 3'-end processing. Our study confirms a cancer-specific nuclear translocation of T?RI and demonstrates its potential function in regulating nuclear RNA processing, as well as a novel gain-of-function mechanism of TGF-? signaling in cancer.

SUBMITTER: Chandra M 

PROVIDER: S-EPMC3372271 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature