Nuclear Translocation of Type I Transforming Growth Factor β Receptor Confers a Novel Function in RNA Processing
AbstractNuclear Translocation of Type I Transforming Growth Factor β Receptor Confers a Novel Function in RNA Processing Manasa Chandra a , g , Shengbing Zang b , k , Haiqing Li e , Lisa J. Zimmerman h , i , Jackson Champer c , g , Akihiro Tsuyada a , Amy Chow a , Weiying Zhou a , Yang Yu a , j , Harry Gao f , Xiubao Ren j , Ren-Jang Lin b , d and Shizhen Emily Wang a , d a Departments of Cancer Biology b Molecular and Cellular Biology c Immunology, Beckman Research Institute of City of Hope d Molecular Oncology Program e Bioinformatics Core Facility f DNA Sequencing/Solexa Core Facility, City of Hope Comprehensive Cancer Center g City of Hope Irell & Manella Graduate School of Biological Sciences, Duarte, California, USA h Jim Ayers Institute for Precancer Detection and Diagnosis, Vanderbilt-Ingram Cancer Center i Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA j Department of Immunology and Biotherapy, Tianjin Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China k Department of Pathology and Institute of Oncology, Fujian Medical University, Fuzhou, Fujian, China 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. We investigated TGF-β signaling by profiling proteins that differentially bound to type I TGF-β receptor (TβRI) 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 TβRI coprecipitates from HER2-transformed cells. Ligand-inducible nuclear translocation of TβRI was observed only 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 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 TβRI and demonstrates its potential function in regulating nuclear RNA processing, as well as a novel gain-of-function mechanism of TGF-β signaling in cancer.