title: 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. 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.
authors.affiliation: Department of Cancer Biology, City of Hope Irell & Manella Graduate School of Biological Sciences, Duarte, California, USA.
authors.forename: Manasa
authors.initials: M
authors.lastname: Chandra
authors.forename: Shengbing
authors.initials: S
authors.lastname: Zang
authors.forename: Haiqing
authors.initials: H
authors.lastname: Li
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Zimmerman
authors.forename: Jackson
authors.initials: J
authors.lastname: Champer
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tsuyada
authors.forename: Amy
authors.initials: A
authors.lastname: Chow
authors.forename: Weiying
authors.initials: W
authors.lastname: Zhou
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.forename: Harry
authors.initials: H
authors.lastname: Gao
authors.forename: Xiubao
authors.initials: X
authors.lastname: Ren
authors.forename: Ren-Jang
authors.initials: RJ
authors.lastname: Lin
authors.forename: Shizhen Emily
authors.initials: SE
authors.lastname: Wang
mesh_terms: D017398:Alternative Splicing; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D028884:Karyopherins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D021381:Protein Transport; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D066246:ErbB Receptors; D028884:Karyopherins; D017346:Protein Serine-Threonine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; C497782:SMAD2 protein, human; C512478:EGFR protein, human