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: Manasa Chandra, Shengbing Zang, Haiqing Li, Lisa J Zimmerman, Jackson Champer, Akihiro Tsuyada, Amy Chow, Weiying Zhou, Yang Yu, Harry Gao, Xiubao Ren, Ren-Jang Lin, Shizhen Emily Wang
• Journal: Molecular and cellular biology (Mol Cell Biol) Vol. 32 Issue 12 Pg. 2183-95 (Jun 2012) ISSN: 1098-5549 [Electronic] United States
• PMID: 22473997 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Karyopherins
• Receptors, Transforming Growth Factor beta
• SMAD2 protein, human
• Smad2 Protein
• EGFR protein, human
• ErbB Receptors
• Receptor, ErbB-2
• Protein Serine-Threonine Kinases
• Receptor, Transforming Growth Factor-beta Type I

Topics

• Alternative Splicing
• Breast Neoplasms (metabolism)
• Cell Line, Tumor
• Cell Nucleus (metabolism)
• ErbB Receptors (metabolism)
• Female
• Humans
• Karyopherins (metabolism)
• Protein Serine-Threonine Kinases (metabolism)
• Protein Transport
• Receptor, ErbB-2 (metabolism)
• Receptor, Transforming Growth Factor-beta Type I
• Receptors, Transforming Growth Factor beta (metabolism)
• Signal Transduction
• Smad2 Protein (metabolism)
• Transcription, Genetic