EGFR feedback-inhibition by Ran-binding protein 6 is disrupted in cancer

• Published in: Nature communications Vol. 8; no. 1; pp. 2035 - 12
• Main Authors: Oldrini, Barbara, Hsieh, Wan-Ying, Erdjument-Bromage, Hediye, Codega, Paolo, Carro, Maria Stella, Curiel-García, Alvaro, Campos, Carl, Pourmaleki, Maryam, Grommes, Christian, Vivanco, Igor, Rohle, Daniel, Bielski, Craig M., Taylor, Barry S., Hollmann, Travis J., Rosenblum, Marc, Tempst, Paul, Blenis, John, Squatrito, Massimo, Mellinghoff, Ingo K.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.12.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 631/67/1922; 631/80/86/2368; Active Transport, Cell Nucleus - genetics; Animals; Antibiotics, Antineoplastic - pharmacology; beta Karyopherins - genetics; beta Karyopherins - metabolism; Brain cancer; Brain tumors; Cancer; Cell Line, Tumor; Cells, Cultured; Chromosome 9; Deregulation; Derepression; Doxorubicin - pharmacology; Epidermal growth factor; Epidermal growth factor receptors; ErbB Receptors - genetics; ErbB Receptors - metabolism; Feedback, Physiological; Female; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Glioblastoma; Glioma; Glioma - drug therapy; Glioma - genetics; Glioma - metabolism; HEK293 Cells; Humanities and Social Sciences; Humans; Macromolecules; Mice, Knockout; Mice, SCID; multidisciplinary; Nuclear transport; Proteins; ran GTP-Binding Protein - genetics; ran GTP-Binding Protein - metabolism; Ran-binding protein; Science; Science (multidisciplinary); Stat3 protein; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Transcription; Translocation; Tumorigenesis; Xenograft Model Antitumor Assays
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-02185-w

Transport of macromolecules through the nuclear pore by importins and exportins plays a critical role in the spatial regulation of protein activity. How cancer cells co-opt this process to promote tumorigenesis remains unclear. The epidermal growth factor receptor (EGFR) plays a critical role in normal development and in human cancer. Here we describe a mechanism of EGFR regulation through the importin β family member RAN-binding protein 6 (RanBP6), a protein of hitherto unknown functions. We show that RanBP6 silencing impairs nuclear translocation of signal transducer and activator of transcription 3 (STAT3), reduces STAT3 binding to the EGFR promoter, results in transcriptional derepression of EGFR, and increased EGFR pathway output. Focal deletions of the RanBP6 locus on chromosome 9p were found in a subset of glioblastoma (GBM) and silencing of RanBP6 promoted glioma growth in vivo. Our results provide an example of EGFR deregulation in cancer through silencing of components of the nuclear import pathway. The epidermal growth factor receptor (EGFR) signalling is regulated at multiple levels. Here the authors show that the importin RanBP6 acts as a tumor suppressor in Glioblastoma and  regulates EGFR signalling through promoting translocation of STAT3 to the nuclei and repressing EGFR transcription.