EGFR feedback-inhibition by Ran-binding protein 6 is disrupted in cancer.
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Embargo End Date
ICR Authors
Authors
Oldrini, B
Hsieh, W-Y
Erdjument-Bromage, H
Codega, P
Carro, MS
Curiel-García, A
Campos, C
Pourmaleki, M
Grommes, C
Vivanco, I
Rohle, D
Bielski, CM
Taylor, BS
Hollmann, TJ
Rosenblum, M
Tempst, P
Blenis, J
Squatrito, M
Mellinghoff, IK
Hsieh, W-Y
Erdjument-Bromage, H
Codega, P
Carro, MS
Curiel-García, A
Campos, C
Pourmaleki, M
Grommes, C
Vivanco, I
Rohle, D
Bielski, CM
Taylor, BS
Hollmann, TJ
Rosenblum, M
Tempst, P
Blenis, J
Squatrito, M
Mellinghoff, IK
Document Type
Journal Article
Date
2017-12-11
Date Accepted
2017-11-09
Abstract
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.
Citation
Nature communications, 2017, 8 (1), pp. 2035 - ?
Source Title
Publisher
NATURE PORTFOLIO
ISSN
2041-1723
eISSN
2041-1723
Collections
Research Team
Molecular Addictions