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

Barbara Oldrini, Wan-Ying Hsieh, Hediye Erdjument-Bromage, Paolo Codega, Maria Stella Carro, Alvaro Curiel-García, Carl Campos, Maryam Pourmaleki, Christian Grommes, Igor Vivanco, Daniel Rohle, Craig M. Bielski, Barry S. Taylor, Travis J. Hollmann, Marc Rosenblum, Paul Tempst, John Blenis, Massimo Squatrito () and Ingo K. Mellinghoff ()
Additional contact information
Barbara Oldrini: Memorial Sloan Kettering Cancer Center
Wan-Ying Hsieh: Memorial Sloan Kettering Cancer Center
Hediye Erdjument-Bromage: Memorial Sloan Kettering Cancer Center
Paolo Codega: Memorial Sloan Kettering Cancer Center
Maria Stella Carro: University of Freiburg
Alvaro Curiel-García: Spanish National Cancer Research Centre
Carl Campos: Memorial Sloan Kettering Cancer Center
Maryam Pourmaleki: Memorial Sloan Kettering Cancer Center
Christian Grommes: Memorial Sloan Kettering Cancer Center
Igor Vivanco: The Institute of Cancer Research
Daniel Rohle: Memorial Sloan Kettering Cancer Center
Craig M. Bielski: Memorial Sloan Kettering Cancer Center
Barry S. Taylor: Memorial Sloan Kettering Cancer Center
Travis J. Hollmann: Memorial Sloan Kettering Cancer Center
Marc Rosenblum: Memorial Sloan Kettering Cancer Center
Paul Tempst: Memorial Sloan Kettering Cancer Center
John Blenis: Weill Cornell Graduate School of Medical Sciences
Massimo Squatrito: Spanish National Cancer Research Centre
Ingo K. Mellinghoff: Memorial Sloan Kettering Cancer Center

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-02185-w

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