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.
Highlights
Transport of macromolecules through the nuclear pore by importins and exportins plays a critical role in the spatial regulation of protein activity
Activation of epidermal growth factor receptor (EGFR) is followed by a series of molecular events that contain EGFR signal strength and duration
About 40% of the proteins (175/431) associating with EGFR were listed as EGFR interactors in the Biological General Repository for Interaction Datasets (BioGRID) and represented well-characterized members of the canonical EGFR pathway, including components of the adaptor protein complex 2 (AP-2), members of the CBL family of E3 ubiquitin-protein ligases, growth factor receptorbound protein 2 (GRB2), SHC-transforming protein 1 (SHC1), son of sevenless homolog 1 (SOS1), the phosphatidylinositol 4,5bisphosphate 3-kinase catalytic subunit α and β isoforms (PIK3CA and PIK3CB, respectively), phosphatidylinositol 3kinase regulatory subunit α (PIK3R1), 1-phosphatidylinositol 4,5bisphosphate phosphodiesterase gamma-1 (PLCG1), and ERBB receptor feedback inhibitor 1 (ERRFI; known as mitogeninducible gene 6 protein)
Summary
Transport of macromolecules through the nuclear pore by importins and exportins plays a critical role in the spatial regulation of protein activity. The study of EGFR and its coreceptors at the systems level identified additional EGFR-binding partners, dynamic patterns of pathway activation, and further layers of EGFR regulation through feedback inhibitors and intracellular signal compartmentalization[4,5,6]. Focal and broad deletions including the RANBP6 gene locus were identified in glioblastoma (GBM) and RanBP6 silencing accelerated glioma growth in vivo. Taken together, these findings suggest that RanBP6 serves as EGFR regulator that is disrupted in human cancer
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
