EGFR feedback-inhibition by Ran-binding protein 6 is disrupted in cancer. Academic Article uri icon

Overview

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.

publication date

  • December 11, 2017

Research

keywords

  • ErbB Receptors
  • Gene Expression Regulation, Neoplastic
  • Glioma
  • beta Karyopherins
  • ran GTP-Binding Protein

Identity

PubMed Central ID

  • PMC5725448

Scopus Document Identifier

  • 85050156809

Digital Object Identifier (DOI)

  • 10.1038/s41467-017-02185-w

PubMed ID

  • 29229958

Additional Document Info

volume

  • 8

issue

  • 1