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

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.

The Epidermal Growth Factor Receptor Ligand Amphiregulin Protects From Cholestatic Liver Injury and Regulates Bile Acids Synthesis

“…First, we validated that pharmacological or genetic inhibition of the STAT3 pathway in HepG2 cells resulted in increased EGFR expression (Supporting Fig. D), thus confirming previous findings in nonliver cells . Next, we tested the role of SOCS3 and found that when the expression of this gene was knocked down, basal EGFR expression levels were reduced, and, most significantly, the stimulatory effects of BA on EGFR levels were lost (Fig.…”

“…Although FXR has been reported to bind other response elements of various geometries, we considered the possibility that FXR could modulate EGFR expression in an indirect manner. EGFR has been recently reported to be transcriptionally repressed by the transcription factor, STAT3 . This notion, together with the fact that the suppressor of cytokine signaling‐3 (SOCS3), a potent inhibitor of STAT3 activity, is a direct FXR target gene up‐regulated by BA in the liver, led us to consider the potential implication of SOCS3 in BA‐mediated EGFR up‐regulation.…”

“…The fact that prominent BA‐/FXR‐regulated genes in the liver, such as CYP7A1 , are not direct FXR targets led us to consider the possibility of an indirect mechanism in the regulation of EGFR by FXR. It was recently demonstrated that the transcription factor, STAT3, is a repressor of the EGFR gene . Interestingly, the feedback inhibitor of the STAT3 signaling pathway, SOCS3, was also recently identified as a direct target of BA‐FXR in hepatocytes .…”

TNPO2 operates downstream of DYNC1I1 and promotes gastric cancer cell proliferation and inhibits apoptosis

“…According to the recent research, karyopherin-β family is regarded as a potential target for cancer therapy. 3,[7][8][9][10] The TNPO2-mediated transport of the material into the nuclear process is similar to the above described system. But TNPO2 only transports limited nuclear-destined cargoes, and participates only in the nuclear process, without participating in the cargo export process.…”

“…Importins are bound by Ran‐GTP, releasing the cargo proteins in the nucleus and recycling them in the cytoplasm. According to the recent research, karyopherin‐β family is regarded as a potential target for cancer therapy . The TNPO2‐mediated transport of the material into the nuclear process is similar to the above described system.…”