RanBP6 is a novel tumor suppressor that negatively regulates EGFR
Oldrini B, CNIO C/ Melchor Fernández Almagro, 3, E-28029 Madrid; Hsieh W, MSKCC 1275 York Avenue New York, NY 10065; Kaufmann M, MSKCC 1275 York Avenue New York, NY 10065; Erdjument-Bromage H, MSKCC 1275 York Avenue New York, NY 10065;Mellinghoff I.K. , MSKCC 1275 York Avenue New York, NY 10065;and Squatrito M., CNIO C/ Melchor Fernández Almagro, 3, E-28029 Madrid
The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is abnormally active due to gene amplification or mutation in ~ 40 % of human glioblastomas (GBM). It has been previously shown that loss of Phosphatase and tensin homolog (PTEN) expression in EGFR mutant GBMs is associated with EGFR kinase inhibitor resistance by blocking the Cbl-mediated downregulation of the activated EGF receptor. To further elucidate the effects of PTEN on the EGFR “degradome”, we have performed an EGFR affinity immunopurification followed Mass Spectrometry (LC-MS/MS) in PTEN-isogenic cells. We identified about 200 EGFR-associated proteins, some of which showed differential EGFR-association between PTEN expressing and PTEN knockdown cells. Of these latter proteins, Ran-binding protein 6 (RanBP6) showed the most consistent pattern and associated with EGFR exclusively in the presence of PTEN.
RanBP6 is a protein of currently unknown function that shares sequence similarity with the family of Ran-binding proteins. We observed that RanBP6 negatively regulates EGFR both at the protein and mRNA levels, possibly through the modulation of an EGFR negative feedback loop. Approximately 40% of GBM samples of the TCGA datasets show heterozygous loss of the RanBP6 locus and several patient-derived GBM neurosphere lines have reduced RanBP6 protein levels. Preliminary evidences indicate that RanBP6 has tumor suppressor activity both in vitro and in vivo. RanBP6 might represent a novel critical regulator of the EGFR receptor in glioblastoma.