Analysis of origin and protein-protein interaction maps suggests a distinct oncogenic role of nuclear EGFR during cancer evolution

Receptor tyrosine kinase EGFR is usually localized on plasma membrane inducing the progression of many cancers including malignancy in children (Bodey et al. In Vivo. 2005, 19:931-41), but it contains a nuclear localization signal (NLS) that mediates EGFR nuclear translocation (Lin et al. Nat Cell Biol. 2001, 3:802-8). In this report, we claim that NLS of EGFR has an old evolutionary origin. In particular, our analysis of protein-protein interaction maps reveals that nuclear EGFR (nEGFR) pathways are different from that of membrane EGFR and EGF is not found in nEGFR network, while androgen receptor (AR) is found, which suggests the evolution of prostate cancer, a well-known AR driven cancer, through changes in androgen- or EGF-dependence. Database analysis shows that nEGFR correlates with the tumor grades especially in prostate cancer patients. Structural prediction analysis indicates that NLS can compromise the differential protein binding to EGFR through stretch linkers with evolutionary mutation from N to V. In the experiment, elevation of nEGFR but not membrane EGFR was found in castration resistant prostate cancer cells. Finally, systems analysis of NLS and transmembrane domain (TM) suggests that NLS has an old origin while NLS neighboring domain of TM has undergone accelerated evolution. Thus, nEGFR has an old origin resembling the cancer evolution, but TM may interfere NLS driven signaling for natural selection of survival to evade NLS induced aggressive cancers. Our data support NLS is a dynamic inducer of EGFR oncogenesis during evolution for advanced cancers. Our model provides a novel insight into the evolutionary role of NLS in oncogenic kinases in cancers.