title: Analysis of origin and protein-protein interaction maps suggests distinct oncogenic role of nuclear EGFR during cancer evolution.
abstract: Receptor tyrosine kinase EGFR usually is localized on plasma membrane to induce progression of many cancers including cancers in children (Bodeyet 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). Here we report that NLS of EGFR has its old evolutionary origin. Protein-protein interaction maps suggests that nEGFR pathways are different from 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 suggests that nEGFR correlates with the tumor grades especially in prostate cancer patients. Structural predication analysis suggests that NLS can compromise the differential protein binding to EGFR through stretch linkers with evolutionary mutation from N to V. In 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 old origin while NLS neighboring domain of TM has been undergone accelerated evolution. Thus nEGFR has an old origin resembling the cancer evolution but TM may interfere with NLS driven signaling for natural selection of survival to evade NLS induced aggressive cancers. Our data suggest NLS is a dynamic inducer of EGFR oncogenesis during evolution for advanced cancers. Our model provides novel insights into the evolutionary role of NLS of oncogenic kinases in cancers.
authors.affiliation: Department of Biology, School of Science and Technology, Nazarbayev University, Astana, 010000, Republic of Kazakhstan.
authors.forename: Ainur
authors.initials: A
authors.lastname: Sharip
authors.affiliation: Department of Biology, School of Science and Technology, Nazarbayev University, Astana, 010000, Republic of Kazakhstan.
authors.forename: Diyora
authors.initials: D
authors.lastname: Abdukhakimova
authors.affiliation: Shandong Analysis and Test Center, Shandong Academy of Sciences, 19 Keyuan Street, Jinan, 250014, P.R. China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Biology, School of Science and Technology, Nazarbayev University, Astana, 010000, Republic of Kazakhstan.
authors.forename: Alexey
authors.initials: A
authors.lastname: Kim
authors.affiliation: Department of Biology, School of Science and Technology, Nazarbayev University, Astana, 010000, Republic of Kazakhstan.
authors.forename: Yevgeniy
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Biology, School of Science and Technology, Nazarbayev University, Astana, 010000, Republic of Kazakhstan.
authors.forename: Aigul
authors.initials: A
authors.lastname: Sharip
authors.affiliation: Department of Biology, School of Science and Technology, Nazarbayev University, Astana, 010000, Republic of Kazakhstan.
authors.forename: Askarbek
authors.initials: A
authors.lastname: Orakov
authors.affiliation: College of Basic Medicine, Wuhan University, Wuhan, 430071, P.R. China.
authors.forename: Lixia
authors.initials: L
authors.lastname: Miao
authors.affiliation: Shandong Analysis and Test Center, Shandong Academy of Sciences, 19 Keyuan Street, Jinan, 250014, P.R. China.
authors.forename: Qinglei
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Department of Mechanical Engineering, Vanderbilt University, Nashville, TN, 37203, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN, 37201, USA.
authors.forename: Zhenbang
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Biology, School of Science and Technology, Nazarbayev University, Astana, 010000, Republic of Kazakhstan.
authors.forename: Yingqiu
authors.initials: Y
authors.lastname: Xie
keywords: EGFR; NLS; prostate cancer.