title: Epidermal growth factor promotes protein degradation of epithelial protein lost in neoplasm (EPLIN), a putative metastasis suppressor, during epithelial-mesenchymal transition.
abstract: Aberrant expression of EGF receptors has been associated with hormone-refractory and metastatic prostate cancer (PCa). However, the molecular mechanism for EGF signaling in promoting PCa metastasis remains elusive. Using experimental models of PCa metastasis, we demonstrated that EGF could induce robust epithelial-mesenchymal transition (EMT) and increase invasiveness. Interestingly, EGF was found to be capable of promoting protein turnover of epithelial protein lost in neoplasm (EPLIN), a putative suppressor of EMT and tumor metastasis. Mechanistic study revealed that EGF could activate the phosphorylation, ubiquitination, and degradation of EPLIN through an extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent signaling cascade. Pharmacological inhibition of the ERK1/2 pathway effectively antagonized EGF-induced EPLIN degradation. Two serine residues, i.e. serine 362 and serine 604, were identified as putative ERK1/2 phosphorylation sites in human EPLIN, whose point mutation rendered resistance to EGF-induced protein turnover. This study elucidated a novel molecular mechanism for EGF regulation of EMT and invasiveness in PCa cells, indicating that blockade of EGF signaling could be beneficial in preventing and retarding PCa metastasis at early stages.
authors.affiliation: Department of Urology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Shumin
authors.initials: S
authors.lastname: Zhang
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.forename: Shareen
authors.initials: S
authors.lastname: Iqbal
authors.forename: Yanru
authors.initials: Y
authors.lastname: Wang
authors.forename: Adeboye O
authors.initials: AO
authors.lastname: Osunkoya
authors.forename: Zhengjia
authors.initials: Z
authors.lastname: Chen
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Chen
authors.forename: Dong M
authors.initials: DM
authors.lastname: Shin
authors.forename: Hongwei
authors.initials: H
authors.lastname: Yuan
authors.forename: Yongqiang A
authors.initials: YA
authors.lastname: Wang
authors.forename: Haiyen E
authors.initials: HE
authors.lastname: Zhau
authors.forename: Leland W K
authors.initials: LW
authors.lastname: Chung
authors.forename: Chad
authors.initials: C
authors.lastname: Ritenour
authors.forename: Omer
authors.initials: O
authors.lastname: Kucuk
authors.forename: Daqing
authors.initials: D
authors.lastname: Wu
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D017930:Genes, Reporter; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D059748:Proteolysis / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection
chemical_list: D003598:Cytoskeletal Proteins; C403263:LIMA1 protein, human; D009363:Neoplasm Proteins; D004815:Epidermal Growth Factor