TY - JOUR
T1 - Epidermal growth factor promotes protein degradation of epithelial protein lost in neoplasm (EPLIN), a putative metastasis suppressor, during epithelial-mesenchymal transition
AU - Zhang, Shumin
AU - Wang, Xu
AU - Iqbal, Shareen
AU - Wang, Yanru
AU - Osunkoya, Adeboye O.
AU - Chen, Zhengjia
AU - Chen, Zhuo
AU - Shin, Dong M.
AU - Yuan, Hongwei
AU - Wang, Yongqiang A.
AU - Zhau, Haiyen E.
AU - Chung, Leland W.K.
AU - Ritenour, Chad
AU - Kucuk, Omer
AU - Wu, Daqing
PY - 2013/1/18
Y1 - 2013/1/18
N2 - Background: The mechanism of EGF signaling in the regulation of prostate cancer (PCa) metastasis remains unclear. Results: EGF promotes epithelial-mesenchymal transition (EMT) and induces degradation of epithelial protein lost in neoplasm (EPLIN), a putative suppressor of PCa metastasis. Conclusion: EGF activates ERK1/2-dependent phosphorylation, ubiquitination, and protein turnover of EPLIN. Significance: This study suggested that blockade of EGF signaling could retard EMT and inhibit invasiveness of PCa cells. 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.
AB - Background: The mechanism of EGF signaling in the regulation of prostate cancer (PCa) metastasis remains unclear. Results: EGF promotes epithelial-mesenchymal transition (EMT) and induces degradation of epithelial protein lost in neoplasm (EPLIN), a putative suppressor of PCa metastasis. Conclusion: EGF activates ERK1/2-dependent phosphorylation, ubiquitination, and protein turnover of EPLIN. Significance: This study suggested that blockade of EGF signaling could retard EMT and inhibit invasiveness of PCa cells. 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.
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U2 - 10.1074/jbc.M112.438341
DO - 10.1074/jbc.M112.438341
M3 - Article
C2 - 23188829
AN - SCOPUS:84872715614
SN - 0021-9258
VL - 288
SP - 1469
EP - 1479
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 3
ER -