Epidermal growth factor promotes protein degradation of epithelial protein lost in neoplasm (EPLIN), a putative metastasis suppressor, during epithelial-mesenchymal transition

Shumin Zhang, Xu Wang, Shareen Iqbal, Yanru Wang, Adeboye O. Osunkoya, Zhengjia Chen, Zhuo Chen, Dong M. Shin, Hongwei Yuan, Yongqiang A. Wang, Haiyen E. Zhau, Leland W.K. Chung, Chad Ritenour, Omer Kucuk, Daqing Wu

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1469-1479
Number of pages11
JournalJournal of Biological Chemistry
Volume288
Issue number3
DOIs
StatePublished - Jan 18 2013

Fingerprint

Epithelial-Mesenchymal Transition
Epidermal Growth Factor
Proteolysis
Neoplasm Metastasis
Degradation
Prostatic Neoplasms
Neoplasms
Proteins
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Phosphorylation
Serine
Ubiquitination
Point Mutation
Refractory materials
Tumors
Theoretical Models

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Epidermal growth factor promotes protein degradation of epithelial protein lost in neoplasm (EPLIN), a putative metastasis suppressor, during epithelial-mesenchymal transition. / Zhang, Shumin; Wang, Xu; Iqbal, Shareen; Wang, Yanru; Osunkoya, Adeboye O.; Chen, Zhengjia; Chen, Zhuo; Shin, Dong M.; Yuan, Hongwei; Wang, Yongqiang A.; Zhau, Haiyen E.; Chung, Leland W.K.; Ritenour, Chad; Kucuk, Omer; Wu, Daqing.

In: Journal of Biological Chemistry, Vol. 288, No. 3, 18.01.2013, p. 1469-1479.

Research output: Contribution to journalArticle

Zhang, S, Wang, X, Iqbal, S, Wang, Y, Osunkoya, AO, Chen, Z, Chen, Z, Shin, DM, Yuan, H, Wang, YA, Zhau, HE, Chung, LWK, Ritenour, C, Kucuk, O & Wu, D 2013, 'Epidermal growth factor promotes protein degradation of epithelial protein lost in neoplasm (EPLIN), a putative metastasis suppressor, during epithelial-mesenchymal transition', Journal of Biological Chemistry, vol. 288, no. 3, pp. 1469-1479. https://doi.org/10.1074/jbc.M112.438341
Zhang, Shumin ; Wang, Xu ; Iqbal, Shareen ; Wang, Yanru ; Osunkoya, Adeboye O. ; Chen, Zhengjia ; Chen, Zhuo ; Shin, Dong M. ; Yuan, Hongwei ; Wang, Yongqiang A. ; Zhau, Haiyen E. ; Chung, Leland W.K. ; Ritenour, Chad ; Kucuk, Omer ; Wu, Daqing. / Epidermal growth factor promotes protein degradation of epithelial protein lost in neoplasm (EPLIN), a putative metastasis suppressor, during epithelial-mesenchymal transition. In: Journal of Biological Chemistry. 2013 ; Vol. 288, No. 3. pp. 1469-1479.
@article{baccfcfd80fd46308195bedc47bbb72c,
title = "Epidermal growth factor promotes protein degradation of epithelial protein lost in neoplasm (EPLIN), a putative metastasis suppressor, during epithelial-mesenchymal transition",
abstract = "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.",
author = "Shumin Zhang and Xu Wang and Shareen Iqbal and Yanru Wang and Osunkoya, {Adeboye O.} and Zhengjia Chen and Zhuo Chen and Shin, {Dong M.} and Hongwei Yuan and Wang, {Yongqiang A.} and Zhau, {Haiyen E.} and Chung, {Leland W.K.} and Chad Ritenour and Omer Kucuk and Daqing Wu",
year = "2013",
month = "1",
day = "18",
doi = "10.1074/jbc.M112.438341",
language = "English (US)",
volume = "288",
pages = "1469--1479",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "3",

}

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.

UR - http://www.scopus.com/inward/record.url?scp=84872715614&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84872715614&partnerID=8YFLogxK

U2 - 10.1074/jbc.M112.438341

DO - 10.1074/jbc.M112.438341

M3 - Article

C2 - 23188829

AN - SCOPUS:84872715614

VL - 288

SP - 1469

EP - 1479

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 3

ER -