Paxillin serine 178 phosphorylation in control of cell migration and metastasis formation through regulation of EGFR expression in breast cancer

作     者：Saertje Verkoeijen Ya-Feng Ma Wies van Roosmalen Reshma Lalai Martine H.A.M.van Miltenburg Marjo de Graauw Bob van de Water Sylvia E.Le Dévédec 

作者机构：Institute for Life Sciences&ChemistryHogeschool Utrecht HUUtrecht 3501 AAthe Netherlands Division of Drug Discovery and SafetyLeiden Academic Centre for Drug ResearchLeiden UniversityLeiden 2300 RAthe Netherlands 

出 版 物：《Journal of Cancer Metastasis and Treatment》 (癌症转移与治疗（英文版）)

年 卷 期：2019年第4卷第6期

页      面：71-86页

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：the EU FP7 Metafight project(HEALTH-F2-2007-201862) Dutch Cancer Society(KWF-UL2007-3860) NWO grant(911-02-022) 

主　　题：Paxillin c-Jun NH2-terminal kinase focal adhesion epidermal growth factor receptor cell migration metastasis breast cancer 

摘      要：Aim:Paxillin is a well-known multidomain scaffold protein that is involved in the regulation of cell-matrix adhesion dynamics,a process required for the tumor cell migration and *** of the serine residue 178 requires c-Jun NH2-terminal kinase(JNK)activation,which occurs downstream of epidermal growth factor receptor(EGFR)-mediated signaling and drives cell *** this study,we investigated the significance of paxillin Ser178 phosphorylation in breast cancer ***:We employed the rat mammary carcinoma MTLn3 cell line with which we established stabile variants of both wild type and mutant GFP-paxillin *** those,we next performed several in vitro assays including cell proliferation,migration and focal adhesion ***,we monitored the metastatic spread of both cell line variants in an othrotopic mouse model for breast ***:Here we show that expression of the phospho-defective mutant paxillinS178A in the metastatic mammary adenocarcinoma MTLn3 cell-line significantly decreased EGF-induced cell migration,which was correlated with impaired focal adhesion ***,paxillinS178A attenuated lung metastasis formation in an orthotopic in vivo mammary gland tumor/metastasis model,demonstrating the importance of JNK-mediated paxillin phosphorylation in breast cancer *** of paxillinS178A caused a decrease in EGFR expression, ;while re-expression of EGFR in MTLn3-paxillinS178A cells fully restored EGF-driven cell motility and focal adhesion ***,re-expression of EGFR in MTLn3-paxillinS178A rescued spontaneous metastasis from breast to ***:Overall our data show an important role for JNK-mediated paxillin Ser178 phosphorylation in the regulation of EGFR expression and thereby,in EGF-driven cell migration and metastasis formation.