RRC ID 68642
Author Menju T, Hashimoto S, Hashimoto A, Otsuka Y, Handa H, Ogawa E, Toda Y, Wada H, Date H, Sabe H.
Title Engagement of overexpressed Her2 with GEP100 induces autonomous invasive activities and provides a biomarker for metastases of lung adenocarcinoma.
Journal PLoS One
Abstract Overexpression of Her2/ErbB2/Neu in cancer is often correlated with recurrent distant metastasis, although the mechanism still remains largely elusive. We have previously shown that EGFR, when tyrosine-phosphorylated, binds to GEP100/BRAG2 to activate Arf6, which induces cancer invasion and metastasis. We now show that overexpressed Her2 in lung adenocarcinoma cells also employs GEP100. Like EGFR-GEP100 binding, this association is primarily mediated by the pleckstrin homology (PH) domain of GEP100 and Tyr1139/Tyr1196 of Her2. Tyr1139/Tyr1196 are autonomously phosphorylated, when Her2 is overexpressed. Accordingly, invasive activities mediated by the Her2-GEP100 pathway are not dependent on external factors. Blocking Her2-GEP100 binding, as well as its signaling pathway all inhibit cancer invasive activities. Moreover, our clinical study indicates that co-overexpression of Her2 with GEP100 in primary lung adenocarcinomas of patients is correlated with the presence of their node-metastasis with a statistical significance. Since the GEP100 PH domain interacts with both Her2 and EGFR, targeting this domain may provide novel cancer therapeutics.
Volume 6(9)
Pages e25301
Published 2011-1-1
DOI 10.1371/journal.pone.0025301
PII PONE-D-11-07424
PMID 21966491
PMC PMC3178645
MeSH Adaptor Proteins, Vesicular Transport / genetics Adaptor Proteins, Vesicular Transport / metabolism Adenocarcinoma / genetics Adenocarcinoma / metabolism* Adenocarcinoma of Lung Cell Line GTPase-Activating Proteins / genetics GTPase-Activating Proteins / metabolism Glutathione Transferase / genetics Glutathione Transferase / metabolism Guanine Nucleotide Exchange Factors / genetics Guanine Nucleotide Exchange Factors / metabolism* Humans Immunoblotting Immunohistochemistry Immunoprecipitation In Vitro Techniques Lung Neoplasms / genetics Lung Neoplasms / metabolism* Neoplasm Metastasis / diagnosis* Neoplasm Metastasis / genetics* Protein Binding RNA Interference Receptor, ErbB-2 / genetics Receptor, ErbB-2 / metabolism*
IF 2.74
Human and Animal Cells Lu99(RCB1900) PC-9(RCB4455)