2024-03-29T14:36:36Zhttps://eprints.lib.hokudai.ac.jp/dspace-oai/requestoai:eprints.lib.hokudai.ac.jp:2115/473842022-11-17T02:08:08Zhdl_2115_20040hdl_2115_121Engagement of Overexpressed Her2 with GEP100 Induces Autonomous Invasive Activities and Provides a Biomarker for Metastases of Lung AdenocarcinomaMenju, ToshiHashimoto, ShigeruHashimoto, AriOtsuka, YutaroHanda, HarukaOgawa, EijiToda, YoshinobuWada, HiromiDate, HiroshiSabe, Hisataka494Overexpression 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.Public Library of ScienceJournal Articleapplication/pdfhttp://hdl.handle.net/2115/47384https://eprints.lib.hokudai.ac.jp/dspace/bitstream/2115/47384/1/PLosOne6-9_e25301.pdf1932-6203PLoS One69e253012011-09-22enginfo:doi/10.1371/journal.pone.0025301http://creativecommons.org/licenses/by/3.0/publisher