title: Engagement of overexpressed Her2 with GEP100 induces autonomous invasive activities and provides a biomarker for metastases of lung adenocarcinoma.
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.
authors.affiliation: Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Toshi
authors.initials: T
authors.lastname: Menju
authors.forename: Shigeru
authors.initials: S
authors.lastname: Hashimoto
authors.forename: Ari
authors.initials: A
authors.lastname: Hashimoto
authors.forename: Yutaro
authors.initials: Y
authors.lastname: Otsuka
authors.forename: Haruka
authors.initials: H
authors.lastname: Handa
authors.forename: Eiji
authors.initials: E
authors.lastname: Ogawa
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Toda
authors.forename: Hiromi
authors.initials: H
authors.lastname: Wada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Date
authors.forename: Hisataka
authors.initials: H
authors.lastname: Sabe
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism*; D000077192:Adenocarcinoma of Lung; D002460:Cell Line; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis / Q000175:diagnosis* / Q000235:genetics*; D011485:Protein Binding; D034622:RNA Interference; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D020690:GTPase-Activating Proteins; D005982:Glutathione Transferase; D020662:Guanine Nucleotide Exchange Factors; D018719:Erb-b2 Receptor Tyrosine Kinases; C407306:GGA adaptor proteins; C504483:IQSEC1 protein, human; C102474:cytohesin-2; C508053:ERBB2 protein, human