Expression screening of 17q12–21 amplicon reveals GRB7 as an ERBB2-dependent oncogene

► We established an integrated analysis system of amplicons. ► Applying this system to 17q12–21 amplicon, we identified GRB7 as an ERBB2-dependent oncogene. ► GRB7 modulates the ERBB2 signaling pathway through enhanced phosphorylation of ERBB2 and Akt. ► BPS domain of GRB7 suppresses, while, the oth...

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Published in:	FEBS letters Vol. 586; no. 12; pp. 1708 - 1714
Main Authors:	Saito, Makoto, Kato, Yukiko, Ito, Emi, Fujimoto, Jiro, Ishikawa, Kosuke, Doi, Ayano, Kumazawa, Kentaro, Matsui, Atsuka, Takebe, Shiori, Ishida, Takaomi, Azuma, Sakura, Mochizuki, Hiromi, Kawamura, Yoshifumi, Yanagisawa, Yuka, Honma, Reiko, Imai, Jun-ichi, Ohbayashi, Hirokazu, Goshima, Naoki, Semba, Kentaro, Watanabe, Shinya
Format:	Journal Article
Language:	English
Published:	England Elsevier B.V 12-06-2012
Subjects:	Animals Cell Transformation, Neoplastic - genetics Chromosomes, Human, Pair 17 - genetics CMV cytomegalovirus Down-Regulation ERBB2 ERK Expression screening extracellular signal-regulated kinase Gene Amplification GRB7 GRB7 Adaptor Protein - genetics GRB7 Adaptor Protein - metabolism growth factor receptor-bound protein 7 Humans IGF1 insulin-like growth factor-1 MAPK MAPK extracellular signal-regulated kinase MEK Mice mitogen-activated protein kinase MMTV mouse mammary tumor virus Mutagenesis NIH 3T3 Cells Phosphorylation Point Mutation Protein Processing, Post-Translational Protein Structure, Tertiary - genetics Proto-Oncogene Proteins c-akt - metabolism Proto-Oncogenes Receptor, ErbB-2 - genetics Receptor, ErbB-2 - metabolism Recombinant Proteins - genetics Recombinant Proteins - metabolism Sequence Deletion Signal Transduction Tumorigenesis v-erb-b2 erythroblastic leukemia viral oncogene homolog GRB7 Expression screening MEK Gene amplification MMTV ERBB2 Tumorigenesis IGF1 MAPK CMV ERK
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Summary:	► We established an integrated analysis system of amplicons. ► Applying this system to 17q12–21 amplicon, we identified GRB7 as an ERBB2-dependent oncogene. ► GRB7 modulates the ERBB2 signaling pathway through enhanced phosphorylation of ERBB2 and Akt. ► BPS domain of GRB7 suppresses, while, the other domains are required for GRB7-mediated transforming activity. Gene amplification is a major genetic alteration in human cancers. Amplicons, amplified genomic regions, are believed to contain “driver” genes responsible for tumorigenesis. However, the significance of co-amplified genes has not been extensively studied. We have established an integrated analysis system of amplicons using retrovirus-mediated gene transfer coupled with a human full-length cDNA set. Applying this system to 17q12–21 amplicon observed in breast cancer, we identified GRB7 as a context-dependent oncogene, which modulates the ERBB2 signaling pathway through enhanced phosphorylation of ERBB2 and Akt. Our work provides an insight into the biological significance of gene amplification in human cancers.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0014-5793 1873-3468
DOI:	10.1016/j.febslet.2012.05.003