https://scholars.lib.ntu.edu.tw/handle/123456789/564350
標題: | Oncogenic Shp2 disturbs microtubule regulation to cause HDAC6-dependent ERK hyperactivation | 作者: | Tien S.-C. ZEE-FEN CHANG |
關鍵字: | ERK; HDAC6; microtubule acetylation; Shp2 | 公開日期: | 2014 | 出版社: | Nature Publishing Group | 卷: | 33 | 期: | 22 | 起(迄)頁: | 2938-2946 | 來源出版物: | Oncogene | 摘要: | Deregulation of Shp2, a non-receptor tyrosine phosphatase, causes hyperactivation of extracellular signal-regulated kinase (ERK), leading to growth abnormality. Here, we show that inhibition of RhoA-Dia is sufficient to upregulate ERK activation in epithelial cells. Oncogenic Shp2 expression attenuates RhoA-Dia signaling, by which microtubule (MT) is destabilized with reduced level of acetylation. Either MT stabilization, silencing of histone deacetylase 6 (HDAC6) or enforcing RhoA-Dia signal prevents oncogenic Shp2-induced ERK hyperactivation. We provide evidence that downregulation of RhoA-Dia-EB1 pathway by oncogenic Shp2 leads to HDAC6-mediated reduction in MT acetylation, in turn affecting ERK regulation. In response to serum stimulation, cells expressing wild-type Shp2 display transient ERK activation. In contrast, cells expressing oncogenic Shp2 have prolonged ERK activation. HDAC6 inhibition diminishes sustained activation of ERK and slows down the growth of these cells. Likewise, in human cancer cells, blocking Shp2 increases MT acetylation and decreases ERK phosphorylation, which are reversed by inhibition of Dia. As such, HDAC6 inhibition in these cells also reduces ERK activity. Our findings link MT regulation by HDAC6 to oncogenic Shp2 and ERK regulation, implicating the therapeutic potential of HDAC6 inhibitor in diseases involving Shp2 deregulation. ? 2014 Macmillan Publishers Limited All rights reserved. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84901841998&doi=10.1038%2fonc.2013.241&partnerID=40&md5=59269bbdfabb27c91629fb9739eacc71 https://scholars.lib.ntu.edu.tw/handle/123456789/564350 |
ISSN: | 0950-9232 | DOI: | 10.1038/onc.2013.241 | SDG/關鍵字: | histone deacetylase 6; mitogen activated protein kinase; protein tyrosine phosphatase SHP 1; acetylation; animal cell; article; controlled study; down regulation; enzyme activation; enzyme inhibition; microtubule; nonhuman; priority journal; protein expression; protein phosphorylation; upregulation; Acetylation; Animals; Cell Line; Cell Line, Tumor; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Gene Silencing; Histone Deacetylases; Humans; Microtubules; Neoplasms; Protein Stability; Protein Tyrosine Phosphatase, Non-Receptor Type 11; rhoA GTP-Binding Protein; Signal Transduction |
顯示於: | 分子醫學研究所 |
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