Science Signaling:致癌受體RTKs激活信號通路作用研究新進展

2010年8月24日，哈佛醫學院和美國Cell Signaling Technology公司和聯合發表Science Signaling文章。該文章探索受體酪氨酸激酶（RTKs）通過PI3K-Akt，Ras-MAPK-RSK，以及mTOR-p70 S6等絲氨酸蘇氨酸激酶信號通路在控制細胞生長，增殖和生存等方面發揮重要作用。

Akt，RSK，p70 S6家族的蛋白激酶通過磷酸化底物蛋白的RxRxxS/T基序傳遞信號。此項研究制定了一種大規模的蛋白質組學方法，可以鑑定出腫瘤細胞系中c-Met，表皮生長因子受體（EGFR），或血小板衍生生長因子受體α（PDGFRα）等受體酪氨酸激酶的300多種底物。該確定了一組具有RxRxxS/T位點的蛋白，這類蛋白的磷酸化可以被RTK抑制劑（RTKIs）減弱，當然也可以被PI3K，mTOR，和MAPK通路抑制劑減弱；又進一步通過RNA幹擾的方法確定了這些蛋白對細胞活力的影響。在PDGFRα依賴的癌細胞中，蛋白質分子伴侶SGTA (small glutamine-rich tetratricopeptide repeat-containing protein α) 305位點絲氨酸的磷酸化對PDGFRα的穩定和細胞存活是必要的。該方法給RTK和Akt-RSK-S6激酶信號通路提供了新的視野，揭示了以前未確認的Akt-RSK-S6激酶的底物，這些底物值得作為RTKIs聯合治療靶點進一步研究。（生物谷Bioon.com）

生物谷推薦英文摘要：

Science Signaling  DOI: 10.1126/scisignal.2000998

Akt-RSK-S6 Kinase Signaling Networks Activated by Oncogenic Receptor Tyrosine Kinases
Albrecht Moritz, Yu Li, Ailan Guo, Judit Villén, Yi Wang, Joan MacNeill, Jon Kornhauser, Kam Sprott, Jing Zhou, Anthony Possemato, Jian Min Ren, Peter
Hornbeck, Lewis C. Cantley, Steven P. Gygi, John Rush and Michael J. Comb

Receptor tyrosine kinases (RTKs) activate pathways mediated by serine-threonine kinases, such as thePI3K (phosphatidylinositol 3-kinase)-Akt pathway, the Ras-MAPK (mitogen-activated protein kinase)-RSK (ribosomal S6 kinase) pathway, and the mTOR (mammalian target of rapamycin)-p70 S6 pathway, that control important aspects of cell growth, proliferation, and survival. The Akt, RSK, and p70 S6 family of protein kinases transmit signals by phosphorylating substrates on an RxRxxS/T motif (R, arginine; S, serine; T, threonine; and x, any amino acid).We developed a large-scale proteomic approach to identify more than 300 substrates of this kinase family in cancer cell lines driven by the c-Met, epidermal growth factor receptor (EGFR), or platelet-derived growth factor receptor a (PDGFRa) RTKs. We identified a subset of proteins with RxRxxS/T sites for which phosphorylation was decreased by RTK inhibitors (RTKIs),as well as by inhibitors of the PI3K, mTOR, and MAPK pathways, and we determined the effects of smallinterfering RNA directed against these substrates on cell viability. Phosphorylation of the protein chaperone SGTA (small glutamine-rich tetratricopeptide repeat-containing protein a) at serine-305 was essential for PDGFRa stabilization and cell survival in PDGFR a-dependent cancer cells. Our approach provides a new view of RTK and Akt-RSK-S6 kinase signaling, revealing previously unidentified Akt-RSK-S6 kinase substrates that merit further consideration as targets for combination therapy with RTKIs.

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會議推薦：

會議時間：2011年6月3日~6月5日
會議地點：同濟大學逸夫樓
主辦單位：華東幹細胞庫 中國細胞生物學學會幹細胞生物學分會 中科院幹細胞庫 北方幹細胞庫 南方幹細胞庫
承辦單位： 生物谷 再生泉