2010年8月24日,，哈佛醫(yī)學(xué)院和美國(guó)Cell Signaling Technology公司和聯(lián)合發(fā)表Science Signaling文章,。該文章探索受體酪氨酸激酶（RTKs）通過(guò)PI3K-Akt,，Ras-MAPK-RSK,，以及mTOR-p70 S6等絲氨酸蘇氨酸激酶信號(hào)通路在控制細(xì)胞生長(zhǎng),，增殖和生存等方面發(fā)揮重要作用,。
Akt，RSK,，p70 S6家族的蛋白激酶通過(guò)磷酸化底物蛋白的RxRxxS/T基序傳遞信號(hào),。此項(xiàng)研究制定了一種大規(guī)模的蛋白質(zhì)組學(xué)方法，可以鑒定出腫瘤細(xì)胞系中c-Met,，表皮生長(zhǎng)因子受體（EGFR）,，或血小板衍生生長(zhǎng)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(diǎn)的蛋白,，這類(lèi)蛋白的磷酸化可以被RTK抑制劑（RTKIs）減弱,，當(dāng)然也可以被PI3K，mTOR,，和MAPK通路抑制劑減弱,；又進(jìn)一步通過(guò)RNA干擾的方法確定了這些蛋白對(duì)細(xì)胞活力的影響。在PDGFRα依賴(lài)的癌細(xì)胞中,，蛋白質(zhì)分子伴侶SGTA (small glutamine-rich tetratricopeptide repeat-containing protein α) 305位點(diǎn)絲氨酸的磷酸化對(duì)PDGFRα的穩(wěn)定和細(xì)胞存活是必要的,。該方法給RTK和Akt-RSK-S6激酶信號(hào)通路提供了新的視野，揭示了以前未確認(rèn)的Akt-RSK-S6激酶的底物,，這些底物值得作為RTKIs聯(lián)合治療靶點(diǎn)進(jìn)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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