2010年8月24日，哈佛医学院和美国Cell Signaling Technology公司和联合发表Science Signaling文章。该文章探索受体酪氨酸激酶（RTKs）通过PI3K-Akt，Ras-MAPK-RSK，以及mTOR-p70 S6等丝氨酸苏氨酸激酶信号通路在控制细胞生长，增殖和生存等方面发挥重要作用。
Akt，RSK，p70 S6家族的蛋白激酶通过磷酸化底物蛋白的RxRxxS/T基序传递信号。此项研究制定了一种大规模的蛋白质组学方法，可以鉴定出肿瘤细胞系中c-Met，表皮生长因子受体（EGFR），或血小板衍生生长因子受体α（PDGFRα）等受体酪氨酸激酶的300多种底物。该确定了一组具有RxRxxS/T位点的蛋白，这类蛋白的磷酸化可以被RTK抑制剂（RTKIs）减弱，当然也可以被PI3K，mTOR，和MAPK通路抑制剂减弱；又进一步通过RNA干扰的方法确定了这些蛋白对细胞活力的影响。在PDGFRα依赖的癌细胞中，蛋白质分子伴侣SGTA (small glutamine-rich tetratricopeptide repeat-containing protein α) 305位点丝氨酸的磷酸化对PDGFRα的稳定和细胞存活是必要的。该方法给RTK和Akt-RSK-S6激酶信号通路提供了新的视野，揭示了以前未确认的Akt-RSK-S6激酶的底物，这些底物值得作为RTKIs联合治疗靶点进一步研究。（生物谷Bioon.com）
生物谷推荐英文摘要：
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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