Systems Biology Ireland, University College Dublin, Dublin 4, Ireland.
1] Systems Biology Ireland, University College Dublin, Dublin 4, Ireland [2] Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Dublin 4, Ireland [3] School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland [4].
Nat Cell Biol. 2014 Jul;16(7):673-84. doi: 10.1038/ncb2986. Epub 2014 Jun 15.
Signal transduction requires the coordination of activities between different pathways. In mammalian cells, Raf-1 regulates the MST-LATS and MEK-ERK pathways. We found that a complex circuitry of competing protein interactions coordinates the crosstalk between the ERK and MST pathways. Combining mathematical modelling and experimental validation we show that competing protein interactions can cause steep signalling switches through phosphorylation-induced changes in binding affinities. These include Akt phosphorylation of MST2 and a feedback phosphorylation of Raf-1 Ser 259 by LATS1, which enables Raf-1 to suppress both MST2 and MEK signalling. Mutation of Raf-1 Ser 259 stimulates both pathways, simultaneously driving apoptosis and proliferation, whereas concomitant MST2 downregulation switches signalling to cell proliferation, transformation and survival. Thus, competing protein interactions provide a versatile regulatory mechanism for signal distribution through the dynamic integration of graded signals into switch-like responses.
信号转导需要不同途径之间的活动协调。在哺乳动物细胞中，Raf-1 调节 MST-LATS 和 MEK-ERK 途径。我们发现，竞争蛋白相互作用的复杂电路协调了 ERK 和 MST 途径之间的串扰。通过结合数学建模和实验验证，我们表明竞争蛋白相互作用可以通过磷酸化诱导的结合亲和力变化引起陡峭的信号开关。其中包括 Akt 对 MST2 的磷酸化和 LATS1 对 Raf-1 Ser259 的反馈磷酸化，这使 Raf-1 能够抑制 MST2 和 MEK 信号。Raf-1 Ser259 的突变同时激活两条途径，同时驱动细胞凋亡和增殖，而 MST2 的下调则将信号切换为细胞增殖、转化和存活。因此，竞争蛋白相互作用为通过将分级信号动态整合到开关样反应中来分配信号提供了一种灵活的调节机制。
