The re-modelling of mRNPs and the regulation of localised mRNA translation during mammalian cell attachment and spreading

在细胞迁移过程中，存储在遗传物质（DNA）中的关键信息必须由细胞解码，以便在适当的数量、地点和时间内产生各种各样的蛋白质，以允许这一过程发生；肿瘤细胞常常会出错！从DNA到蛋白质的一般信息传递是由信使RNA （mRNA）完成的，信使RNA是DNA序列的副本。这种mRNA必须通过一种复杂的、高度调控的机器——核糖体——解码成蛋白质，这个过程被称为翻译。为了高效、准确地工作，并使核糖体在细胞的最佳利益中发挥作用，这一机制需要相互作用的辅助蛋白（翻译起始因子；eIF），并确保mRNA和核糖体结合成一个高度调节的大型起始复合物，以制造所需的蛋白质。那么细胞是如何控制的呢？起始因子本身的相互作用是哺乳动物细胞调控的主要部位。调控蛋白，如4E-BP1和CYFIP，阻止eIF4E与支架蛋白eIF4G的相互作用，停止mRNA向核糖体的募集，停止蛋白质合成。当需要蛋白质合成时，细胞发出信号，从被抑制的复合物中释放eIF4E/mRNA，使其在需要的时间和地点发挥作用。然而，我们仍然不知道细胞是如何控制在细胞扩散和迁移过程中蛋白质合成被激活的确切位置的。通过使用专门的显微镜技术“观察”细胞内部，我们知道起始因子和它们的调节蛋白在细胞移动的方向上被分散地定位在细胞边缘；它们不只是漂浮着。在这里描述的工作中，我们想要研究细胞用来调节局部蛋白质合成的特殊信号的性质，观察在这些位点发现的蛋白质和mRNA的复合物，并了解mRNA的哪些部分对细胞边缘的这些mRNA结合蛋白有吸引力。这些研究将大大增加我们对控制蛋白质合成在调节细胞生长和迁移中的重要性的总体理解，为控制已经获得在体内移动能力的癌细胞开辟了新的潜在途径。

During cell migration, critical information stored in the genetic material (DNA) has to be decoded by the cell to produce a wide variety of proteins in the right amount, place and time to allow for this process occur; tumour cells often get this wrong! The general transfer of information from DNA to protein is carried out by the messenger RNA (mRNA), which is a copy of the DNA sequence. This mRNA has to be decoded into protein by a complex, highly regulated machine termed a ribosome, in a process known as translation. To work efficiently, accurately, and to allow the ribosome to function in the best interests of the cell, this machinery requires helper proteins (translation initiation factors; eIF) that interact with each other, and also make sure that the mRNA and the ribosome come together into a highly regulated, large initiation complex to make the proteins required. So how does the cell control this? The interaction of the initiation factors themselves is a major site for regulation in mammalian cells. Regulatory proteins, such as 4E-BP1 and CYFIP, prevent the interaction of eIF4E with the scaffold protein, eIF4G, and stop the recruitment of mRNA to the ribosome and halt protein synthesis. When protein synthesis is needed, the cell signals for the release the eIF4E/mRNA from the inhibited complex to let it work when and where it is needed. However, we still do not know how the cell controls exactly where protein synthesis is activated in cells which are in the process of spreading and migrating. From "looking" inside the cell with specialised microscopy techniques, we know that the initiation factors and their regulatory proteins are discretely localised to the edge of cells in the direction that they are moving; they are not just floating about. In the work described here we want to investigate the nature of the specialised signals used by the cell to regulate localised protein synthesis, look at the complexes of proteins and mRNA found at such sites and understand what parts of the mRNA make it attractive to these mRNA binding proteins at the edge of cells.These studies will substantially increase our general understanding of the significance of the control of protein synthesis in the regulation of cell growth and migration, opening up new potential avenues for controlling cancer cells which have acquired the ability to move about the body.