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How do cells shape and interpret PIP3 signals?

细胞如何塑造和解释 PIP3 信号？

基本信息

批准号：
BB/I003428/1
负责人：
Nicolas Le Novere
金额：
$ 47.19万
依托单位：
European Bioinformatics Institute
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2011
资助国家：
英国
起止时间：
2011 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FI003428%2F1
关键词：
How do cells shape interpret

项目摘要

Multi-cellular organisms rely on a large array of different transmitter substances to allow certain cells to control the behavior of others. The more sophisticated the organism the more complex the cell to cell communication. In mammals this language probably involves hundreds of fundamentally different types of transmitter. Clearly such systems need a large collection of specialized receptor molecules that can detect the individual presence of any particular transmitter. Further, these receptors, typically found on the outer surface of the cell's limiting membrane, have to signal their specific stimulation by passing a molecular message into the cells interior, effectively informing the cell that the receptor has been activated. Clearly, if a cell has many different types of receptors on its surface the molecular signal generated inside the cell by each different receptor (often called an intracellular message) must identify and distinguish which specific receptor has been stimulated. Otherwise the cell could not discriminate between the transmitters present on the outside of the cell and could not respond correctly. Hence, mammalian cells have vastly complex intracellular signalling mechanisms continuously informing the cell of what is happening in other parts of the organism or its environment. One such intracellular signalling molecule or 'message' is PIP3. It is a phospholipid molecule found on the inside surface of the cell's limiting membrane. Levels of PIP3 rise rapidly on activation of a large number of receptors. This is surprising given the problems the cell faces in knowing precisely which receptor has been activated when it detects an intracellular signal. This grant application is to understand how it is possible that rises in PIP3 can encode specific messages from so many different receptors. We have performed some experiments that have, in fact, shown that PIP3 in cells is not a single type of molecule. At least four tiny variants of PIP3 can be detected, called molecular species of PIP3. Interestingly, we find that these different molecular species of PIP3 do not respond equivalently to different ways of activating the cells we work with. We and others have also found that the different receptors can make the levels of PIP3 rise for different times and to different maximum levels. We propose that these small differences are very important inside the cell for discriminating whether a certain receptor has been stimulated. This is a 'clever' economy or efficiency on the part of the cell and allows it to use similar mechanisms to perform many different jobs. Although on the surface these might appear trivial details in the business of understanding biology, it has recently been discovered that many different cancers are caused by mutations in genes that regulate PIP3 levels in cells. Mutations that by chance cause the production of PIP3 to be increased without any need for receptor stimulation make cancers much more likely to occur. Mutations that by chance stop the enzymes that normally break down PIP3 from working also make cancer more likely to occur. As a result it is clear that understanding how PIP3 is made and then interpreted by cells is crucial for us to better understand how cancer occurs and how to treat it. Many companies are already trying to design drugs that will reduce PIP3 levels to fight cancer. This work will help us understand how to make better drugs of that type.

多细胞生物体依赖于大量不同的递质物质，以允许某些细胞控制其他细胞的行为。有机体越复杂，细胞间的通讯就越复杂。在哺乳动物中，这种语言可能涉及数百种基本上不同类型的传输器。显然，这样的系统需要大量的专门受体分子，以检测任何特定递质的个体存在。此外，这些受体通常存在于细胞界膜的外表面上，必须通过将分子信息传递到细胞内部来发出其特异性刺激的信号，有效地通知细胞受体已被激活。显然，如果细胞表面有许多不同类型的受体，细胞内由每种不同受体产生的分子信号（通常称为细胞内信息）必须识别和区分哪种特定受体受到刺激。否则，细胞无法区分细胞外部的发射器，无法正确响应。因此，哺乳动物细胞具有非常复杂的细胞内信号传导机制，不断地向细胞通知生物体其他部分或其环境中发生的事情。一种这样的细胞内信号传导分子或“信息”是PIP3。它是在细胞界膜内表面发现的磷脂分子。PIP3的水平在大量受体活化时迅速升高。这是令人惊讶的，因为当细胞检测到细胞内信号时，它面临着准确知道哪个受体被激活的问题。这项拨款申请是为了了解PIP3的上升如何可能编码来自如此多不同受体的特定信息。事实上，我们已经进行了一些实验，表明细胞中的PIP3不是单一类型的分子。至少可以检测到PIP3的四种微小变体，称为PIP3的分子种类。有趣的是，我们发现这些不同的PIP3分子种类对我们所研究的细胞的不同激活方式的反应并不相同。我们和其他人还发现，不同的受体可以使PIP3水平升高不同的时间和不同的最大水平。我们认为，这些微小的差异在细胞内对于区分某个受体是否被刺激是非常重要的。这是一个“聪明”的经济或效率的一部分，细胞，并允许它使用类似的机制来执行许多不同的工作。虽然从表面上看，这些在理解生物学方面可能显得微不足道，但最近发现，许多不同的癌症是由调节细胞中PIP3水平的基因突变引起的。偶然导致PIP3产生增加而不需要任何受体刺激的突变使癌症更容易发生。偶然阻止通常分解PIP3的酶工作的突变也使癌症更容易发生。因此，很明显，了解PIP3是如何产生的，然后由细胞解释，对于我们更好地了解癌症是如何发生的以及如何治疗它是至关重要的。许多公司已经在尝试设计药物，将降低PIP3水平来对抗癌症。这项工作将帮助我们了解如何制造更好的药物。