How do cells shape and interpret PIP3 signals?

细胞如何塑造和解释 PIP3 信号？

• 批准号: BB/I003916/1
• 负责人: Len Stephens
• 金额: $ 138.44万
• 依托单位: Babraham 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%2FI003916%2F1
• 关键词: How; do; cells; shape; interpret

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.

多细胞生物体依靠大量不同的递质物质来允许某些细胞控制其他细胞的行为。生物体越复杂，细胞间的交流就越复杂。在哺乳动物中，这种语言可能涉及数百种根本不同类型的传递器。显然，这样的系统需要大量专门的受体分子来检测任何特定递质的单独存在。此外，这些受体通常位于细胞限制膜的外表面，必须通过将分子信息传递到细胞内部来发出特定刺激的信号，从而有效地通知细胞受体已被激活。显然，如果一个细胞表面有许多不同类型的受体，每个不同受体在细胞内产生的分子信号(通常被称为细胞内信息)必须识别和区分哪个特定的受体受到了刺激。否则，细胞不能区分细胞外部的发射器，也不能正确地作出反应。因此，哺乳动物细胞具有极其复杂的细胞内信号机制，不断地告知细胞在有机体的其他部分或其环境中正在发生的事情。PIP3就是一种这样的细胞内信号分子或“消息”。它是一种磷脂分子，位于细胞限制膜的内表面。随着大量受体的激活，PIP3水平迅速上升。考虑到细胞在检测到细胞内信号时准确知道哪个受体被激活所面临的问题，这是令人惊讶的。这项授权申请是为了了解PIP3中的RISS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。至少可以检测到四种PIP3的微小变体，称为PIP3的分子物种。有趣的是，我们发现这些不同的PIP3分子物种对激活我们工作的细胞的不同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水平在不同的时间和不同的最高水平上升。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受到刺激非常重要。这是一个“聪明的”经济或效率的细胞部分，并允许它使用类似的机制来执行许多不同的工作。尽管从表面上看，这些在理解生物学的行业中似乎是微不足道的细节，但最近人们发现，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。在不需要任何受体刺激的情况下，偶然导致PIP3产生增加的突变使癌症发生的可能性更大。意外地阻止正常情况下分解PIP3的酶发挥作用的突变也会使癌症更有可能发生。因此，很明显，了解PIP3是如何产生并被细胞解释的，对于我们更好地了解癌症是如何发生以及如何治疗至关重要。许多公司已经在尝试设计降低PIP3水平的药物来抗击癌症。这项工作将帮助我们了解如何制造更好的那种药物。

项目成果

Quantification of PtdInsP3 molecular species in cells and tissues by mass spectrometry.

• DOI: 10.1038/nmeth.1564
• 发表时间: 2011-03
• 期刊: NATURE METHODS
• 影响因子: 48
• 作者: Clark, Jonathan;Anderson, Karen E.;Juvin, Veronique;Smith, Trevor S.;Karpe, Fredrik;Wakelam, Michael J. O.;Stephens, Len R.;Hawkins, Phillip T.
• 通讯作者: Hawkins, Phillip T.

Signaling via class IA Phosphoinositide 3-kinases (PI3K) in human, breast-derived cell lines.

• DOI: 10.1371/journal.pone.0075045
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Juvin V;Malek M;Anderson KE;Dion C;Chessa T;Lecureuil C;Ferguson GJ;Cosulich S;Hawkins PT;Stephens LR
• 通讯作者: Stephens LR

Lysophosphatidylinositol-acyltransferase-1 (LPIAT1) is required to maintain physiological levels of PtdIns and PtdInsP(2) in the mouse.

• DOI: 10.1371/journal.pone.0058425
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Anderson KE;Kielkowska A;Durrant TN;Juvin V;Clark J;Stephens LR;Hawkins PT
• 通讯作者: Hawkins PT

Perturbations of PIP3 signalling trigger a global remodelling of mRNA landscape and reveal a transcriptional feedback loop.

• DOI: 10.1093/nar/gkv1015
• 发表时间: 2015-11-16
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Kiselev VY;Juvin V;Malek M;Luscombe N;Hawkins P;Le Novère N;Stephens L
• 通讯作者: Stephens L