Defining the role of ERK5 kinase and ERK5 transcriptional activities in cell migration and EMT using novel ERK5 inhibitors

使用新型 ERK5 抑制剂定义 ERK5 激酶和 ERK5 转录活性在细胞迁移和 EMT 中的作用

• 批准号: BB/N015886/1
• 负责人: Simon Cook
• 金额: $ 43.56万
• 依托单位: Babraham Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FN015886%2F1
• 关键词: Defining; role; ERK5; kinase; transcriptional

The cells in our body are constantly subjected to changes in their environment and they contain an extensive network of signalling pathways that coordinate appropriate responses. In the developing embryo, cells may receive stimuli or cues telling them to divide (so called growth factors) or they may receive cues telling them to cease dividing and undergo 'differentiation', a process in which cells acquire the characteristics of specialized cell types that make up the discrete tissues in our adult bodies such as nerves, blood cells in the immune system or our skin. This process of cell division and differentiation continues in adults in certain tissues; which constantly renew themselves such as our skin. For cells to respond to growth or differentiation cues they must activate key growth or differentiation proteins; this often involves increasing the abundance of these proteins. The genetic information for these proteins is stored in discrete pieces of DNA (genes), which reside on chromosomes in the nucleus. When a cell receives a growth signal these genes are 'read' by 'transcription factors', discrete proteins that bind to DNA and transcribe the DNA information the into messenger RNA (mRNA) molecules, which are in turn 'translated' into the relevant proteins. This coupled process of transcription and translation is called 'gene expression'.This whole complex process is orchestrated by signalling pathways, which control every step. Control is the key word here. For example, if the cells divide too much or fail to differentiate correctly they may become cancerous. The signalling pathways controlling cell division and differentiation typically involve cascades of enzymes called protein kinases. These enzymes 'tag' other proteins with a phosphate group (a process called phosphorylation) and this changes the activity, abundance or localisation of the protein. The tagged protein is referred to as the 'substrate' of the protein kinase enzyme. This project concerns a protein kinase called ERK5. 1. There is much interest in finding drugs that block ERK5 activity (ERK5 inhibitors or ERK5i) as they may help to treat inflammation, cardiovascular disease or cancer. Indeed, we have been working with a team of scientists to identify new ERK5i that inhibit ERK5 kinase activity. However, to our surprise they actually promote gene reading or transcription. The ERK5 protein is unusual in that it has two quite different functional regions or domains. The first is the kinase domain, which phosphorylates substrates; the second is a transcription factor domain, which binds DNA to read genes. Our results suggest that when an ERK5i inhibits the kinase domain it causes structural changes that activate the transcription factor domain. So one aim is to understand at the molecular level how this happens and whether this is a good thing or a bad thing for designing ERK5 inhibitors.2. Second, we want to identify the genes that ERK5 binds to so we can better understand the role of ERK5 - and specifically the two functional domains of ERK5 - in gene expression. 3. Our recent experiments have suggested that ERK5 activity is important in regulating a differentiation process called epithelial-to-mesenchymal transition (or EMT). EMT is important during development of the embryo, during wound repair and for cancer cells to spread around the body and invade new sites - a process called metastases. Indeed, we have found that blocking ERK5 activity reverses EMT and prevents the movement of cells. So a final aim of this project is to understand how ERK5 controls this EMT process and whether it is controlled by the kinase domain or the gene reading domain of ERK5.This study should tell us more about the normal role and regulation of ERK5. ERK5 may also be important in clinical conditions (inflammation, cardiovascular disease, cancer) so our results may have wider impacts and we will work with scientists in these areas to progress this.

我们体内的细胞不断受到环境变化的影响，它们包含一个广泛的信号通路网络，协调适当的反应。在发育中的胚胎中，细胞可能会收到刺激或提示，告诉它们分裂（所谓的生长因子），或者它们可能会收到提示，告诉它们停止分裂并进行“分化”，这是一个细胞获得特殊细胞类型特征的过程，这些细胞类型构成我们成年身体中的离散组织，如神经，免疫系统中的血细胞或我们的皮肤。这种细胞分裂和分化的过程在成年人的某些组织中继续进行;这些组织不断更新自己，例如我们的皮肤。对于细胞响应生长或分化的线索，他们必须激活关键的生长或分化蛋白;这往往涉及增加这些蛋白质的丰度。这些蛋白质的遗传信息存储在离散的DNA片段（基因）中，这些DNA片段位于细胞核中的染色体上。当细胞接收到生长信号时，这些基因被“转录因子”“读取”，“转录因子”是与DNA结合并将DNA信息转录成信使RNA（mRNA）分子的离散蛋白质，而信使RNA（mRNA）分子又被“翻译”成相关蛋白质。这个转录和翻译的耦合过程被称为“基因表达”，整个复杂的过程由信号通路协调，控制着每一步。控制是这里的关键词。例如，如果细胞分裂过多或未能正确分化，它们可能会癌变。控制细胞分裂和分化的信号通路通常涉及称为蛋白激酶的酶的级联。这些酶用磷酸基团（称为磷酸化的过程）“标记”其他蛋白质，这会改变蛋白质的活性，丰度或定位。标记的蛋白质被称为蛋白激酶的“底物”。该项目涉及一种名为ERK 5的蛋白激酶。1.人们对寻找阻断ERK 5活性的药物（ERK 5抑制剂或ERK 5i）很感兴趣，因为它们可能有助于治疗炎症，心血管疾病或癌症。事实上，我们一直在与一个科学家团队合作，以确定新的ERK 5i抑制ERK 5激酶活性。然而，令我们惊讶的是，它们实际上促进了基因阅读或转录。ERK 5蛋白质是不寻常的，因为它有两个完全不同的功能区域或结构域。第一个是激酶结构域，它使底物磷酸化;第二个是转录因子结构域，它结合DNA以读取基因。我们的研究结果表明，当ERK 5i抑制激酶结构域时，它会引起激活转录因子结构域的结构变化。因此，一个目标是在分子水平上了解这是如何发生的，以及这对设计ERK 5通路是好事还是坏事。其次，我们希望确定ERK 5结合的基因，以便我们能够更好地了解ERK 5的作用-特别是ERK 5的两个功能域-在基因表达中。3.我们最近的实验表明，ERK 5活性在调节称为上皮-间充质转化（或EMT）的分化过程中很重要。EMT在胚胎发育、伤口修复以及癌细胞在身体周围扩散并侵入新部位--这一过程称为转移过程--期间非常重要。事实上，我们已经发现阻断ERK 5活性可以逆转EMT并阻止细胞的运动。因此，本课题的最终目的是了解ERK 5是如何调控EMT过程的，它是由ERK 5的激酶结构域还是基因阅读结构域控制的。ERK 5在临床疾病（炎症、心血管疾病、癌症）中也可能很重要，因此我们的研究结果可能会产生更广泛的影响，我们将与这些领域的科学家合作，以推动这一研究的进展。

项目成果

Parallel Optimization of Potency and Pharmacokinetics Leading to the Discovery of a Pyrrole Carboxamide ERK5 Kinase Domain Inhibitor.

• DOI: 10.1021/acs.jmedchem.1c01756
• 发表时间: 2022-05-12
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 7.3
• 作者: Miller, Duncan C.;Reuillon, Tristan;Molyneux, Lauren;Blackburn, Timothy;Cook, Simon J.;Edwards, Noel;Endicott, Jane A.;Golding, Bernard T.;Griffin, Roger J.;Hardcastle, Ian;Harnor, Suzannah J.;Heptinstall, Amy;Lochhead, Pamela;Martin, Mathew P.;Martin, Nick C.;Myers, Stephanie;Newell, David R.;Noble, Richard A.;Phillips, Nicole;Rigoreau, Laurent;Thomas, Huw;Tucker, Julie A.;Wang, Lan-Zhen;Waring, Michael J.;Wong, Ai-Ching;Wedge, Stephen R.;Noble, Martin E. M.;Cano, Celine
• 通讯作者: Cano, Celine

ERK5 Signalling and Resistance to ERK1/2 Pathway Therapeutics: The Path Less Travelled?

• DOI: 10.3389/fcell.2022.839997
• 发表时间: 2022
• 期刊: Frontiers in cell and developmental biology
• 影响因子: 5.5
• 作者: Cook SJ;Lochhead PA
• 通讯作者: Lochhead PA

Tumor cells with KRAS or BRAF mutations or ERK5/MAPK7 amplification are not addicted to ERK5 activity for cell proliferation.

• DOI: 10.1080/15384101.2015.1120915
• 发表时间: 2016
• 期刊: Cell cycle (Georgetown, Tex.)
• 作者: Lochhead PA;Clark J;Wang LZ;Gilmour L;Squires M;Gilley R;Foxton C;Newell DR;Wedge SR;Cook SJ
• 通讯作者: Cook SJ