New insights into the function of the protein kinase DYRK1B, an ERK1/2 target gene

对 ERK1/2 靶基因蛋白激酶 DYRK1B 功能的新见解

• 批准号: BB/L008793/1
• 负责人: Simon Cook
• 金额: $ 44.14万
• 依托单位: Babraham Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FL008793%2F1
• 关键词: New; insights; into; function; protein

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. For example, exposure to noxious chemicals will activate signal pathways that allow repair of cellular damage and promote cell survival. 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 or muscles. This process of cell division and differentiation is not only important in the developing embryo but also throughout our adult lives in responding to cell and tissue damage. For example, if we tear a muscle, special 'stem cells' in the muscle start to divide and then differentiate into new muscle cells to repair muscle tissue. As we get older this process become less efficient and our capacity to repair and renew tissues is reduced. This accounts for the progressive decline in our ability to recover from injuries that pose little problem to our younger selves.For cells to respond to growth or damage cues they must activate key growth and repair proteins; this often involves increasing the abundance of these proteins. The genetic information for these proteins is stored in discrete pieces of DNA termed genes, which reside on chromosomes in the nucleus. When a cell receives a growth or damage signal these genes are 'transcribed' into messenger RNA (mRNA) molecules, which are in turn 'translated' into the relevant proteins. This whole complex process is orchestrated by signalling pathways, which control every step. Control is the key word here. If the cells divide too much during the repair response they may become cancerous; if they do not divide enough then muscle repair may be defective.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 DYRK1B.DYRK1B is one of a small family of protein kinases that are poorly understood but are believed to be very important. For example, the closely related DYRK1A may be important in Down Syndrome whilst DYRK1B itself may be a cancer-causing gene. Importantly, the abundance of DYRK1B increases substantially during the switch from cell division to cell differentiation. However we are currently ignorant about how DYRK1B controls these processes because we know very few proteins that are DYRK1B substrates (i.e. that are tagged with phosphate by DYRK1B).We have now identified a group of proteins that are phosphorylated by DYRK1B. These proteins are involved in controlling the abundance of the mRNA molecules that are ultimately translated into growth and repair proteins. In this project we will define how DYRK1B controls these proteins, the importance of this for regulating mRNA abundance and the role that DYRK1B plays in muscle differentiation using cells that can be stimulated to change into muscle in the lab.The results of this study should tell us more about the normal role of DYRK1B in muscle differentiation, which is important in the elderly where muscle repair can be defective. It may also be relevant in other models of differentiation where DYRK1B may be important including fat cells, which is relevant to the rise in obesity. Finally, the ability of DYRK1B to control cell division may be important in cancer. To help us maximize the impact of our research we will work with other scientists in these area.

我们体内的细胞不断地经历环境变化，它们包含一个广泛的信号通路网络，以协调适当的响应。例如，暴露于有害化学物质将激活信号途径，以修复细胞损伤并促进细胞存活。在发育中的胚胎中，细胞可能会受到刺激或提示，告诉他们分裂（所谓的生长因子），或者他们可能会收到线索，告诉他们停止分裂和经历“分化”，在该过程中，细胞获得了构成我们成人身体的特定细胞类型的特征，例如神经，血细胞或肌肉。这种细胞分裂和分化的过程不仅在发育中的胚胎中很重要，而且在我们的整个成年生活中也很重要，以应对细胞和组织损伤。例如，如果我们撕裂肌肉，则肌肉中的特殊“干细胞”开始分裂，然后分化为新的肌肉细胞以修复肌肉组织。随着年龄的增长，这个过程的效率降低了，我们修复和更新组织的能力降低了。这解释了我们从对年轻人造成的伤害中恢复的能力的逐渐下降。为了对生长或损害提示的响应，它们必须激活关键的生长和修复蛋白；这通常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称为基因的基因中，该基因驻留在细胞核中的染色体上。当细胞收到生长或损伤信号时，这些基因被“转录”到信使RNA（mRNA）分子中，这些分子又被“翻译”到相关的蛋白质中。整个复杂过程都通过信号通路来精心策划，该信号通路控制每个步骤。控制是这里的关键词。如果细胞在修复反应过程中分裂过多，则可能会变成癌。如果它们不够分裂，那么肌肉修复可能会有缺陷。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反应。这些酶与磷酸基团（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。标记的蛋白被称为蛋白激酶酶的“底物”。该项目涉及一种称为dyrk1b.dyrk1b的蛋白激酶是一个小家族的蛋白激酶之一，该家族知之甚少，但被认为非常重要。例如，与唐氏综合症密切相关的DYRK1A可能很重要，而DYRK1B本身可能是造成癌症的基因。重要的是，在从细胞分裂到细胞分化的转换过程中，DYRK1B的丰度大大增加。但是，我们目前对DYRK1B如何控制这些过程一无所知，因为我们知道很少有DYRK1B底物的蛋白质（即用DYRK1B标记为磷酸盐）。我们现在已经鉴定了一组由DYRK1B磷酸化的蛋白质。这些蛋白质参与控制最终转化为生长和修复蛋白的mRNA分子的丰度。在这个项目中，我们将定义DYRK1B如何控制这些蛋白质，这对于调节mRNA丰度的重要性以及DyRK1b在肌肉分化中使用可以刺激实验室中肌肉变成肌肉的细胞在肌肉分化中所扮演的作用。这项研究的结果应该更多地告诉我们Dyrk1b在肌肉差异中的正常作用，在肌肉差异中，在肌肉差异中很重要。它可能与其他分化模型有关，在其他分化模型中，DYRK1B可能很重要，包括脂肪细胞，这与肥胖症的升高有关。最后，DYRK1B控制细胞分裂的能力在癌症中可能很重要。为了帮助我们最大化研究的影响，我们将与这些领域的其他科学家合作。

项目成果

DYRK1A-mediated Cyclin D1 Degradation in Neural Stem Cells Contributes to the Neurogenic Cortical Defects in Down Syndrome.

• DOI: 10.1016/j.ebiom.2015.01.010
• 发表时间: 2015
• 期刊: EBIOMEDICINE
• 影响因子: 11.1
• 作者: Najas, Sonia;Arranz, Juan;Lochhead, Pamela A.;Ashford, Anne L.;Oxley, David;Delabar, Jeanm.;Cook, Simon J.;Jose Barallobre, Maria;Arbones, Maria L.
• 通讯作者: Arbones, Maria L.

Identification of DYRK1B as a substrate of ERK1/2 and characterisation of the kinase activity of DYRK1B mutants from cancer and metabolic syndrome.

• DOI: 10.1007/s00018-015-2032-x
• 发表时间: 2016-02
• 期刊: Cellular and molecular life sciences : CMLS
• 作者: Ashford AL;Dunkley TP;Cockerill M;Rowlinson RA;Baak LM;Gallo R;Balmanno K;Goodwin LM;Ward RA;Lochhead PA;Guichard S;Hudson K;Cook SJ
• 通讯作者: Cook SJ