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

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。例如，暴露在有毒化学物质中会激活允许修复细胞损伤和促进细胞存活的信号通路。在发育中的胚胎中，细胞可能会收到刺激或指示它们分裂的信号（所谓的生长因子），也可能会收到指示它们停止分裂并进行“分化”的信号，在这个过程中，细胞获得了构成我们成人身体中离散组织（如神经、血细胞或肌肉）的特殊细胞类型的特征。这个细胞分裂和分化的过程不仅在胚胎发育中很重要，而且在我们成年后对细胞和组织损伤的反应中也很重要。例如，如果我们撕裂肌肉，肌肉中的特殊“干细胞”开始分裂，然后分化成新的肌肉细胞来修复肌肉组织。随着年龄的增长，这个过程的效率会降低，我们修复和更新组织的能力也会降低。这就解释了为什么我们从伤害中恢复的能力会逐渐下降，而这些伤害对我们年轻时的自己来说几乎没有什么问题。细胞要对生长或损伤信号作出反应，必须激活关键的生长和修复蛋白；这通常涉及到增加这些蛋白质的丰度。这些蛋白质的遗传信息储存在被称为基因的离散DNA片段中，这些片段位于细胞核中的染色体上。当细胞接收到生长或损伤信号时，这些基因被“转录”成信使RNA （mRNA）分子，然后被“翻译”成相关的蛋白质。这整个复杂的过程是由控制每一步的信号通路精心策划的。控制是这里的关键词。如果细胞在修复过程中分裂过多，它们可能会癌变；如果它们分裂不够，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被称为蛋白激酶的酶级联反应。这些酶用磷酸基团“标记”其他蛋白质（这一过程被称为磷酸化），这改变了蛋白质的活性、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DYRK1B的蛋白激酶。DYRK1B是一个小的蛋白激酶家族中的一个，人们对它知之甚少，但认为它非常重要。例如，密切相关的DYRK1A可能在唐氏综合症中很重要，而DYRK1B本身可能是一种致癌基因。重要的是，DYRK1B的丰度在细胞分裂到细胞分化的过程中显著增加。然而，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蛋白质是DYRK1B底物（即被DYRK1B标记为磷酸盐的蛋白质）。我们现在已经确定了一组被DYRK1B磷酸化的蛋白质。这些蛋白质参与控制mRNA分子的丰度，这些mRNA分子最终被翻译成生长和修复蛋白。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在肌肉分化中发挥的作用，使用可以在实验室中刺激成肌肉的细胞。这项研究的结果应该告诉我们更多关于DYRK1B在肌肉分化中的正常作用，这对于肌肉修复可能存在缺陷的老年人很重要。它也可能与DYRK1B可能很重要的其他分化模型有关，包括脂肪细胞，这与肥胖的增加有关。最后，DYRK1B控制细胞分裂的能力可能在癌症中很重要。为了帮助我们最大限度地发挥我们研究的影响，我们将与这些领域的其他科学家合作。

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.