Juxtamembrane control of DDR1 kinase activity

我们身体里的细胞不是被动的、静态的积木，就像墙上的砖一样；相反，它们不断地监测环境并对其做出反应。它们通过发送和接收信号分子形式的信息来做到这一点。为了感知特定的信号，细胞必须有合适的传感器。对于从细胞环境中接收到的信息，传感器通常是一种称为受体酪氨酸激酶（RTK）的特殊蛋白质分子。RTK的一部分伸出细胞外，另一部分在细胞内。当外部部分与信号分子相互作用时，受体会改变其形状。这导致内部部分变得活跃，并进行化学反应（磷酸化），最终改变细胞的行为。RTKs控制着许多重要的功能，如细胞分裂，为了防止癌症等疾病的发生，必须严格控制它们的活性。研究RTKs是如何被控制的，对于理解正常的人类生理，以及理解疾病中的问题是很重要的。RTKs是许多癌症治疗药物的靶点，为了设计更有效的药物，需要对RTKs进行基础研究。该项目将确定如何控制名为DDR1的RTK的活动。当胶原蛋白存在时，DDR1会指示细胞改变其行为。我们发现DDR1的一部分，我们命名为JM4，是DDR1信号活动所必需的。当JM4缺失时，DDR1仍能与胶原结合，但细胞内不发生磷酸化反应。当磷酸化反应在试管中而不是在细胞中进行时，也需要JM4。因此，我们认为JM4是调控DDR1中进行磷酸化反应的部分（称为激酶）的重要控制区。在这个项目中，我们的目标是详细了解JM4如何控制DDR1的激酶活性。我们将确定JM4增强了磷酸化反应的哪一部分，以及JM4是否推动激酶进入活性形态。除了直接影响激酶的形状外，JM4还可以通过与另一种称为Src的细胞成分相互作用间接影响其活性。我们已经确定Src增加细胞中DDR1的磷酸化。在这个项目中，我们将确定Src如何增加DDR1激酶活性，以及这是否在JM4的帮助下发生。这项研究很重要，因为它可能为设计针对人类疾病中有缺陷的DDR1信号传导的新药提供基础。大多数抗rtk的药物都是通过直接阻断激酶的活性部分来阻断激酶的活性。由于细胞中含有数百种具有类似形状的活性部分的其他激酶，这类药物通常会导致严重的副作用。JM4只存在于DDR1（和一种类似的蛋白质DDR2）中。了解JM4在控制DDR1激酶活性中的确切作用将有助于设计阻断DDR1激酶活性的药物，而不干扰所有其他激酶的活性。这有望产生副作用更少的药物，用于治疗DDR1信号异常的疾病，如关节炎、纤维化和癌症。

The cells in our body are not passive and static building blocks like bricks in a wall; rather, they constantly monitor and react to their environment. They do this by sending and receiving messages in the form of signalling molecules. In order to perceive a particular signal, a cell has to have appropriate sensors. For messages that are received from the cell's environment, the sensor is often a specialised protein molecule called a receptor tyrosine kinase (RTK). One part of the RTK sticks out from the cell and another part is inside the cell. When the outside part interacts with a signalling molecule, the receptor changes its shape. This causes the inside part to become active and carry out a chemical reaction (phosphorylation) that ultimately changes the cell's behaviour. RTKs control many important functions, such as cell division, and their activity must be tightly controlled in order to prevent the development of diseases, such as cancer. Research into how RTKs are controlled is important for understanding normal human physiology, as well as for understanding what goes wrong in disease. RTKs are the targets of many drugs used in cancer therapy, and basic research of RTKs is required for designing more effective drugs.This project will establish how the activity of an RTK called DDR1 is controlled. DDR1 instructs cells to change their behaviour when collagen is present. We discovered that a part of DDR1, which we named JM4, is needed for DDR1 signalling activity. When JM4 is missing, DDR1 can still bind to collagen, but no phosphorylation reaction results inside the cell. JM4 is also needed when the phosphorylation reaction is done in a test tube rather than in a cell. Therefore, we believe that JM4 is an important control region that regulates the part of DDR1 that carries out the phosphorylation reaction, which is called the kinase.In this project, we aim to obtain a detailed understanding of how JM4 controls the kinase activity of DDR1. We will determine which part of the phosphorylation reaction is enhanced by JM4 and whether JM4 pushes the kinase into an active shape. In addition to directly affecting the shape of the kinase, JM4 could also affect its activity indirectly by interacting with another cellular component called Src. We already determined that Src increases DDR1 phosphorylation in cells. In this project, we will determine how Src increases DDR1 kinase activity and whether this occurs with the help of JM4.This research is important because it may provide the basis for designing novel drugs against faulty DDR1 signalling in human disease. Most drugs against RTKs are designed to block the kinase activity by directly blocking the active part of the kinase. Because cells contain hundreds of other kinases with active parts of similar shape, these types of drugs often lead to serious side effects. JM4 is only found in DDR1 (and a similar protein called DDR2). Understanding the precise role of JM4 in controlling DDR1 kinase activity will help in designing drugs that block DDR1 kinase activity, without interfering with the activity of all the other kinases. This is expected to result in drugs with fewer side effects that could be used in diseases with abnormal DDR1 signalling, such as arthritis, fibrosis and cancer.