Unravelling c-Met signalling from autophagic endomembranes

我们的身体由数十亿个细胞组成。这些细胞不断地以信号的形式交换信息，这对它们以协调的方式行动至关重要。这些信号可以诱导细胞增殖、运动和死亡。这种通讯通常由两种蛋白质的相互作用启动：配体和受体。配体与通常存在于细胞表面的受体结合，传递细胞外的信号。然后，受体激活额外的蛋白质，称为信号转导器，将信号传递到细胞内部，在那里它们被解释并改变细胞的行为。细胞必须严格控制这些受体的活性，因为不受控制的受体活性可能导致疾病，如慢性炎症或癌症。因此，有必要更好地了解受体是如何运作的，以便在它们出错时进行纠正。细胞就像一个城镇，细胞中的每个构件都有自己的角色。自噬就是其中之一；它就像一个家庭废物回收中心：细胞废物被送到自噬点被破坏和回收。令人惊讶的是，我们最近发现，在癌细胞中，这些回收中心被劫持了，从事一些“非法活动”：我们发现，负责癌症的受体去那里不是为了降解，而是更加活跃。这个新的科学概念改变了我们对受体如何运作的理解。它为理解受体如何将信息传递给细胞内的信号转导器，以及为什么自噬部位的受体活性，而不是细胞表面的活性，是调节细胞行为所必需的，带来了新的挑战。我们建议使用一种受体模型c-Met来研究这一概念。这种受体在控制细胞生长、细胞存活和细胞运动中起着重要作用，从而有助于适当的器官功能和更新。它在慢性炎症和癌症等疾病中也不受管制，因此需要针对这些疾病进行治疗。我们的目标是充分了解c-Met从自噬位点传递信号的必要机制。为了实现我们的目标，我们将使用最先进的细胞生物学、成像和生物化学技术。特别是，我们将使用一种新颖的技术，可以捕获存在于自噬位点上的c-Met的所有伙伴。我们的工作将导致发现控制受体活性的新分子机制。我们的结果应该有利于研究受体、信号转导、细胞生长、细胞存活和细胞运动的研究人员，无论是在英国还是在国际上。由于自噬c-Met活性解释了某些肿瘤的侵袭性，我们的研究也可以使研究癌症的研究人员受益。此外，考虑到c-Met对于正常的器官功能和更新是必需的，我们的研究结果可能会对再生医学和衰老领域产生影响。因此，这项研究的受益者包括制药公司、公共卫生领域（NHS）和患者。

Our body is composed of billions of cells. These cells are constantly exchanging information in the form of signals, which is crucial for them to act in a coordinated fashion. These signals can induce cell multiplication, movement, and cell death. This communication is often initiated by the interaction of two proteins: a ligand and a receptor. Ligands bind to the receptors, which are normally present at the surface of cells, to transmit signals from outside the cell. The receptors then activate additional proteins, called signal transducers, to transmit the signals to the inside of the cell, where they are interpreted and alter the cell's behaviour. Cells must tightly control the activity of these receptors because deregulated receptor activity can lead to diseases, such as chronic inflammation or cancer. Thus, there is a need to better understand how receptors operate so that they can be corrected when they go wrong. A cell is like a town, and each building block in a cell has a role. Autophagy is one of these blocks; it is like a household waste recycling centre: cell waste are sent to autophagic sites to be destroyed and recycled. Surprisingly we recently find out that in cancer cells, these recycling centre were hijacked for some "illegal activities": we have found that receptors responsible for cancer go there not to be degraded but on the contrary to be even more active. This new scientific concept changes our understanding of how receptors operate. It opens new challenges to understand how receptors transmit information to signal transducers inside the cell, and why receptor activity on autophagic sites, as opposed to activity at the cell surface, is required to modulate cell behaviour. We propose investigating this concept using one receptor model, c-Met. This receptor plays a major role in controlling cell growth, cell survival and cell movement, thus contributing to proper organ function and renewal. It is also deregulated in diseases such as chronic inflammation and cancer and therefore need to be targeted in these conditions. We aim to fully understand the mechanisms necessary for c-Met to transmit signals from autophagic sites. To achieve our objectives we will use state of the art cell biology, imaging and biochemistry techniques. In particular, we will use a novel technique that allows the capturing of all the partners of c-Met that are present on autophagic sites.Our work will lead to the discovery of novel molecular mechanisms controlling receptor activity. Our results should benefit researchers working on receptors, signal transducers, cell growth, cell survival and cell movement, both within the UK and internationally. Since autophagic c-Met activity accounts for the aggressiveness of certain tumours, our research could also benefit researchers working on cancer. Furthermore, given that c-Met is necessary for proper organ function and renewal, our results may have an impact in the fields of regenerative medicine and ageing. Thus the beneficiaries of this research include pharmaceutical companies, the public health domain (NHS) and patients.