Unravelling c-Met signalling from autophagic endomembranes

解开自噬内膜的 c-Met 信号传导

• 批准号: MR/R009732/1
• 负责人: Stephanie Kermorgant
• 金额: $ 52.09万
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR009732%2F1
• 关键词: Unravelling; Met; signalling; autophagic; endomembranes

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.

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，这对它们协调行动至关重要。这些信号可以诱导细胞增殖、运动和细胞死亡。这种通讯通常是由两种蛋白质的相互作用引发的：一种配体和一种受体。配体与通常存在于细胞表面的受体结合，以从细胞外传递信号。然后，受体激活额外的蛋白质，称为信号转导，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，因为受体活性失调可能导致疾病，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，以便在它们出错时能够得到纠正。细胞就像一个城镇，细胞中的每一块积木都有自己的角色。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场所进行销毁和回收。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，而是相反，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。它开启了新的挑战，以了解受体如何将信息传递到细胞内的信号转导器，以及为什么自噬位点上的受体活性（而不是细胞表面的活性）需要调节细胞行为。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，从而有助于正常的器官功能和更新。它在慢性炎症和癌症等疾病中也是失调的，因此需要在这些疾病中靶向治疗。我们的目标是充分了解c-Met从自噬位点传递信号所必需的机制。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，我们将使用一种新的技术，允许捕获所有的合作伙伴的c-Met是目前的自噬sites.我们的工作将导致发现新的分子机制控制受体的活动。我们的研究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，无论是在英国还是国际上。由于自噬c-Met活性是某些肿瘤侵袭性的原因，我们的研究也可能使癌症研究人员受益。此外，鉴于c-Met是正常器官功能和更新所必需的，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。

项目成果

MET exon 14 skipping mutation is a hepatocyte growth factor (HGF)-dependent oncogenic driver in vitro and in humanised HGF knock-in mice.

• DOI: 10.1002/1878-0261.13397
• 发表时间: 2023-11
• 期刊: MOLECULAR ONCOLOGY
• 影响因子: 6.6
• 作者: Fernandes, Marie;Hoggard, Brynna;Jamme, Philippe;Paget, Sonia;Truong, Marie-Jose;Gregoire, Valerie;Vinchent, Audrey;Descarpentries, Clotilde;Morabito, Angela;Stanislovas, Justas;Farage, Enoir;Meneboo, Jean-Pascal;Sebda, Sheherazade;Bouchekioua-Bouzaghou, Katia;Nollet, Marie;Humez, Sarah;Perera, Timothy;Fromme, Paul;Grumolato, Luca;Figeac, Martin;Copin, Marie-Christine;Tulasne, David;Cortot, Alexis B.;Kermorgant, Stephanie;Kherrouche, Zoulika
• 通讯作者: Kherrouche, Zoulika

Proximity interactome of LC3B in normal growth conditions

• DOI: 10.1101/2021.10.08.463639
• 发表时间: 2021-10
• 期刊: bioRxiv
• 作者: M. Nollet;A. Agrotis;Fanourios Michailidis;Arran Dokal;V. Rajeeve;J. Burden;T. Nightingale;P. Cutillas;R. Ketteler;S. Kermorgant

c-Met-integrin cooperation: Mechanisms, tumorigenic effects, and therapeutic relevance.

• DOI: 10.3389/fcell.2022.994528
• 发表时间: 2022
• 期刊: Frontiers in cell and developmental biology
• 影响因子: 5.5

The role of MET in chemotherapy resistance.

• DOI: 10.1038/s41388-020-01577-5
• 发表时间: 2021-03
• 期刊: Oncogene
• 影响因子: 8
• 作者: Wood GE;Hockings H;Hilton DM;Kermorgant S
• 通讯作者: Kermorgant S

Unconventional role of RAC1 in MET-driven anchorage-independent tumor growth.

• DOI: 10.1080/23723556.2020.1803029
• 发表时间: 2020-08-18
• 期刊: Molecular & cellular oncology
• 影响因子: 2.1
• 作者: Hervieu A;Kermorgant S
• 通讯作者: Kermorgant S