Dynamic Regulation of the Cell Surface Proteome

每个活着的细胞必须通过其外表面上的分子与周围环境相互作用。蛋白质是存在于每个细胞表面的一种重要的分子。这些细胞表面蛋白对许多细胞功能是必不可少的，包括从细胞周围吸收糖和维生素等营养物质，附着到其他细胞或组织，以及感知来自其他细胞或生物体的信息(例如通过激素)。在细胞表面发现的蛋白质是细胞过程的一部分，这可能需要细胞的大量能量资源，例如在细胞移动或迁移过程中。就像家庭的收入和支出应该平衡一样，细胞的能量消耗过程必须得到严格控制，以使能量消耗与细胞的需求和能力保持一致。 我们研究的长期目标是了解细胞如何控制其表面数百甚至数千种不同类型的蛋白质，以使细胞能够生存并适应不断变化的环境。特别是，我们试图了解细胞如何感知自己的能量状态，并利用这些信息来控制或限制细胞表面的耗能过程。我们最近发现，细胞有一种特殊的适应机制，当它们感觉到自己没有足够的能量时，就会关闭它们最耗能的过程之一：细胞运动和迁移。细胞内的关键分子传感器是一种名为AMP激活的蛋白激酶(AMPK)的蛋白质，其功能类似于细胞的燃料计；AMPK在能量储备耗尽时激活，并作用于恢复细胞的能量储备。 我们建议开展研究，旨在了解人类细胞如何控制其表面蛋白质(特别是那些控制细胞迁移和附着的蛋白质)，以应对自身能量储存和燃料生产的可用性。我们将重点研究控制细胞迁移的细胞表面蛋白家族，称为整合素，以及这些蛋白是如何由能量状态和AMPK控制的。要做到这一点，我们将使用先进形式的显微镜和工具，用荧光标记标记一些蛋白质，如整合素，这将使我们能够在活细胞中“看到”它们。 了解细胞新陈代谢如何控制细胞表面的蛋白质，将提供有关人体几乎每个细胞为确保生存而发生的基本生物过程的宝贵信息。通过更多的实验，我们还计划揭示AMPK是如何控制肾细胞的功能的，肾细胞是一种特别容易出现“能量短缺”的细胞。因此，这些实验将提供有关肾脏功能的新信息，并将提供关于一种重要的、基本的、但尚未探索的生物学现象的前所未有的新知识，这种现象控制着人体中每个细胞的行为。

Each living cell must interact with its surroundings through the molecules present on its outer surface. Proteins are an important type of molecule found on every cell’s surface. These cell surface proteins are essential for many cellular functions including the uptake of nutrients such as sugar and vitamins from a cell's surroundings, for attachment to other cells or tissues and for sensing messages from other cells or organisms (e.g. through hormones). The proteins found on a cell’s surface work as part of cellular processes that can require a lot of a cell’s energy resources, for example in cell movement or migration. Much like household income and expenditures should be balanced, a cell’s energetically demanding processes have to be tightly controlled so that energy expenditure is kept in line with a cell’s needs and abilities. The long-term goal of our research is to understand how a cell controls the hundreds and perhaps thousands of different types of proteins at its surface to allow that cell to survive and adapt to changing environments. In particular, we seek to understand how a cell senses its own energetic state, and uses this information to control or limit energy-demanding processes that the cell surface. We have recently found that cells have a specific adaptive mechanism to shut down one of their most energy-demanding processes when they sense that they do not have enough energy: cell movement and migration. The key molecular sensor within a cell is a protein called AMP-activated protein kinase (or AMPK), which functions like a cell's fuel gauge; AMPK becomes activated when energy stores are depleted, and works to restore a cell’s energy stores. We propose to undertake research aiming to understand how human cells control their surface proteins (in particular those that govern cell migration and attachment) in response to the availability of their own energy stores and fuel production. We will focus on the study of a family of cell surface proteins that control cell migration that are called integrins, and how these are controlled by energy state and AMPK. To do this, we will use advanced forms of microscopy along with tools to “tag” a number of proteins such as integrins with a fluorescent label, which will allow us to “see” them in living cells. Understanding how cell metabolism controls the proteins at the surface of a cell will provide valuable information about a fundamental biological process taking place in virtually every cell in the human body to ensure survival. Through additional experiments, we also plan to reveal how AMPK controls the function of kidney cells, a type of cell that is particularly prone to “energy shortage”. Hence, these experiments will provide new information about kidney function and will provide unprecedented new knowledge about an important, fundamental, yet unexplored phenomenon of biology that controls the behavior of every cell in the human body.