The regulation of pleiotropic responses by phospho-Ser/Tyr binary switches embedded in growth factor receptors

人体内的细胞能够在其生命周期内完成一系列令人印象深刻的功能。细胞功能的这种多样性背后是一系列基本的细胞反应，包括细胞存活、细胞增殖(生长)和细胞分化(致力于更成熟的细胞身份)。可扩散因子(称为生长因子)在调节这些细胞反应中起着重要作用。这是通过生长因子与细胞表面的特定蛋白质(称为受体)结合来实现的，这些蛋白质反过来激活信号级联，在细胞内传递指示特定反应的信息。我们已经确定了一种新的机制，允许生长因子受体将模拟输入(以生长因子刺激的形式)转换为数字输出(其中细胞以决定性的方式做出反应)。这种模数转换是由嵌入在生长因子受体中的分子开关编码的，该开关在两个交替的位置之间切换，以促进细胞单独存活或细胞存活以及细胞分化-增殖。通过这种方式，这些分子开关具有二元(非此即彼)的特性，并为不同细胞功能的独立调节和协调提供了新的解释。这些发现对于理解特定的细胞反应，如细胞的存活、增殖和分化如何被调节，或者可能被利用来改善损伤后的组织再生(例如，在中风、心脏病发作的创伤中)，或者对于理解在癌症等疾病中，细胞的存活、增殖和分化被解除调控的情况是如何出错的，这些发现具有重要意义

Cells in the body are able to accomplish an impressive range of functions within their lifetime. Underlying this diversity in cellular functions are a quorum of fundamental cellular responses that include cell survival, cell proliferation (growth) and cell differentiation (commitment to a more mature cell identity). Diffusible factors (called growth factors) are important in regulating these cellular responses. This is achieved through growth factor binding to specific proteins (called receptors) on the surface of cells which in turn activate signalling cascades that convey messages within the cell instructing a specific response. We have identified a new mechanism that allows a growth factor receptor to convert analogue inputs (in the form of growth factor stimulation) to a digital output (where a cell responds in a decisive fashion). This analogue-to-digital conversion is encoded by a molecular switch embedded in growth factor receptors that toggles between two alternate positions to promote either cell survival alone or cell survival as well as cell differentiation-proliferation. In this manner, these molecular switches have binary (either-or) characteristics and provide a new explanation for the independent regulation and coordination of different cell functions. These findings have implications for understanding how specific cellular responses such as cell survival, proliferation and differentiation can be regulated and perhaps harnessed to improve tissue regeneration after damage (e.g. in stroke, heart attack trauma) or in understanding how things go wrong in diseases such as cancer where cell survival, proliferation and differentiation become deregulated