Regulation of ERK Signalling by the Scaffold Protein KSR1

哺乳动物细胞包含几个信号通路，使它们能够对环境的变化做出反应。被描述得最好的信号分子之一是RAS蛋白，它是多细胞生物体中细胞增殖、分化和生存的关键调节因子。RAS传递细胞信号的一个主要途径是通过蛋白激酶Raf-1、MEK和ERK的顺序激活。这一途径的激活通常会导致细胞周期的进展和随后的细胞增殖。由于其在哺乳动物细胞生长调控中的核心作用，这一途径必须受到精确的调控，其调控缺陷被认为是包括癌症在内的许多疾病所致。支架蛋白通过将相关蛋白引导到细胞的特定隔间来提供对细胞信号的空间和时间控制。此外，它们在物理上连接了一条通路的几个组成部分，并可以将其他成分排除在复合体之外。在这项建议中，我们的目的是描述支架蛋白KSR1在哺乳动物细胞生长因子刺激后调节ERK活性中的作用。这些研究将为ERK信号转导通路的调控提供新的见解，并将有助于理解导致癌症等增殖性疾病的过程。

Mammalian cells contain several signalling pathways that allow them to react to changes in their environment. One of the best-described signalling molecules is the Ras protein, a critical regulator of cellular proliferation, differentiation and survival in multicellular organisms. A major route by which Ras transmits cellular signals is through the sequential activation of the protein kinases Raf-1, MEK and ERK. Activation of this pathway often results in progression through the cell cycle and subsequent cellular proliferation. Because of its central role in growth regulation of mammalian cells, this pathway has to be precisely regulated and defects in its regulation have been attributed to many diseases, including cancer. Scaffold proteins provide spatial and temporal control to cellular signalling by directing associated proteins to specific compartments of the cell. In addition, they physically link several components of a pathway and can exclude others from the complex. In this proposal, we aim to characterise the role of the scaffold protein KSR1 in the regulation of ERK activity after growth factor stimulation of mammalian cells. These studies will provide new insight into the regulation of the ERK signal transduction pathway and will help to understand the processes that cause proliferative diseases like cancer.