Defining the role and contribution of Cdc37 to signal transduction and tumourigenesis by Src-family kinases

细胞通过激活细胞内的信号分子网络来响应细胞外刺激，如生长因子和激素。正是这些信号网络的激活，最终负责调节细胞对细胞外刺激(如胰岛素刺激细胞的葡萄糖代谢)的生物反应。酪氨酸激酶的Src家族成员在信号分子中是最重要的，因为它们能够直接启动调节细胞活动的一系列信号网络的激活。然而，值得注意的是，Src家族激酶的不适当激活与人类癌症的发展有关，特别是乳腺癌和结肠癌。然而，为了完成它们的信号功能，Src家族的激酶必须首先在细胞内合成时折叠成活性构象，然后保持在这种构象中。尽管之前的研究，包括我们自己的研究，已经发现一类称为分子伴侣的蛋白质参与了这一过程，但对于这些蛋白质是如何实现和调控Src家族的折叠的，我们知之甚少。这项研究的总体目的是确定酪氨酸激酶家族中的一个成员HCK如何折叠成一种构象，使其能够参与信号网络的实现和调控。预计这项研究的结果将为这一过程如何影响细胞对细胞外刺激的反应能力提供重要的新见解，并可能有助于将正常细胞转化为具有致瘤特性的细胞。这个项目的发现在人类癌症的背景下可能特别重要。更好地了解分子伴侣如何调节Src家族的信号活性，可能为新的化疗药物的鉴定提供一条新的研究途径。

Cells respond to extracellular stimuli, such as growth factors and hormones, by activating intracellular networks of signaling molecules. It is the activation of these signaling networks that is ultimately responsible for mediating the biological responses of cells to extracellular stimuli (e.g. insulin stimulating glucose metabolism by cells). Members of the Src-family of tyrosine kinases are paramount among signaling molecules, as they are able to directly initiate the activation of a cascade of signaling networks that regulate the activity of the cell. Significantly though, the inappropriate activation of Src-family kinases has been implicated in the development of cancer, particularly breast and colon cancer, in humans. To fulfill their signaling functions however, Src-family kinases must first be folded into an active conformation upon their synthesis in the cell then be maintained in this conformation. Although previous studies, including our own, have implicated a class of proteins called molecular chaperones in this process, little is known about how the folding of Src-family kinases by these proteins is achieved and regulated. The overall aim of this study is to determine how the folding of Hck, one member of the Src-family of tyrosine kinases, into a conformation that enables it to participate in signaling networks is achieved and regulated. It is expected that the results from this study will provide significant new insight into how this process might influence the ability of cells to respond to extracellular stimuli and potentially contribute to the conversion of a normal cell into one with tumourigenic properties. Findings from this project may be particularly important in the context of human cancer. A better knowledge of how the signaling activity of Src-family kinases is regulated by molecular chaperones might provide a new avenue of investigation for the identification of novel chemotherapeutic agents.