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

定义 Cdc37 对 Src 家族激酶信号转导和肿瘤发生的作用和贡献

• 批准号: nhmrc : 191501
• 负责人: A/Pr Glen Scholz
• 金额: $ 27.43万
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2002
• 资助国家: 澳大利亚
• 起止时间: 2002-01-01 至 2004-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/defining-role-contribution-family-kinases/96476
• 关键词: Defining; role; contribution; Cdc37; signal

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.

细胞通过激活细胞内的信号分子网络来响应细胞外刺激，例如生长因子和激素。正是这些信号传导网络的激活最终负责介导细胞对细胞外刺激（例如胰岛素刺激细胞的葡萄糖代谢）的生物反应。酪氨酸激酶Src家族的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性的信号网络级联的激活。然而，值得注意的是，Src家族激酶的不适当激活与人类癌症，特别是乳腺癌和结肠癌的发展有关。然而，为了实现它们的信号传导功能，Src家族激酶必须首先在它们在细胞中合成时折叠成活性构象，然后保持这种构象。虽然以前的研究，包括我们自己的，有牵连的一类蛋白质称为分子伴侣在这一过程中，很少有人知道如何折叠Src家族激酶的这些蛋白质的实现和调节。本研究的总体目的是确定如何折叠的HCK，Src家族的酪氨酸激酶的成员之一，到一个构象，使其能够参与信号网络的实现和调节。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，并可能有助于正常细胞转化为具有致瘤特性的细胞。该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Src家族激酶的信号活性是如何通过分子伴侣调节的，可能为鉴定新型化疗药物提供新的研究途径。