MINORITY PREDOCTORAL FELLOWSHIP PROGRAM

描述(由申请人提供)：本项目的长期目标是了解Src如何诱导足体的形成，从而导致侵袭性表型。许多人类癌症的Src激酶活性升高，肿瘤进展，特别是转移性肿瘤，与这种活性增加相关。增加的Src活性结构性地刺激许多下游信号通路，导致侵袭性结构的形成，称为足体。足体是肌动蛋白聚合、细胞附着和蛋白酶分泌的场所。与这些过程相关的许多蛋白质都是直接的Src底物。我们希望深入了解哪些蛋白质和信号通路是足体形成和细胞入侵所必需的。为此，我们将利用RNAi技术敲除整合素-F-肌动蛋白连接蛋白和Src底物vinculin。然后，我们可以在体内测试纽蛋白的Src磷酸化对其整体功能的影响。其次，我们将研究ERK5在足体形成和入侵中的作用。我们实验室的初步数据表明，ERK5活性是足体形成所必需的。利用ERK5-/-细胞，我们将表达一种激活形式的Src，并确定其诱导足体形成的能力。

DESCRIPTION (provided by applicant): The long term goal of this project is to understand how Src can induce the formation of podosomes leading to an invasive phenotype. Many human cancers have elevated Src kinase activity, and tumor progression, especially metastatic tumors, correlates with this increase in activity. Increased Src activity constitutively stimulates many downstream signaling pathways leading to the formation of invasive structures termed podosomes. Podosomes are sites of actin polymerization, cell attachment and protease secretion. Many proteins associated with these processes are direct Src substrates. We hope to gain insight into what proteins and signaling pathways are essential for podosome formation and cellular invasion. To do this, we are going to utilize RNAi technology to knockout the integrin-F-actin linker protein and Src substrate vinculin. We can then test how Src phosphorylation of vinculin effects its overall function in vivo. Second, we are going to look at the role of ERK5 in podosome formation and invasion. Preliminary data from our lab indicate that ERK5 activity is required for podosome formation. Using ERK5 -/- cells we will express an activated form of Src and determine its capacity to induce podosome formation.