MINORITY PREDOCTORAL FELLOWSHIP PROGRAM

描述（由申请人提供）：本项目的长期目标是了解Src如何诱导形成导致侵袭性表型的podosomes。许多人类癌症具有升高的Src激酶活性，并且肿瘤进展，特别是转移性肿瘤，与这种活性的增加相关。Src活性的增加组成性地刺激许多下游信号传导途径，导致称为podosomes的侵入性结构的形成。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是直接Src底物。我们希望能够深入了解哪些蛋白质和信号通路对podosome形成和细胞入侵至关重要。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底物黏着斑蛋白。然后我们可以测试黏着斑蛋白的Src磷酸化如何影响其体内的整体功能。第二，我们将研究ERK 5在podosome形成和侵袭中的作用。我们实验室的初步数据表明，ERK 5活性是podosome形成所必需的。使用ERK5-/-细胞，我们将表达Src的活化形式，并确定其诱导podosome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.