CD98 (4F2 antigen) and Integrin Signaling in Vascular Smooth Muscle Cells.

描述（由申请人提供）：已提出整联蛋白信号传导在调节血管平滑肌细胞（VSMC）行为中起主要作用。VSMC的增殖需要CD 98 hc（4F 2 hc，SLC 3A 2）的表达，其是与氨基酸转运和整合素相关的膜蛋白。CD 98 hc与几种不同组织中的细胞增殖相关，但CD 98 hc的功能如何与其在增殖中的作用相关尚未确定。有几项研究表明，整合素在CD 98 hc调节细胞增殖的能力中起着重要作用。此外，VSMC的增殖通过ECM相互作用来调节，ECM相互作用主要通过整合素介导。为了测试是否CD 98 hc介导整合素信号调节VSMCs的增殖，我建议首先调查CD 98 hc的功能调节VSMCs的增殖。我将利用一个连接的删除和重建的策略来表征区域的CD 98 hc介导的增殖。先前已经鉴定了影响整联蛋白或氨基酸转运蛋白的CD 98 hc突变体。因此，这些突变体将使我能够建立两个相互作用在VSMC反应的相对作用。阻断CD 98 hc结合的Δ 1整联蛋白的突变以前也已被鉴定。我将用这些突变体重建<$1个无效的VSMC，作为研究整合素相互作用在VSMC增殖中的作用的伴随策略。其次，我将确定CD 98 hc调节整合素依赖性信号传导的机制。我将研究CD 98 hc寡聚化在整合素信号转导中的可能作用，通过系统诱变CD 98 hc的胞外和跨膜结构域来鉴定破坏寡聚化的突变体，并研究其对VSMC和成纤维细胞中整合素信号转导的影响。作为一种替代机制，我将测试CD 98 hc结合的可能性，因此招募关键的信号中间体整合素。这些研究将提供CD 98 hc在VSMC增殖中的作用的基本见解，VSMC增殖是包括动脉粥样硬化和血管成形术后再狭窄在内的各种疾病的发病机制的重要方面，因此可能代表治疗靶点。血管平滑肌细胞增殖与动脉粥样硬化、血管成形术后再狭窄等疾病的发生发展密切相关.旨在减少血管平滑肌细胞增殖的新治疗靶点的开发依赖于诸如调查控制血管平滑肌细胞增殖的机制的研究。

DESCRIPTION (provided by applicant): Integrin signaling has been proposed to play a major role in the regulation of vascular smooth muscle cell (VSMC) behaviours. Proliferation of VSMCs requires the expression of CD98hc (4F2hc, SLC3A2), which is a membrane protein that is associated with amino acid transport and integrins. CD98hc is associated with cell proliferation in several different tissues but how CD98hc's functions relate to its role in proliferation has not yet been established. There are several studies that suggest a central role of integrins in CD98hc's ability to regulate cell proliferation. Furthermore, proliferation of VSMC is regulated through the ECM interaction, which are mainly mediated through integrins. To test whether CD98hc mediates integrin signaling to regulate the proliferation of VSMCs, I propose to first investigate which function of CD98hc regulates the proliferation of VSMCs. I will utilize a linked deletion and reconstitution strategy to characterize the regions of CD98hc that mediates proliferation. Mutants of CD98hc that affect either integrins or amino acid transporters have been identified previously. These mutants will thus enable me to establish the relative roles of the two interactions in VSMC responses. Mutations of the ¿1 integrin that block CD98hc binding have also been previously identified. I will reconstitute ¿1 null VSMCs with these mutants as a companion strategy to examine the role of integrin interactions in VSMC proliferation. Second I will determine the mechanism by which CD98hc regulates integrin-dependent signaling. I will examine the possible role of CD98hc oligomerization in integrin signaling by systematic mutagenesis of the extracellular and transmembrane domains of CD98hc to identify mutants that disrupt oligomerization and examine their effects on integrin signaling in VSMCs and in fibroblasts. As an alternative mechanism, I will test the possibility that CD98hc binds and therefore recruits key signaling intermediates to integrins. These studies will provide fundamental insight into the role of CD98hc in VSMC proliferation which is an important aspect of the pathogenesis of various diseases including atherosclerosis and post-angioplasty restenosis and may therefore represent a therapeutic target. VSMC proliferation contributes to the pathogenesis of many diseases such as atherosclerosis and post- angioplasty restenosis. The development of new therapeutic targets aimed at reducing vascular smooth muscle cell proliferation relies on studies such as this one that investigate the mechanism controlling vascular smooth muscle cell proliferation.