SHC FAMILY PROTEINS

描述：(改编自调查人员的摘要)现在很清楚 Shc蛋白是一组不同蛋白质的靶标，包括 受体和非受体酪氨酸激酶，免疫球蛋白受体， G蛋白偶联受体和细胞因子受体。激活这些 导致Shc酪氨酸磷酸化的因素导致 Grb2-SOS复合体的招募和随后RAS的激活 信号转导级联。此外，很明显，Shc 除了RAS的激活外，蛋白质也可能参与信号的传递。虽然 SHC蛋白代表一系列不同的信号分子的靶标， Shc蛋白在这些蛋白的功能中的重要性仍然是 不清楚。这项建议的目的是研究房委会的职能。 一般的蛋白质，特别是特定的Shc家族成员ShcC。 这一目标将通过以下具体目标来实现： (1)确定Shc蛋白在受体酪氨酸激酶功能中的作用； (2)研究ShcC PTB结构域在结合磷脂和 膜定位；以及(3)确定ShcD是否在神经中起作用 发展和信号传递。 利用ShcC的突变形式，他们将研究Shc蛋白的重要性 在RTK介导的RAS的转化和激活中。这些突变的蛋白质 将测试它们对受刺激的生化途径的影响 不同的受体，例如MAPK的激活，以及它们对 慢性受体激活的生物学后果，例如转化。 最近的证据表明，PTB结构域可能具有膜的功能 定位信号。此外，他们还可能在 磷脂信号的调节。他们将决定 ShcC PTB结构域在膜上的定位与其能力的关系 结合酪氨酸磷酸化蛋白和磷脂。 鉴于ShcC仅在神经起源的组织中表达，他们 将研究ShcC在神经发育和信号传递中的作用。穿过 胚胎小鼠和成年小鼠的免疫组织化学染色 组织他们将确定ShcC的精确时间和空间模式 表情。利用原代培养的小鼠神经元，他们将确定 ShcC在神经元分化过程中的表达模式。结合 通过这种方法，他们还将利用永生化的神经母细胞瘤细胞 检测ShcC在生长和发育过程中的生化功能的品系 差异化。 本文提出的研究将有助于阐明Shc的功能 蛋白质，特别是ShcC。此外，这些实验 将开始讨论ShcC在神经功能中的重要性。给定 影响Shc蛋白的信号多样性及其多样性 总体来说，这项提议将开始确定Shc蛋白的 一个小说中Shc家族成员的具体角色。

DESCRIPTION: (adapted from the investigator's abstract) It is now clear that Shc proteins are targets of a diverse group of proteins including both receptor and non-receptor tyrosine kinases, immunoglobulin receptors, G-protein coupled receptors and cytokine receptors. Activation of these factors leads to tyrosine phosphorylation of Shc resulting in the recruitment of the Grb2-Sos complex and subsequent activation of the Ras signal transduction cascade. In addition, it has become clear that Shc proteins may also mediate signals in addition ro Ras activation. Although Shc proteins represent targets of a diverse array of signaling molecules, the importance of Shc proteins in the function of these proteins is still unclear. The objective of this proposal is to examine the function of Shc proteins in general and a specific Shc family member, ShcC, in particular. This objective will be accomplished through the following specific aims: (1) determine the role of Shc proteins in receptor tyrosine kinase function; (2) examine the role of the ShcC PTB domain in binding phospholipids and membrane localization; and (3) determine if ShcD functions in neural development and signaling. Using mutant forms of ShcC, they will examine the importance of Shc proteins in RTK-mediated transformation and activation of Ras. These mutant proteins will be tested for their effect on the biochemical pathways stimulated by various receptors, e.g. MAPK activation, as well as their effect on the biological consequences of chronic receptor activation, e.g. transformation. Recent evidence suggests that PTB domains may function as membrane localization signals. In addition, they may also play a role in the regulation of phospholipid signaling. They will determine the role of the ShcC PTB domain in membrane localization as a function of its ability to bind tyrosine phosphorylated proteins as well as phospholipids. Given the restricted expression of ShcC to tissues of neural origin, they will examine the role of ShcC in neural development and signaling. Through immunohistochemical staining of both embryonic as well as adult mouse tissues they will determine the precise temporal and spatial pattern of ShcC expression. Using primary mouse neuronal culture, they will determine the pattern of ShcC expression during neuronal differentiation. In conjunction with this approach, they will also utilize immortalized neuroblastoma cell lines to examine the biochemical function of ShcC in growth and differentiation. The studies proposed here will help to elucidate the function of Shc proteins in general and ShcC in particular. Furthermore, these experiments will begin to address the importance of ShcC in neural function. Given the diversity of signals which impinge on Shc proteins as well as the diversity of Shc proteins in general, this proposal will begin to determine the specific role of a novel Shc family member.