Cell Surface Receptor Trafficking

细胞表面受体运输

• 批准号: 7085471
• 负责人: BRUCE F HORAZDOVSKY
• 金额: $ 24.08万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7085471
• 关键词: 3T3 cells; CHO cells; PC12 cells; SDS polyacrylamide gel electrophoresis; autoradiography; biological signal transduction; cell surface receptors; green fluorescent proteins; guanine nucleotide exchange factors; immunoprecipitation; intracellular transport; laboratory rabbit; mass spectrometry; matrix assisted laser desorption ionization; northern blottings; phosphorylation; posttranslational modifications; protein localization; protein protein interaction; protein structure function; receptor mediated endocytosis; western blottings

DESCRIPTION (provided by applicant): Endocytosis of cell surface receptors plays an important role in regulating cell signaling cascades. In some cases, internalization of an activated receptor is thought to attenuate the signaling process, while in other cases the clustering of activated receptors on early endosomal structures have been proposed to be essential for fully activating signaling cascades. In either case, these scenarios indicate that the intracellular trafficking of cell surface receptors are linked directly or indirectly to cell signaling cascades. There are many potential points at which the endocytic pathway and signaling cascades can intersect. The activation of Rab proteins is one point that signaling cascades could influence flux through the endocytic pathway as demonstrated by the fact that cells expressing activated forms of Rab5 (GTPase defective) exhibit increased flux of cell surface receptors through the early stages of the endocytic pathway. The activation of Rab5 is mediated by several guanine nucleotide exchange factors. One of these, RIN1 is itself activated by binding Ras.GTP and we have proposed that this Ras-GTP mediated activation serves as a link between signaling cascades and the endocytic pathway. The catalytic domain found in RIN1 that is responsible for mediating Rab5 nucleotide exchange is its Vps9p-domain. This domain is highly conserved and has been found in a large number of proteins from budding yeast to mammals. Like the RIN1 protein family members, many of these proteins contain other domains in addition to their Vpsgp domain, which offer additional functionalities to these proteins. We propose that proteins that contain the Vps9p domain serve as specific Rab5 activators and link the regulation of a variety of cellular processes to the endocytic pathway. To test this hypothesis we will determine the precise functional role of the three members of the RIN1 family (RIN1, RIN2 and RIN3) in the process of receptor mediated endocytosis.

描述（由申请人提供）：细胞表面受体的内吞作用在调节细胞信号级联反应中起重要作用。在某些情况下，人们认为活化受体的内在化可以减弱信号传导过程，而在其他情况下，已经提出，在早期内体结构上激活受体的聚类对于完全激活信号级联反应至关重要。无论哪种情况，这些情况都表明细胞表面受体的细胞内运输直接或间接与细胞信号级联有关。内吞通路和信号级联反应可以相交的潜在点很多。 Rab蛋白的激活是信号传导级联反应可能影响通过内吞途径的通量的一个，这证明了表达活化形式的Rab5（GTPase缺陷）的细胞通过内吞途径的早期阶段表现出细胞表面受体的通量增加。 Rab5的激活是由几种鸟嘌呤核苷酸交换因子介导的。其中之一，RIN1本身是通过结合Ras.GTP激活的，我们建议该RAS-GTP介导的激活作为信号级联和内吞途径之间的联系。在RIN1中发现的催化结构域介导Rab5核苷酸交换是其VPS9P结构域。该结构域是高度保守的，并且已经在从萌芽酵母到哺乳动物的大量蛋白质中发现。像RIN1蛋白家族成员一样，除了其VPSGP结构域外，许多这些蛋白质都包含其他域，这些结构域为这些蛋白质提供了其他功能。我们建议包含VPS9P结构域的蛋白质是特定的RAB5激活剂，并将各种细胞过程的调节与内吞途径联系起来。为了检验这一假设，我们将在受体介导的内吞作用过程中确定RIN1家族三个成员（RIN1，RIN2和RIN3）的精确功能作用。

项目成果

Subcutaneous IGF-1 is not beneficial in 2-year ALS trial.

• DOI: 10.1212/01.wnl.0000335970.78664.36
• 发表时间: 2008-11-25
• 期刊: NEUROLOGY
• 影响因子: 9.9
• 作者: Sorenson, E. J.;Windbank, A. J.;Mandrekar, J. N.;Bamlet, W. R.;Appel, S. H.;Armon, C.;Barkhaus, P. E.;Bosch, P.;Boylan, K.;David, W. S.;Feldman, E.;Glass, J.;Gutmann, L.;Katz, J.;King, W.;Luciano, C. A.;McCluskey, L. F.;Nash, S.;Newman, D. S.;Pascuzzi, R. M.;Pioro, E.;Sams, L. J.;Scelsa, S.;Simpson, E. P.;Subramony, S. H.;Tiryaki, E.;Thornton, C. A.
• 通讯作者: Thornton, C. A.