IDENTIFICATION OF PUTATIVE PROTEIN CANDIDATES IN THE EXPORT MECHANISM OF ANNEXI

附件出口机制中推定候选蛋白质的鉴定

• 批准号: 7722216
• 负责人: KATHERINE AMBERSON HAJJAR
• 金额: $ 0.11万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7722216
• 关键词: Acute Promyelocytic Leukemia; Alteplase; Annexins; Biological Assay; Blood Vessels; Cell Death; Cell membrane; Cell surface; Cells; Computer Retrieval of Information on Scientific Projects Database; Cytolysis; Cytoplasm; Disease susceptibility; Endothelial Cells; Fibrin; Funding; Generations; Grant; Hemorrhage; In Vitro; Injury; Institution; Mass Spectrum Analysis; Messenger RNA; Mus; Mutation; Pathway interactions; Peptide Signal Sequences; Plasmin; Plasminogen; Protein Secretion; Protein Tyrosine Kinase; Proteins; Research; Research Personnel; Resources; S100 family protein p11; Source; Stress; Stress-Induced Protein; Temperature; Thrombus; Tyrosine; Tyrosine Phosphorylation; United States National Institutes of Health; human subject; in vivo; novel; plasminogen receptor; protein expression; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Annexin 2 is a profibrinolytic co-receptor for plasminogen and tissue plasminogen activator that stimulates activation of the major fibrinolysin, plasmin, at cell surfaces. In human subjects, over-expression of annexin 2 in acute promyelocytic leukemia leads to a bleeding diathesis reflective of excessive cell surface annexin 2-dependent generation of plasmin. In addition, mice completely deficient in annexin 2 display fibrin accumulation within blood vessels and impaired clearance of injury-induced thrombi. We have previously shown that endothelial cell annexin 2, a protein that lacks a typical signal peptide, translocates from the cytoplasm to the extracytoplasmic plasma membrane in response to brief temperature stress both in vitro and in vivo in the absence of cell death or cell lysis. This regulated response is independent of new protein or mRNA synthesis and does not require the classical endoplasmic reticulumGolgi pathway. Translocation of annexin 2 induced by temperature stress is dependent on both expression of protein p11 (S100A10) and tyrosine phosphorylation of annexin 2 because the release of annexin 2 is completely eliminated on depletion of p11, inactivation of tyrosine kinase, or mutation of tyrosine 23. Translocation of annexin 2 to the cell surface dramatically increases tissue plasminogen activator-dependent plasminogen activation potential and may represent a novel stress-induced protein secretion pathway. We have identified by immunoaffinity assays and mass spectrometry at least four proteins that may be associated with the translocation mechanism of annexin 2 to the cell surface. These putative protein candidates are currently being investigated.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 膜联蛋白2是纤溶酶原和组织纤溶酶原激活剂的前纤溶联合受体，刺激细胞表面主要的纤溶酶--纤溶酶的激活。在人类中，急性早幼粒细胞白血病中膜联蛋白2的过度表达导致了反映细胞表面膜联蛋白2过度依赖的纤溶酶生成的出血性质。此外，完全缺乏膜联蛋白2的小鼠表现出血管内纤维蛋白堆积和损伤诱导的血栓清除障碍。我们先前已经证明，内皮细胞膜联蛋白2是一种缺乏典型信号肽的蛋白质，在体外和体内都能在没有细胞死亡或细胞裂解的情况下，响应短暂的温度应激，从细胞质转移到细胞质外质膜。这种受调控的反应不依赖于新的蛋白质或mRNA的合成，也不需要经典的内质网高尔基体途径。温度应激诱导的膜联蛋白2的易位依赖于蛋白p11(S100A10)的表达和膜联蛋白2的酪氨酸磷酸化，因为膜联蛋白2的释放在p11耗尽、酪氨酸激酶失活或酪氨酸23突变时被完全消除。膜联蛋白2转位到细胞表面，显著增加了组织纤溶酶原激活剂依赖的纤溶酶原激活潜能，可能代表了一种新的应激诱导的蛋白质分泌途径。我们已经通过免疫亲和分析和质谱仪鉴定了至少四种可能与膜联蛋白2向细胞表面转运机制相关的蛋白质。目前正在对这些可能的蛋白质候选进行研究。