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的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 膜联蛋白2是纤溶酶原和组织纤溶酶原激活物的促纤溶共受体，其刺激细胞表面的主要纤溶酶纤溶酶的激活。在人类受试者中，急性早幼粒细胞白血病中膜联蛋白2的过度表达导致出血素质，这反映了过度的细胞表面膜联蛋白2依赖性纤溶酶产生。此外，膜联蛋白2完全缺乏的小鼠显示血管内纤维蛋白积聚和损伤诱导的血栓清除受损。我们以前已经表明，内皮细胞膜联蛋白2，缺乏一个典型的信号肽的蛋白质，易位从细胞质到细胞质外质膜在短暂的温度应激反应在体外和体内的细胞死亡或细胞裂解的情况下。这种受调节的反应不依赖于新蛋白质或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易位依赖于蛋白质p11（S100 A10）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突变时完全消除。膜联蛋白2易位到细胞表面显着增加组织纤溶酶原激活物依赖的纤溶酶原激活的潜力，并可能代表一种新的应激诱导的蛋白质分泌途径。我们已经确定了免疫亲和试验和质谱至少四种蛋白质，可能与膜联蛋白2的易位机制的细胞表面。目前正在研究这些推定的候选蛋白。