This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor 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.
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