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 II is a profibrinolytic co-receptor for plasminogen (Kd = 114 nM) and tissue plasminogen activator (Kd = 30nM), which stimulates activation of the major fibrinolysin, plasmin, 60-fold. Endothelial cell annexin II, a protein that lacks a typical signal peptide, is translocated 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 II induced by temperature stress is dependent on both expression of protein p11 (S100A10) and tyrosine phosphorylation of annexin II because the release of annexin II is completely eliminated on depletion of p11, inactivation of tyrosine kinase, or mutation of tyrosine 23. Translocation of annexin II to the cell surface dramatically increases tissue plasminogen activator-dependent plasminogen activation potential and may represent a novel stress-induced protein secretion pathway. The formation of the annexin II heterotetramer, composed of two annexin II and two p11 molecules, induces activation of plasmin even further. We have shown that sequestering of p11 for degradation via the ubiquitination pathway leads to a significant decrease in plasminogen activation, thus plasmin formation. We have undergone extensive mapping of the putative ubiquitination sites on p11 by mass spectrometric techniques and have currently covered 94% of the protein sequence. The remaining sequence region is located on the carboxyl terminal of p11 and contains three lysyl residues. It still remains to ascertain which one the three residues is actually being modified by ubiquitination.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Biotechnology Resource Grants (P41)
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Special Emphasis Panel (ZRG1-BCMB-Q (40))
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Rockefeller University
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New York
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