An annexin 2 phosphorylation switch mediates p11-dependent translocation of annexin 2 to the cell surface.
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, overexpression of annexin 2 in acute promyelocytic leukemia leads to a bleeding diathesis reflective of excessive cell surface annexin 2-dependent generation of plasmin (Menell, J. S., Cesarman, G. M., Jacovina, A. T., McLaughlin, M. A., Lev, E. A., and Hajjar, K. A. (1999) N. Engl. J. Med. 340, 994-1004). In addition, mice completely deficient in annexin 2 display fibrin accumulation within blood vessels and impaired clearance of injury-induced thrombi (Ling Q., Jacovina, A.T., Deora, A.B., Febbraio, M., Simantov, R., Silverstein, R. L., Hempstead, B. L., Mark, W., and Hajjar, K. A. (2004) J. Clin. Investig. 113, 38-48). Here, we show 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 reticulum-Golgi pathway. Temperature stress-induced annexin 2 translocation is dependent on both expression of protein p11 (S100A10) and tyrosine phosphorylation of annexin 2 because annexin 2 release 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.
Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, New York 10021, USA.
Arunkumar B
AB
Deora
Geri
G
Kreitzer
Andrew T
AT
Jacovina
Katherine A
KA
Hajjar
D017306:Annexin A2 / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D003001:Cloning, Molecular; D018076:DNA, Complementary; D004730:Endothelium, Vascular / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D010766:Phosphorylation; D021381:Protein Transport; D011994:Recombinant Proteins / Q000378:metabolism; D009418:S100 Proteins / Q000378:metabolism*; D013816:Thermodynamics; D014471:Umbilical Veins; D000099248:S100 Calcium Binding Protein A10
D017306:Annexin A2; D018076:DNA, Complementary; D011994:Recombinant Proteins; D009418:S100 Proteins; D000099248:S100 Calcium Binding Protein A10; C472822:ANXA2 protein, human