WAISMAN, DAVID M. - University of Calgary - Department of Biochemistry & Molecular Biology

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Plasmin is a fundamentally important enzyme involved in physiological processes such as blood clot lysis and pathological processes such as tumor growth and metastasis. Recent work from our laboratory has shown that the multifunctional Ca2+-binding protein, annexin II heterotetramer (AIIt) regulates the production and activity of plasmin. We are utilizing biochemical, cellular and molecular biological approaches to study the mechanism by which AIIt regulates plasmin and contributes to the metastatic potential of cancerous cells. We are also examining the potential role of AIIt in tumor cell activated fibrin turnover and fibrin blood clot dissolution using antisense and knock-out strategies. In addition to its extracellular function, AIIt is also present at the intracellular surface of the plasma membrane where it has been proposed to form a link between the cortical actin cytoskeleton and the plasma membrane. We have therefore begun an extensive series of site-directed mutagenesis studies aimed at identification of the F-actin, phospholipid and heparin-binding regions of the molecule. The role of these domains in the intracellular functions of the protein is being examined by cellular transfection experiments utilizing mutant AIIt cDNA. We have also initiated studies aimed at identification of the mechanism by which the plasmin fragment, angiostatin, blocks the recruitment of blood vessels to primary and metastatic tumors. These studies will establish the structural regions of angiostatin that are involved in the tumor-killing activity of the protein.

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Kang, H-M,. Fiipenko, N.R., Kassam, G. and Waisman, D.M. (2002) Recombinant Annexin II Tetramer. Methods in Molecular Biology: Calcium binding Proteins. Vogel, H. J. ed. Humana Press 172, 225-234. Kwon, M., Caplan, J.F., Filipenko, N.R., Choi, K.-S., Fitzpatrick, S.L., Zhang, L., and Waisman, D.M. (2002). Identification of annexin II heterotetramer as a plasmin reductase. J Biol Chem, 277, 10903-10911. Fogg, D.K., Bridges, D.E., Cheung, K.T., Kassam, G., Filipenko, N.R., Choi, K.-S., Fitzpatrick, S.L., Nesheim, M. and Waisman, D.M. (2002). The p11 subunit of annexin II heterotetramer is regulated by basic carboxypeptidase. Biochemistry, 41, 4953-4961. Brooks, N.D., Grundy, J.E., Lavigne, N., Derry, M.C., Restall, C.M., MacKenzie, C.R., Waisman, D.M., and Pryzdial, E.L.G. (2002) Ca2+-dependent, phospholipid -independent binding of annexin 2 to annexin 5. Biochem. J. epub ahead of print. Choi, K.-S., Fogg, D.K., Fitzpatrick, S.L. and Waisman, D.M. (2003). Role of Annexin II tetramer in the regulation of plasmin activity. Annexins: Biological importance and annexin-related pathologies. Joanna Bandorowicz-Pikula Ed., , Landes Bioscience, in press. Filipenko, N.R. and Waisman, D.M. (2003). Annexin II-Analysis of a Pleiotropic Protein. Annexins: Biological importance and annexin-related pathologies. Joanna Bandorowicz-Pikula Ed., Landes Bioscience, in press. Kwon, M. and Waisman, D.M. (2003) Mechanism of angiostatin formation from plasminogen. Plasminogen:Structure, Activation and Regulation. David M. Waisman, editor. Kluwer Academic/Plenum publishers. Fogg, D.K., and Waisman, D.M. (2003) Plasminogen Binding Proteins. Plasminogen:Structure, Activation and Regulation. David M. Waisman, editor. Kluwer Academic/Plenum publishers. Choi, K-S., Fogg, D.K., Yoon, C.-S. and Waisman, D.M. (2003) P11 Regulates Extracellular Plasmin Production and Invasiveness of HT1080 Fibrosarcoma Cells. FASEB J. (in press). McLeod, T. Kwon, M., Filipenko, N.R. and Waisman, D. M. Characterization of the Interaction of Phospholipid-Associated Annexin II with Plasminogen. (in preparation). Caplan, J.F., Filipenko, N.R., Fitzpatrick, S.L. and Waisman, D.M. The unexpected critical role of cysteine 8 in the biological activity of annexin II; Regulation by reversible glutathionylation. (in preparation). Hirasawa K., Nishikawa, S.G. , Norman, K.L., Coffey, M.C., Thompson, B.G., Yoon, C-S., Waisman, D.M., and Lee, P.W.K. (2003) Systemic reovirus therapy of metastatic cancer in immune competent mice. Cancer Res. (in press). Le, D.M., Besson, A., Fogg, D.K., Choi, K.-S., Goodyear, C.G., Waisman, D. M., Rewcastle, B. and Yong, V.W. (2003) Explotation of astrocytes by glioma cells to facilitate invasiveness: A mechanism involving MMP-2 and uPA-plasmin cascade. Cellular/Molecular Neuroscience. in revision. Kang, H-M., Fiipenko, N.R., Kassam, G. and Waisman, D.M. (2001) Recombinant Annexin II Tetramer. Methods in Molecular Biology: Calcium binding Proteins. Vogel, H. J. ed. Humana Press Vol. 172, 225-234. Filipenko, N.R., and Waisman, D.M. (2001) The C-Terminus of annexin II mediates binding of F-actin. J. Biol. Chem. 276, 5310-5315. Kassam, G., Kwon, M., Yoon, Chang-Soon, Graham, K.S., Young, M.k., Gluk, S. and Waisman, D.M. (2001) Purification and characterization of A61: An angiostatin-like plasminogen fragment produced by plasmin autodigestion in the absence of sulfhydryl donors. J. Biol. Chem. 276, 8924-8933. Choi KS, Fitzpatrick SL, Filipenko NR, Fogg DK, Kassam G, Magliocco AM, Waisman DM. (2001) Regulation of plasmin-dependent fibrin clot lysis by annexin II heterotetramer. J. Biol. Chem. 276, 25212-21. Kwon, M., Yoon, C-S., Fitzpatrick S.L, Kassam, G., Graham, K.S., Young, M.K., and Waisman, D.M. (2001) p22 is a novel plasminogen fragment with anti-angiogenic activity. Biochemistry 40, 13253-13252.

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