Traditionally, fibrinolysis has been conceptualized as a process oriented on a and confined to the surface of a fibrin clot. Recent published data generated by the applicant, however, demonstrate specific, high affinity, saturable binding for both glu-plasminogen (PLG) and tissue plasminogen activator (t-PA) to the surface of cultured human umbilical vein endothelial cells (HUVEC). Upon binding to HUVEC, PLG acquired a 12.7-fold increase in catalytic efficiency of activation by c-PA. Similarly, the ability of t-PA to activate PLG was preserved when t-PA was associated with the cell surface. The current studies will examine the molecular mechanisms by which PLG and t-PA interact with the endothelial cell surface. The applicant will (1) study the mechanism by which surface associated PLG acquires enhanced """"""""activatability,"""""""" by examining the possible role of modified forms of PLG in this interaction; (2) identify potential PLG and t-PA binding sites using detergent extracts of isolated HUVEC plasma membranes in ligand blotting, affinity chromatography, bifunctional cross- linking, and monoclonal antibody immunodetection procedures; (3) identify the cell surface binding domain of t-PA in experiments employing specific deletion mutants of t-PA, chemically modified forms of t-PA, and anti-t-PA monoclonal antibodies with defined epitope specificity; regulation of PLG or t-PA binding by cytokines known to influence HUVEC study the synthesis and secretion of t-PA and its major inhibitor, PAI; and (5) examine the relationship of PLG binding sites on HUVEC to apolipoprotein a """"""""kringle-""""""""containing protein which is correlated with atherosclerosis, and highly homologous to PLG.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL042493-03
Application #
3360751
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1989-07-01
Project End
1994-06-30
Budget Start
1991-07-01
Budget End
1992-06-30
Support Year
3
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Type
Schools of Medicine
DUNS #
201373169
City
New York
State
NY
Country
United States
Zip Code
10065
Li, Wenlu; Chen, Zhigang; Yuan, Jing et al. (2018) Annexin A2 is a Robo4 ligand that modulates ARF6 activation-associated cerebral trans-endothelial permeability. J Cereb Blood Flow Metab :271678X18777916
Staquicini, Daniela I; Rangel, Roberto; Guzman-Rojas, Liliana et al. (2017) Intracellular targeting of annexin A2 inhibits tumor cell adhesion, migration, and in vivo grafting. Sci Rep 7:4243
Luo, Min; Flood, Elle C; Almeida, Dena et al. (2017) Annexin A2 supports pulmonary microvascular integrity by linking vascular endothelial cadherin and protein tyrosine phosphatases. J Exp Med 214:2535-2545
Liu, Wei; Hajjar, Katherine A (2016) The annexin A2 system and angiogenesis. Biol Chem 397:1005-16
Hajjar, David P; Hajjar, Katherine A (2016) Alterations of Cholesterol Metabolism in Inflammation-Induced Atherogenesis. J Enzymol Metab 1:
Stukes, Sabriya; Coelho, Carolina; Rivera, Johanna et al. (2016) The Membrane Phospholipid Binding Protein Annexin A2 Promotes Phagocytosis and Nonlytic Exocytosis of Cryptococcus neoformans and Impacts Survival in Fungal Infection. J Immunol 197:1252-61
Salameh, Ahmad; Daquinag, Alexes C; Staquicini, Daniela I et al. (2016) Prohibitin/annexin 2 interaction regulates fatty acid transport in adipose tissue. JCI Insight 1:
Chapin, John C; Hajjar, Katherine A (2015) Fibrinolysis and the control of blood coagulation. Blood Rev 29:17-24
Morozova, Kateryna; Sridhar, Sunandini; Sidhar, Sunandini et al. (2015) Annexin A2 promotes phagophore assembly by enhancing Atg16L? vesicle biogenesis and homotypic fusion. Nat Commun 6:5856
Hajjar, Katherine A (2015) The Biology of Annexin A2: From Vascular Fibrinolysis to Innate Immunity. Trans Am Clin Climatol Assoc 126:144-55

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