| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Concise Reviews |
Department of Hematology, Herlev Hospital;
a Finsen Laboratory, Rigshospitalet, University Hospitals, University of Copenhagen, Copenhagen, Denmark
Key Words. Urokinase-type plasminogen activator receptor (uPAR) • Urokinase • Plasminogen activator • Adhesion molecule • Vitronectin • Integrins • Differentiation antigen • Myelopoiesis
Dr. Torben Plesner, Department of Hematology, Herlev Hospital, University Hospital, DK-2730 Herlev, Denmark.
Several important functions have been assigned to the receptor for urokinase-type plasminogen activator, uPAR. As implied by the name, uPAR was first identified as a high affinity cellular receptor for urokinase plasminogen activator (uPA). It mediates the binding of the zymogen, pro-uPA, to the plasma membrane where trace amounts of plasmin will initiate a series of events referred to as "reciprocal zymogen activation" where plasmin converts pro-uPA to the active enzyme, uPA, which in turn converts plasma membrane-associated plasminogen to plasmin. This is an efficient machinery to generate broad-spectrum proteolytic activity which is spatially restricted to the plasma membrane, since plasmin that diffuses away from the plasma membrane is rapidly inactivated by circulating inhibitors (i.e.,
In addition to its role in plasminogen activation, compelling evidence has demonstrated a role for uPAR in cell-cell and cell-extracellular matrix adhesion, both directly and indirectly. uPAR is directly involved in binding to the extracellular matrix molecule, vitronectin, and the affinity of this binding is increased when uPAR is occupied by (pro-)uPA. A more indirect but presumably very important role of uPAR in cell adhesion seems to be mediated through interactions between uPAR and ß1- or ß2-integrins. It has been demonstrated that uPAR may bind physically to integrins in a reversible manner. The interaction seems to be of functional importance since the affinity of the integrin for its corresponding ligand is modulated by the association of integrin with uPAR. In some experimental setups uPAR has been shown to reduce the affinity of the associated integrin for certain ligands, while other experimental systems have demonstrated an increased affinity of the interaction between integrin and ligand after binding of uPAR to the integrin.
Finally, uPAR has also been shown to participate in signal transduction events. Since uPAR is not a transmembrane molecule but belongs to the group of proteins that are tethered to the plasma membrane via a glycosyl-phosphatidylinositol anchor, association with a transmembrane adaptor is required for transmission of signals via uPAR. Integrins may serve as such signal transducers, and indeed uPAR has been shown to be associated in the plasma membrane with complexes of integrins and (phosphorylated) tyrosin kinases suggesting a role for these complexes in transmembrane transmission of signals via uPAR.
In the hematopoietic system it has been shown that urokinase-type plasminogen activator (uPAR) is expressed as a differentiation antigen on cells of the myelomonocytic lineage and as an activation antigen on monocytes and T lymphocytes. Neutrophils contain intracellular reservoirs of uPAR that are translocated to the plasma membrane upon activation, and neutrophils from patients with the rare blood disease paroxysmal nocturnal hemoglobinuria (PNH) that fail to express glycosyl-phosphatidylinositol-anchored proteins including uPAR, show a very significantly reduced transmigration over an endothelial barrier. Cell-associated plasminogen activation by PNH-affected neutrophils is severely impaired, and it has been proposed that this may be causally related to the propensity for thrombosis in PNH. The pattern of expression of uPAR in hematological malignancies mirrors the expression by normal blood and bone marrow counterparts with some exceptions (differentiated myeloid leukemias are positive, undifferentiated myeloid may be negative and the majority of lymphoid leukemias and lymphomas are negative). The potential clinical relevance of uPAR expression in leukemias and lymphomas has not been determined.
2-antiplasmin). The system is controlled by a series of plasminogen activator inhibitors (PAIs), most importantly PAI-1 and PAI-2, providing means of temporally restricting the process of plasminogen activation.
This article has been cited by other articles:
|
|
 |
|
  M. Suelves, B. Vidal, A. L. Serrano, M. Tjwa, J. Roma, R. Lopez-Alemany, A. Luttun, M. M. de Lagran, M. A. Diaz, M. Jardi, et al. uPA deficiency exacerbates muscular dystrophy in MDX mice J. Cell Biol., September 7, 2007; 178(6): 1039 - 1051. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H Kliem, H Welter, W D Kraetzl, M Steffl, H H D Meyer, D Schams, and B Berisha Expression and localisation of extracellular matrix degrading proteases and their inhibitors during the oestrous cycle and after induced luteolysis in the bovine corpus luteum Reproduction, September 1, 2007; 134(3): 535 - 547. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. J. H. Sachs, C. L. Andrei-Selmer, A. Maniar, T. Weiss, C. Paddock, V. V. Orlova, E. Y. Choi, P. J. Newman, K. T. Preissner, T. Chavakis, et al. The Neutrophil-specific Antigen CD177 Is a Counter-receptor for Platelet Endothelial Cell Adhesion Molecule-1 (CD31) J. Biol. Chem., August 10, 2007; 282(32): 23603 - 23612. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. M. Kilpatrick, R. L. Harris, K. A. Owen, R. Bass, C. Ghorayeb, A. Bar-Or, and V. Ellis Initiation of plasminogen activation on the surface of monocytes expressing the type II transmembrane serine protease matriptase Blood, October 15, 2006; 108(8): 2616 - 2623. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-H. Kwak, S. Mitra, K. Bdeir, D. Strassheim, J. S. Park, J. Y. Kim, S. Idell, D. Cines, and E. Abraham The kringle domain of urokinase-type plasminogen activator potentiates LPS-induced neutrophil activation through interaction with {alpha}V{beta}3 integrins J. Leukoc. Biol., October 1, 2005; 78(4): 937 - 945. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. M. Sloand Soluble urokinase activator receptor (suPAR) in stem cell mobilization Blood, March 1, 2005; 105(5): 1847 - 1848. [Full Text] [PDF]
|
|
|
|
 |
|
 C. Ferland, N. Flamand, F. Davoine, J. Chakir, and M. Laviolette IL-16 Activates Plasminogen-Plasmin System and Promotes Human Eosinophil Migration into Extracellular Matrix via CCR3-Chemokine-Mediated Signaling and by Modulating CD4 Eosinophil Expression J. Immunol., October 1, 2004; 173(7): 4417 - 4424. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Scortegagna, M. A. Morris, Y. Oktay, M. Bennett, and J. A. Garcia The HIF family member EPAS1/HIF-2{alpha} is required for normal hematopoiesis in mice Blood, September 1, 2003; 102(5): 1634 - 1640. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Shetty, M. J. Wolkowicz, L. C. Digilio, K. L. Klotz, F. L. Jayes, A. B. Diekman, V. A. Westbrook, E. M. Farris, Z. Hao, S. A. Coonrod, et al. SAMP14, a Novel, Acrosomal Membrane-associated, Glycosylphosphatidylinositol-anchored Member of the Ly-6/Urokinase-type Plasminogen Activator Receptor Superfamily with a Role in Sperm-Egg Interaction J. Biol. Chem., August 15, 2003; 278(33): 30506 - 30515. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Alfano, N. Sidenius, B. Panzeri, F. Blasi, and G. Poli Urokinase-urokinase receptor interaction mediates an inhibitory signal for HIV-1 replication PNAS, June 25, 2002; 99(13): 8862 - 8867. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Ferland, M. Guilbert, F. Davoine, N. Flamand, J. Chakir, and M. Laviolette Eotaxin promotes eosinophil transmigration via the activation of the plasminogen-plasmin system J. Leukoc. Biol., May 1, 2001; 69(5): 772 - 778. [Abstract] [Full Text]
|
|
|
|
 |
|
 J. H. Chou, C. I. Bargmann, and P. Sengupta The Caenorhabditis elegans odr-2 Gene Encodes a Novel Ly-6-Related Protein Required for Olfaction Genetics, January 1, 2001; 157(1): 211 - 224. [Abstract] [Full Text]
|
|
|
|
|
|
N. Sidenius, C. F. M. Sier, H. Ullum, B. K. Pedersen, A. C. Lepri, F. Blasi, and J. Eugen-Olsen Serum level of soluble urokinase-type plasminogen activator receptor is a strong and independent predictor of survival in human immunodeficiency virus infection Blood, December 15, 2000; 96(13): 4091 - 4095. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Guilbert, C. Ferland, M. Bossé, N. Flamand, S. Lavigne, and M. Laviolette 5-Oxo-6,8,11,14-Eicosatetraenoic Acid Induces Important Eosinophil Transmigration through Basement Membrane Components . Comparison of Normal and Asthmatic Eosinophils Am. J. Respir. Cell Mol. Biol., July 1, 1999; 21(1): 97 - 104. [Abstract] [Full Text]
|
|
|
|
|
|
M. Pucci, G. Fibbi, L. Magnelli, and M. Del Rosso Regulation of Urokinase/Urokinase Receptor Interaction by Heparin-like Glycosaminoglycans J. Biol. Chem., February 9, 2001; 276(7): 4756 - 4765. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| STEM CELLS | THE ONCOLOGIST | CME | ALPHAMED PRESS JOURNALS |
