Plasminogen binding and cancer: promises and pitfalls.
The urokinase plasminogen activation system is a key modulator of the tissue remodeling processes required for tumor cell invasion and metastasis. Malignant progression is characterised by inappropriately high cell surface levels of receptor- bound active urokinase. This enhances the rate of plasminogen activation resulting in markedly increased levels of cell surface plasmin. The repercussions of this are significant and include the activation of growth factors and signaling pathways, and the degradation of extracellular matrices, either directly or indirectly, via the activation of matrix metalloproteinases. Native, circulating plasminogen binds in a lysine- and/or carbohydrate-dependent manner to tumor and endothelial cells with low affinity but high capacity and a heterogeneous group of plasminogen receptors have been identified. This heterogeneity underscores the complexity of the mechanisms responsible for the regulation of cell-surface plasminogen binding. This review summarizes the literature on known plasminogen receptor candidates and shows that they can be subdivided into three classes based on their mode of interaction with plasminogen. We also aim to emphasize the notion that in the tumor environment the known intrinsic functional relationship between plasminogen conformation and activation is essentially connected to cellular binding. This allows plasminogen to be co-localised in an activation-susceptible form with the enhanced uPA levels seen in malignancy and together furnishes tumor cells with elevated tissue remodeling capacity. In addition, some of the pitfalls and strategies encountered when conducting plasminogen receptor experiments are also addressed.
Ranson
Marie
M
Department of Biological Sciences and Institute for Biomolecular Sciences, University of Wollongong, Australia, 2522. marie_ranson@uow.edu.au
Andronicos
Nicholas M
NM
D000818:Animals; D006801:Humans; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D010958:Plasminogen / Q000378:metabolism* / Q000502:physiology; D011485:Protein Binding / Q000502:physiology
D010958:Plasminogen