Regulation of Cell Migration and Invasion by Specific Modules of uPA: Mechanistic Insights and Specific Inhibitors

Maria      Vincenza Carriero; Paola      Franco; Giuseppina      Votta; Immacolata      Longanesi-Cattani; Maria      Teresa Vento; Maria      Teresa Masucci; Alessandro      Mancini; Mario      Caputi; Ingram      Iaccarino; Maria      Patrizia Stoppelli

Abstract

Urokinase (uPA) is a 411 residues serine protease originally identified for its ability to activate plasminogen and generate plasmin, a broad-spectrum matrix- and fibrin-degrading enzyme. Later, this protease has been shown to possess also a clear-cut ability to stimulate cell migration and survival in a catalytic-independent manner. This activity turned out to be exerted through the growth factor-like domain (GFD-like, residues 1-49) of the protease binding to a GPIanchored membrane receptor (uPAR), in complex with transmembrane receptors such as integrins, the epidermal growth factor and the formyl-peptide receptors. Direct binding of uPA to integrins through its kringle (residues 50-131) and connecting peptide (residues 132-158) regions results in enhanced migration. The dual function of uPA in promoting migration while reducing the physical resistance of extracellular matrix underlies its crucial role in the invasion of malignant tumours. Consolidated evidence emerging from animal models and clinical studies shows that the overexpression of uPA is a causal determinant to tumour metastasis and is associated to a poor prognosis. Therefore, pinpointing the molecular interactions and identifying novel agents to interfere with the diverse activities of uPA is a goal of basic and applied research. In this review, we discuss the general theme of cell migration and invasion. A description of the uPA structure-function relationship and the functional effects of isolated domains is presented. Current information on molecular agonistic as well as antagonistic compounds, including the compounds which have reached clinical trials, is provided.

Keywords: Cell migration, cell invasion, inhibitors of cell migration, inhibitors of cell invasion, peptides, urokinase, serine proteases, inhibitors, uPA, protease urokinase, antagonist, anticancer therapy