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
Current Drug Targets
Title: Regulation of Cell Migration and Invasion by Specific Modules of uPA: Mechanistic Insights and Specific Inhibitors
Volume: 12 Issue: 12
Author(s): Maria Vincenza Carriero, Paola Franco, Giuseppina Votta, Immacolata Longanesi-Cattani, Maria Teresa Vento, Maria Teresa Masucci, Alessandro Mancini, Mario Caputi, Ingram Iaccarino and Maria Patrizia Stoppelli
Affiliation:
Keywords: Cell migration, cell invasion, inhibitors of cell migration, inhibitors of cell invasion, peptides, urokinase, serine proteases, inhibitors, uPA, protease urokinase, antagonist, anticancer therapy
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.
Export Options
About this article
Cite this article as:
Vincenza Carriero Maria, Franco Paola, Votta Giuseppina, Longanesi-Cattani Immacolata, Teresa Vento Maria, Teresa Masucci Maria, Mancini Alessandro, Caputi Mario, Iaccarino Ingram and Patrizia Stoppelli Maria, Regulation of Cell Migration and Invasion by Specific Modules of uPA: Mechanistic Insights and Specific Inhibitors, Current Drug Targets 2011; 12 (12) . https://dx.doi.org/10.2174/138945011797635777
DOI https://dx.doi.org/10.2174/138945011797635777 |
Print ISSN 1389-4501 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5592 |
Call for Papers in Thematic Issues
Drug-Targeted Approach with Polymer Nanocomposites for Improved Therapeutics
Polymer nanocomposites have been recognized as an advanced and cutting-edge technique in drug targeting administration. These materials combine the unique features of nanoparticles with the adaptability of polymers to produce highly personalized drug administration devices. Integrating nanoparticles containing pharmaceuticals into a polymer matrix enables researchers to regulate the rates at ...read more
RNA Molecules in the Treatment of Human Diseases
Messenger and non-coding RNAs, including long and small transcripts, are mediators of gene expression. Gene expression at the RNA level shows significant aberrations in human diseases, including cancer, leukemia, lymphoma, cardiovascular diseases, and neurological disorders. Human transcripts serve either as biomarkers of diagnosis, prognosis, prediction of treatment response and/or therapy ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Association of Oxidative Stress to the Genesis of Anxiety: Implications for Possible Therapeutic Interventions
Current Neuropharmacology Adverse Reactions and Pathogen Safety of Intravenous Immunoglobulin
Current Drug Safety Disorders of Innate Immunity in Human ageing and effects of Nutraceutical Administration
Endocrine, Metabolic & Immune Disorders - Drug Targets Oral Glucose-lowering Drugs and Cardiovascular Outcomes: From the Negative RECORD and ACCORD to Neutral TECOS and Promising EMPA-REG
Current Vascular Pharmacology Screening Aortic Drug Treatments Through Arterial Compliance Measurements
Current Vascular Pharmacology Metabolic Syndrome and Non-Cardiac Vascular Diseases: An Update from Human Studies
Current Pharmaceutical Design Value of Real Time Three Dimensional Transesophageal Echocardiography in General Cardiology Practice
Recent Patents on Medical Imaging New Insights into the Pleiotropic Effects of Statins for Stroke Prevention
Mini-Reviews in Medicinal Chemistry Increased Radioisotope Accumulation Around Pulmonary Arteriovenous Fistula Illustrated by Tc-99m-macroaggregated Albumin Scintigraphy and SPECT/CT in a Patient with Osler-Weber-Rendu Syndrome
Current Medical Imaging Therapeutic Hypothermia as a Neuroprotective Strategy in Neonatal Hypoxic-Ischemic Brain Injury and Traumatic Brain Injury
Current Molecular Medicine Chymase Inhibitor As a Novel Therapeutic Strategy for Anti-Vascular Remodeling
Vascular Disease Prevention (Discontinued) Perspectives of Gene Therapies in Autosomal Dominant Polycystic Kidney Disease
Current Gene Therapy Propofol and Systemic Inflammatory Response in Abdominal Aortic Surgery
Letters in Drug Design & Discovery Improved Anti-inflammatory Activity and Potential Cytoprotective Properties of Tolfenamic Acid, Naproxen and Indomethacin Derivatives
Letters in Drug Design & Discovery The FDG-PET Revolution of Medical Imaging – Four Decades and Beyond
Current Molecular Imaging (Discontinued) Kinin Receptors in Vascular Biology and Pathology
Current Vascular Pharmacology Impact of the Renin-Angiotensin-Aldosterone-System on Cardiovascular and Renal Complications in Diabetes Mellitus
Current Vascular Pharmacology A Survey on Medical Image Segmentation
Current Medical Imaging Internal Carotid Artery Dissecting Aneurysm Associated with Persistent Trigeminal Artery: A Case Report
Current Medical Imaging Potential Use of Dendritic Cells for Anti-Atherosclerotic Therapy
Current Pharmaceutical Design