Review
Urokinase receptor: a molecular organizer in cellular communication

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Abstract

In a variety of cell types, the glycolipid-anchored urokinase receptor (uPAR) is colocalized pericellularly with components of the plasminogen activation system and endocytosis receptors. uPAR is also coexpressed with caveolin and members of the integrin adhesion receptor superfamily. The formation of functional units with these various proteins allows the uPAR to mediate the focused proteolysis required for cell migration and invasion and to contribute both directly and indirectly to cell adhesive processes in a non-proteolytic fashion. This dual activity, together with the initiation of signal transduction pathways by uPAR, is believed to influence cellular behaviour in angiogenesis, inflammation, wound repair and tumor progression/metastasis and open up the way for uPAR-based therapeutic approaches.

Introduction

Cell adhesion, migration and invasion depend on the coordinated expression and function of various adhesion receptors (such as integrins), together with the pericellular activities of protease systems that counteract cell–substratum and cell–cell interactions. The plasminogen activation system (which includes the plasminogen activators, their inhibitors, plasminogen, and their respective cell-surface-binding proteins/receptors) plays a central role in cell invasion [1]. The nonclassical activities of the plasminogen activation system and the pericellular cooperation of its components with adhesion receptors, extracellular matrix (ECM) proteins and signaling molecules, have provided new insights into their role as molecular coordinators of cell adhesion [2].

The tissue-type plasminogen activator and the urokinase-type plasminogen activator (uPA), respectively, promote the formation of intra- and extravascular plasmin, the key protease in fibrinolysis. Plasmin activates matrix-metalloproteinases, which constitute a proteolytic system for cell migration and tissue remodelling [3]. Together, these proteases may activate latent growth factors or release them from their ECM-binding sites and degrade a variety of proteins in the ECM. This results in cell invasion. The plasminogen activators can be neutralized by different plasminogen activator inhibitors (PAIs) one of which, the fast acting PAI-1, plays the predominant role [1]. PAI-1 is a serine protease inhibitor, but unlike the others, the active conformation of PAI-1 is stabilized by high affinity binding to ECM-associated vitronectin (VN). VN is an Arg–Gly–Asp-containing adhesive glycoprotein found in the wound matrix or in degenerated tissues where PAI-1 can accumulate [4]. All other components of the plasminogen activation system bind to the cell surface via specific receptors (for example, pro-uPA binds to the urokinase receptor [uPAR] [5]) or via carboxy-terminal lysine-containing surface proteins (for plasminogen) [6] or via members of the LDL-receptor family such as LRP/α2-macroglobulin receptor or VLDL-receptor (for uPA–PAI-1 complex) [7]. PAI-1 also affects uPAR occupancy, as it triggers the internalization of the uPA–uPAR complex, the lysosomal degradation of uPA and eventually the recycling of free uPAR to the cell surface 7, 8. Thus, the dynamic expression of components of the uPAR system enables them to simultaneously participate in diverse reactions in the pericellular space of individual cells.

The targeted disruption of each of the murine genes for uPA, uPAR, PAI-1, plasminogen or VN does not affect embryonic development or growth to adulthood or fertility despite predictions of a general role for this system in cell migration and invasion. However, different disease models have been very informative and have helped to elucidate the role of the uPAR system in vascular pathology, inflammation and cancer 9, 10. For example, deletion of uPAR in mice had no significant effect on the uPA-mediated plasmin formation required for wound healing [11], which would indicate a proteolysis-independent role for uPAR. Also, when compared with plasminogen−/− mice, there was less disseminated fibrin deposition than in (uPAR/uPA)−/− mice, implying a minor role for this complex in fibrinolysis [12]. Mice deficient in uPA, plasminogen and uPAR exhibited an increased susceptibility to certain site-specific bacterial infections as well as diminished recruitment of leukocytes to the site of infection, respectively 13, 14, 15, 16, 17•. These protease-independent functions of uPAR in vivo might relate to various interactions of the molecule with adhesion receptor systems and intracellular signal transduction cascades 18, 19•. The role of the uPAR system in this respect will be discussed below with regard to the direct role of uPAR as an adhesion receptor in cellular interactions and its function as an organizer of adhesive cell–cell and cell–ECM communications. These communications involve multicomponent complexes, composed particularly of various types of integrins and caveolin.

Section snippets

Expression of uPAR, ligand binding and linkage to cell adhesion

Both, the expression pattern of uPAR and its proximity to adhesion and signaling molecules places this protease receptor at the crossroads of cellular adhesion. The uPAR is expressed on the surface of many cell types including circulating blood leukocytes, endothelial and vascular smooth muscle cells, fibroblasts and bone marrow cells, as well as a variety of neoplastic cells 1•, 5. uPAR gene expression is influenced/increased by tumor promoters, growth factors, cytokines and hormones as well

uPAR ligands

Three nonrelated extracellular protein ligands have been identified for uPAR, namely uPA, VN, and kininogen. These are multifunctional factors with overlapping activities in pericellular proteolysis, cell migration, wound healing and inflammatory reactions. In addition, certain integrin α-chains may directly interact with uPAR in a cis- or trans-type manner and thereby constitute cell-anchored counter-ligands for uPAR ([29]; Y Takada et al., personal communication). In particular, intact uPAR

Direct role of uPAR in cellular adhesion

Conceptionally, uPAR can act in cell adhesion either directly, as a cell-linked adhesion protein or counter-receptor, or indirectly, as a modulator of integrins in association with additional cytoskeletal and signaling proteins. Direct cell adhesion predominantly relates to VN-dependent adhesion of mostly leukocytic cells, which do not express caveolin and VN-responsive integrins. uPAR can indirectly influence adhesive properties, particularly of leukocytic β2-integrins, and regulate both

uPAR, VN and leukocyte adhesion

Owing to the GPI-anchor of uPAR, the cellular contacts formed directly between uPAR-bearing cells and VN-rich substratum are different from typical cytoskeleton-associated (clustered) adhesion receptors, which can resist mechanical stress. Oligomerization of uPAR and the uPAR–uPA complex might ensure at least a temporary mechanical stability for direct uPAR-mediated cell adhesion to VN [45]. This could explain our observation that multimeric VN, rather than monomers, serves as the predominant

uPAR and chemotaxis

Manipulation of the uPA/uPAR system by proteolysis or post-translational modifications can alter physical interactions with putative signaling molecules, which change cellular adhesion [55]. Cell motility (e.g. chemotaxis, migration) stimulated by active uPA can involve plasmin generation and the subsequent degradation of ECM proteins or/and proteolytic trimming of cell surface components, including adhesion receptors and uPAR itself. The latter process refers to the generation of truncated

Conclusions

Since the original description of the GPI-anchored uPAR as a binding protein and adhesion receptor for VN 31, 32, additional molecular interactions of the uPAR-system with integrins and other adaptor proteins have been described that shed light on the dual roles of this protein, with particular emphasis on cellular communication. Although the uPA-dependent role of uPAR in cell invasion has been established, and clinical trials with respective low molecular weight inhibitors are underway [23],

Acknowledgements

The authors thank colleagues who provided access to their work prior to publication and also Trian Chavakis for critical comments. Due to the limited number of citations permitted, we apologize to all those whose work is not featured. Our work is funded by the Deutsche Forschungs-gemeinschaft (Pr 327/1-4), the Ministry of Science and Technology and the Novartis-Foundation.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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