The Urokinase Receptor Interactome

Abstract

The urokinase receptor (uPAR) was originally identified as the membrane receptor of the serine protease urokinase (uPA), thereby implicated in the plasminogen activation cascade and regulation of pericellular proteolysis. Later on, vitronectin was showed to be another major ligand providing uPAR with a role in cell adhesion. Other unrelated ligands have been subsequently reported including for example factor XII and SRPX2 expanding the functions of uPAR to unexpected biological areas such as the initiation of the coagulation cascade or the regulation of language development. Due to its glycosylphosphatidylinositol (GPI) anchor, uPAR has no intracellular domain and thus exerts its signaling capacity through lateral interactions with other components of the plasma membrane that actually mediate uPAR-induced signals. As yet, a total 42 proteins interacting directly with uPAR can be numbered comprising 9 soluble ligands and 33 lateral partners. The fact that uPAR interacts with members of three major families of membrane receptors i.e. G protein-coupled receptors, receptor tyrosine kinases, and integrins implies that the actual number of components constituting the uPAR interacome is extremely high. For example, 156 factors belong to the integrin adhesome. Moreover, in the light of the wide diversity of the components of the uPAR interactome, uPAR appears to be an essential player of major biological systems including the blood coagulation, complement and plasma kallikrein-kinin cascades. This review describes the soluble ligands and lateral partners of the uPAR interactome, the mechanisms regulating uPAR interactions and their proved and/or potential biological functions.

The acidic microenvironment as a possible niche of dormant tumor cells

“…Upon interaction of α chain with uPAR, integrins α5β1 and αvβ3 can interact and activate Receptor Tyrosine Kinases (RTKs). Such interaction is potentiated by catalytic and non-catalytic uPA binding to uPAR and can induce RTKs activity even in the absence of the relevant ligand (EGF, PDGF, ILGF, and HGF) [61,62] in an FAK-dependent manner [63]. In head and neck carcinoma, uPAR drives tumor growth by interacting with α5β1 integrin, a complex that activates focal adhesion kinase (FAK) and EGF receptor (EGFR), final effector of this mitogenic signal.…”

Integrins in Wound Healing

“…71,72 In addition, other cell surface receptors (e.g., urokinase-type plasminogen activator receptor [uPAR]), transmembrane adaptor proteins such as caveolin-1, or members of the transmembrane-4 superfamily (also called tetraspanins or tetraspans) and membrane lipids (gangliosides) modulate integrin function and cellular signaling. [83][84][85][86] These binding partners may alter integrin conformation and affinity directly, modulate the avidity of integrins by regulating their clustering, assist in recruiting signaling molecules to cell adhesion sites, regulate receptor endocytosis, or facilitate cell migration through tissues. Integrins also cross talk with cadherins via reactive oxygen species (ROS)-mediated signaling to coordinate cell-matrix and cell-cell adhesions during tissue remodeling.…”

Proteomic Identification of VEGF-dependent Protein Enrichment to Membrane Caveolar-raft Microdomains in Endothelial Progenitor Cells

“…VEGF stimulates a caveolar-raft redistribution of uPAR coupled with inhibition of EPC production of matrix-metalloproteinase-12 (MMP12) (3), the main enzyme responsible for cleavage of uPAR between its domain 1 and 2. Such a cleavage deprives uPAR of its angiogenesic properties by elimination of its domain-1-uPA-binding ability and by loss of uPAR integrity, which is required in order for uPAR to retain its domain-2/3 affinity for vitronectin (VN) and EC membrane integrins (7). In ECFCs uPAR, a typical glycosyl-phosphatidyl-inositol (GPI)-anchored protein, preferentially partitions on caveolar-rafts.…”