Figure 3.
Function and regulation of the urokinase-type plasminogen activator receptor (uPAR) in the biology of cancer. (a) Through a high binding affinity interaction (KD ~0.2 nM), the urokinase receptor binds active uPA and its zymogen pro-uPA, favoring its focused cell-surface activation. Active uPA proteolytically converts the zymogen plasminogen (plg) into active plasmin (plm), which can reciprocally activate pro-uPA, while remaining protected from its primary plasma physiological inhibitors, α2-antiplasmin (α2-AP). These mutual zymogen activation reactions start a powerful positive feedback mechanism, resulting in efficient and localized plasmin generation on the cell surface of migrating cancer cells at their leading edge. The increased cell surface concentration of the reactants involved, respectively, uPA or pro-uPA, by binding to uPAR, and plasmin and plasminogen, via multiple receptors, strongly accelerate and amplify this reciprocal activation loop. Once activated, the broad-spectrum protease plasmin mediates the non-specific proteolysis of several ECM and basement membrane (BM) components, either directly or through the activation of pro-matrix metalloproteinases (pro-MMPs), thereby promoting cancer cell migration, invasion, and metastasis. Plasmin and MMPs can also release or activate ECM-bound cancer-related growth factors (GF) contributing to tumor progression and angiogenesis. Most of these factors then feedback in an autocrine or paracrine fashion to enhance the expression of different pro-cancer genes, including urokinase plasminogen activating system (uPAS) components, such as uPA and uPAR, that further supports the proteolytic cascade and thus tumor progression. Besides α2-AP, another important physiological regulator of uPA-uPAR-induced plg-activation is the serine protease inhibitor (serpin) plasminogen activator inhibitor 1 (PAI1), which specifically inhibits uPA by forming stable ternary complexes with uPAR-bound uPA, which are subsequently internalized via the α2-macroglobulin receptor/low-density lipoprotein receptor-related protein 1 (LRP1). (b) By becoming a part of functional units involving distinct extracellular molecules and membrane co-receptors (e.g., its second main cognate ligand, the matrix protein Vn, members of the integrin adhesion receptor superfamily, G-protein-coupled receptors (GPCR), and growth factors receptors (GFR, e.g., EGFR and VEGFR-2, epidermal growth and vascular endothelial growth factor receptor 2)), uPAR is believed to indirectly choreograph—in a non-proteolytic fashion—several cancer-associated intracellular signal-transduction pathways regulating other tumor hallmarks, including, among others, proliferation, survival, migration, invasion, metastasis, angiogenesis, and epithelial–mesenchymal transition (EMT). The intracellular signaling components are indicated (focal adhesion kinase (FAK), Src, Rac, mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), etc.), but the pathways remain speculative. A more comprehensive list of uPAR putative non-canonical interacting proteins and related signaling consequences is reported in [4,16,73]. (c) Cell surface uPAR may undergo two major post-translational processing events, namely proteolytic cleavage (in the DI–DII linker region) and shedding (via hydrolysis of the GPI-anchor), resulting in diverse uPAR isoforms, including suPAR D1, suPAR DI–D3, suPAR D2–D3, and GPI-anchored uPAR D2–D3. Created with BioRender.com.