UPA-UPAR Pathway
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UPA-UPAR Pathway
Proteases are expressed by normal cells in tissue remodeling events and also during pathological events such as tumor invasion and metastasis. Some of the proteases including serine proteinases and MMPs (Metalloproteinases) have been implicated in remodeling of the ECM (Extracellular Matrix) in lung injury and lung neoplasia. These enzymes influence inflammatory cell traffic or cancer cell invasiveness via the breakdown of basement membranes and ECM. Plasmin, a serine protease, is involved in the dissolution of ECM and basement membrane during tissue degradation. This protease is generated via the action of plasminogen activators such as Urokinase (UPA, Urokinase-type Plasminogen Activator) or tPA (tissue Plasminogen Activator) and can influence tissue remodeling either directly or through activation of latent collagenases. Urokinase is mainly involved in extravascular proteolysis in stromal remodeling in ARDS (Acute Respiratory Distress Syndrome) and interstitial lung diseases (Ref.1) and in metastatic neoplasia. Interaction between the UPA and its receptor UPAR at the surface of epithelial cells contributes to the pathogenesis of lung inflammation and neoplasia and localizes cellular proteolysis and also promotes cellular proliferation and migration.

UPA is a serine protease of 45-55 kDa that exists in a proenzyme form (pro-UPA), which, upon activation, activates plasminogen to the active serine-protease plasmin. UPAR is composed of three homologous domains (D1, D2, and D3) and is extensively glycosylated and attached to the cell membrane by a GPI (Glycosyl Phosphatidylinositol) anchor. Plasmin is a broad-specificity protease, which degrades several ECM components, such as Fibronectin, Laminin and collagen (Ref.2). In addition, UPA triggers a proteolytic cascade that involves the activation of MMPs, which are responsible for collagen degradation. In addition, the ability of UPAR to localize and focalize the proteolytic activity of UPA on the cell surface is extremely important for the invasive ability of tumor cells. The UPA/UPAR complex, besides its proteolytic function as a zymogen, also functions as a vitronectin receptor and it participates in normal and tumor cell motility processes such as monocyte migration and tumor cells migration and invasion (Ref.3). UPA bound to its receptor activates intracellular signaling through many Integrins; it has the highest affinity for the bona fide fibronectin receptors. The Integrins-UPAR interaction regulates not only cell adhesion, but also the EGF (Epidermal Growth Factor)-receptor-dependent proliferation of a tumor cell line by activating FAK (Focal Adhesion Kinase), GRB2 (Growth Factor Receptor-bound protein-2), and ERK (Extracellular signal Regulated Kinase)/MAPK (Mitogen Activated Protein Kinases) and downregulating p38 MAPK. UPA binding to UPAR activates several tyrosine kinases from the Src family (Fyn, Lck, HCK), which in turn activates SHC, PI3K (Phosphatidylinositol 3-Kinase)-Akt1 pathway and cell migration. It also stimulates the JAK (Janus kinase)-STAT (Signal Transducer and Activator Of Transcription) pathway, PKC-Epsilon (Protein Kinase-C), and CSNK2 (Casein Kinase-2) (Ref.4). Nuclear STAT binds to SIE (Sis-Inducible Element) in the c-Fos promoter, conferring activation of c-Jun and c-Fos transcription.

Receptor-bound UPA can be inhibited by PAI1 (Plasminogen Activator Inhibitor-1) and PAI2, and UPAR provides a mechanism for internalization of PAI1-inactivated UPA. The UPAR therefore plays an important role both in localizing and modulating cell surface plasminogen activation. UPA expression can also be up-regulated in tumor cells by GFs (Growth Factors), including HGF/SF (Hepatocyte Growth Factor/Scatter Factor), VEGF (Vascular Endothelial Growth Factor), EGF, IGF-I (Insulin-like Growth Factors-I) and IGF-II, bFGF (basic Fibroblast Growth Factor), LPA (Lysophosphatidic Acid), CSF1 (Colony Stimulating Factor-1), vasopressin, and thrombin, among others. Most of these exogenous signals, through their receptors, activate PLC (Phospholipase-C), PKC, Ras, Raf, MEK1 (MAPK/ERK Kinase-1) and ERK1/2 and also members of the Ras,Rho, Rac and CDC42 family of small GTP-binding proteins.

UPA/plasmin-mediated proteolysis is critical for cellular migration and tissue remodeling in inflammation, tumor propagation, and metastasis. UPA is also essential for pericellular proteolysis and is localized to the leading edge of migrating cells. Interactions between UPA and UPAR can facilitate cellular movement, which contribute to remodeling of the lung in ARDS or the interstitial lung diseases. The interaction between UPA and UPAR at the cancer cell surface is critical event in the pathogenesis of neoplastic growth and metastasis, mediating tissue remodeling, tumor cell invasion, adhesion, and proliferation. In addition, the binding of UPA to UPAR mediates cell proliferation in several cell types, including nonmalignant lung epithelial cells, lung carcinoma-derived cells, and mesothelioma cells (Ref.5). Vascular smooth muscle cells express increased amounts of UPAR in atherosclerotic coronary arteries or transplanted veins. UPAR is also highly expressed during tissue remodelling in the placenta and migrating keratinocytes in wounds. The receptor is, however, implicated in providing oval progenitor cells with a growth advantage during liver regeneration. Regulation of the UPA-UPAR system is therefore germane to the pathogenesis of disparate pathological conditions, including lung injury and neoplasia.