Cell Surface Remodeling by Plasmin: A New Function for an Old Enzyme

Abstract

Plasmin, one of the most potent and reactive serine proteases, is involved in various physiological processes, including embryo development, thrombolysis, wound healing and cancer progression. The proteolytic activity of plasmin is tightly regulated through activation of its precursor, plasminogen, only at specific times and in defined locales as well as through inhibition of active plasmin by its abundant natural inhibitors. By exploiting the plasminogen activating system and overexpressing distinct components of the plasminogen activation cascade, such as pro-uPA, uPAR and plasminogen receptors, malignant cells can enhance the generation of plasmin which in turn, modifies the tumor microenvironment to sustain cancer progression. While plasmin-mediated degradation and modification of extracellular matrix proteins, release of growth factors and cytokines from the stroma as well as activation of several matrix metalloproteinase zymogens, all have been a focus of cancer research studies for decades, the ability of plasmin to cleave transmembrane molecules and thereby to generate functionally important cleaved products which induce outside-in signal transduction, has just begun to receive sufficient attention. Herein, we highlight this relatively understudied, but important function of the plasmin enzyme as it is generated de novo at the interface between cross-talking cancer and host cells.

Matrix metalloproteinases in head and neck cancer: current perspectives

“…[71][72][73][74][75] Furthermore, MMP9 degrades type IV collagen and promotes HNSCC invasion. 76,77 Indeed, immunohistochemical studies correlated MMP expression with loss of type IV collagen α-chain areas in OSCC, and MMP9 has been proposed as an invasion-and infiltration-pattern marker of OSCC at the invasive front.…”

“…Plasmin activates MMP2 and MMP9, and multiple MT-MMPs process the pro-MMP2 to its active form. 77 Activated MMP9 induces angiogenic switch, increases the availability of growth factors, and plays an important role in recruiting pericytes from the bone marrow. It also converts the Kit ligand from a membrane-bound molecule to a soluble survival/mitogenic factor soluble Kit ligand and promotes tumor angiogenesis through the release of ECM-bound angiogenic factors, such as VEGF.…”

Direct evidence of the importance of vitronectin and its interaction with the urokinase receptor in tumor growth

“…6 In addition, uPA and plasmin are caable of activating latent growth factors, such as transforming growth factor b and hepatocyte growth factor, thus modulating cell migration, proliferation, and differentiation. 7 Subsequent to the identification of uPAR as the cellular binding site for uPA, it became clear that overexpression of uPAR, or the treatment of uPAR-expressing cells with catalytically inactive uPA variants, induces a variety of cellular responses that are dependent on cell type, including changes in adhesion, migration, and proliferation and commonly known as the nonproteolytic functions of the receptor. Compilation of the published data on the nonproteolytic functions of uPAR yields a complex scenario in which the interactions with a variety of different ligands and coreceptors are required to explain the receptor's many biological activities.…”

Rapid Binding of Plasminogen to Streptokinase in a Catalytic Complex Reveals a Three-step Mechanism

“…The serine proteinase plasmin (Pm) 2 is primarily known for its role in dissolving fibrin thrombi (1). It also causes cell surface remodeling, signaling, and cancer progression (2).…”

“…It also causes cell surface remodeling, signaling, and cancer progression (2). Proteolytic activation of the zymogen plasminogen (Pg) by tissue plasminogen activator and urokinase-type plasminogen activator differs from conformational activation by the non-enzymatic streptococcal pathogenicity factor streptokinase (SK).…”