The Biochemical, Biological, and Pathological Kaleidoscope of Cell Surface Substrates Processed by Matrix Metalloproteinases

Abstract

Matrix metalloproteinases (MMPs) constitute a family of more than 20 endopeptidases. Identification of specific matrix and non-matrix components as MMP substrates showed that, aside from their initial role as extracellular matrix modifiers, MMPs play significant roles in highly complex processes such as the regulation of cell behavior, cell-cell communication, and tumor progression. Thanks to the comprehensive examination of the expanded MMP action radius, the initial view of proteases acting in the soluble phase has evolved into a kaleidoscope of proteolytic reactions connected to the cell surface. Important classes of cell surface molecules include adhesion molecules, mediators of apoptosis, receptors, chemokines, cytokines, growth factors, proteases, intercellular junction proteins, and structural molecules. Proteolysis of cell surface proteins by MMPs may have extremely diverse biological implications, ranging from maturation and activation, to inactivation or degradation of substrates. In this way, modification of membrane-associated proteins by MMPs is crucial for communication between cells and the extracellular milieu, and determines cell fate and the integrity of tissues. Hence, insights into the processing of cell surface proteins by MMPs and the concomitant effects on physiological processes as well as on disease onset and evolution, leads the way to innovative therapeutic approaches for cancer, as well as degenerative and inflammatory diseases.

Emerging roles of ADAM and ADAMTS metalloproteinases in cancer

“…The active metalloproteinase domain might indeed be needed to degrade extracellular matrix components and to shed growth factors and cytokines [8,59], contributing in this way to the control of cell proliferation, migration and angiogen-esis [60]. Adhesion and migration of cells might be regulated by the disintegrin or cystein-rich domains whose importance has been evidenced by different studies [12,[61][62][63].…”

“…Ligands for several growth factor receptors are processed by ADAM family members. Among them, EGF receptor ligands (heparin-binding EGF (HB-EGF), amphiregulin, betacellulin, epiregulin) are synthesized as transmembrane precursors and require ectodomain shedding for activation [59,80]. ADAM-17 has been shown to play a key role in such a process [60,81].…”

Association of Matrix Metalloproteinase (MMP)-2 and -9 Expression with Extra-gastrointestinal Stromal Tumor Metastasis

“…The expression and activation of MMPs are also involved in various physiological and pathological events, such as inflammation, tissue fibrosis, angiogenesis, invasion, and tumor metastasis. Specifically, MMPs selectively degrade different components of the ECM (Roy et al, 2009;Hatfield et al, 2010) and thus regulate numerous biological events including cell growth, inflammation, invasion, and angiogenesis by eliminating cell surface proteins such as the cytokine receptor, cell adhesion molecules, and urokinase receptors (Backstrom et al, 1995;Cauwe et al, 2007;Kessenbrock et al, 2010;Rodriguez et al, 2010;Klein et al, 2011). Among these MMPs, MMP-2 is secreted by tumor cells and interstitial cells in the form of a zymogen and can specifically degrade collagen IV when it is hydrolyzed and activated.…”

The Metalloprotease ADAMTS8 Displays Antitumor Properties through Antagonizing EGFR–MEK–ERK Signaling and Is Silenced in Carcinomas by CpG Methylation

“…Dysregulated expression of ADAMTSs, such as ADAMTS1 (2), ADAMTS8, ADAMTS9 (5), ADAMTS12 (3), ADAMTS15 (4), ADAMTS18 (6), and ADAMTS20 (9,10), have been detected in diverse types of malignancies including lung, brain, breast, gastric, prostate, pancreatic cancers, and glioblastoma (8). Various ADAMTSs have been shown to regulate cell proliferation, adhesion, migration, angiogenesis, and intracellular signaling (8,11), thus involved in multiple tumor pathogenesis (1,6).…”