Matriptase activates stromelysin (MMP‐3) and promotes tumor growth and angiogenesis

Abstract

These proteinases include MMPs, ADAMs, type II transmembrane serine proteinases, and secretory serine proteinases such as plasminogen activators and trypsin. It is well known that some soluble and membrane-bound MMPs significantly contribute to tumor invasion and angiogenesis by degrading or processing extracellular matrix proteins and membrane proteins.(1-3)The type II transmembrane serine proteinase family is a newly identified superfamily of membrane-associated serine proteinases and consists of four subfamilies, including the hepsin subfamily and the matriptase subfamily.(4) Recently, considerable attention has been focused on matriptase, a member of the type II transmembrane serine proteinases superfamily. The matriptase family includes matripase/MT-SP1, matriptase-2, and matriptase-3. Matriptase contains a transmembrane domain, two CUB domains, four low-density lipoprotein-receptor domains and a serine protease domain.(5,6) Among the four family members, matriptase has been the most extensively characterized. Matriptase is expressed in a wide range of epithelial tissues, such as the epidermis, gastrointestinal tract and respiratory tract, and also in endothelial cells, neural cells and white blood cells. (7,8) Matriptase-deficient mice die within 48 h of birth due to a loss of the epithelial water barrier function, and they also exhibit profound abnormalities in follicular and thymic development. (9) Recent studies have suggested an association between defective matriptase regulation and/or activation and tumor development. Matriptase and its inhibitor HAI-1 are often co-expressed in cultured cancer cells and carcinomas as well as normal epithelial cells.(10-13) Co-expression of matriptase, HAI-1 and the HGFreceptor c-Met is correlated with poor prognosis of node-negative breast cancer patients.(12) In ovarian cancer, matriptase and HAI-1 are commonly co-expressed at an early stage, whereas the expression of HAI-1 is lost at stages III and IV, presumably leading to unopposed, active matriptase.(11) Matriptase activates PAR-2, latent HGF (pro-HGF) and pro-uPA. (14,15) Some animal studies have shown that matriptase promotes tumor growth. (16)(17)(18) For example, down-regulation of matriptase in human ovarian cancer cells by an antisense cDNA inhibits the activation of uPA and suppresses tumor growth in nude mice.(17) Furthermore, a recent study has shown that transgenic expression of matriptase in the epidermis of mice causes spontaneous squamous cell carcinoma.(19) However, it is still unclear how matriptase contributes to the development and malignant progression of human cancers.To clarify the roles of matriptase in tumor growth, here we overexpressed a matriptase cDNA in human stomach cancer cells. Our results demonstrate that the overexpression of matriptase strongly promotes tumor growth and angiogenesis in vivo.

Emerging roles of serine proteinases in tissue turnover in arthritis

“…Thus, cartilage resorption involves both metalloproteinases and serine proteinases, which are likely to function through a series of interacting cascades (Figure 2). A large number of serine proteinases have been shown to activate proMMPs, especially proMMP-3 (trypsin, chymotrypsin, tryptase, chymase, plasmin, plasma kallikrein, NE, CTG, trypsinogen 2, thrombin, and matriptase) (38,81,84,(189)(190)(191)(192). However, the precise activation mechanisms for many of the proMMPs that occur in vivo in both cartilage and other matrices are unknown (175).…”

Role of Angiogenesis and Microenvironment in Melanoma Progression

“…This clearly suggests that expression of matrix metalloproteinase -9 is an early event in melanoma progression (Kerkela & Saarialho-Kere, 2003). Several studies using either cell lines or animal models have demonstrated that the balance between matrix metalloproteinases and their inhibitors finally determines melanoma progression (Hofmann et al, 2000b;Wojtowicz-Praga et al, 1998;Rudek et al, 2001;Jin et al, 2006;Wojtowicz-Praga et al, 1996;Bodey et al, 2001;Airola et al, 1999). Overexpression of TIMP-1, -2, and -3 significantly reduces melanoma tumour cell invasion, migration, growth and metastasis, and significantly reduces tumour neovascularization in several tumour models (Anand-Apte et al, 1996).…”

Cleavage of hepatocyte growth factor activator inhibitor‐1 by membrane‐type MMP‐1 activates matriptase

“…(31) Detection of matriptase by gelatin zymography was carried out by modifying the protocol for MMP. (34) …”