Roles of membrane‐type matrix metalloproteinase‐1 in tumor invasion and metastasis

Abstract

Degradation of extracellular matrix (ECM) is(1-3) Under normal physiological conditions, the activities of MMP are precisely regulated at the level of transcription, activation of the precursor zymogens, interaction with specific ECM components, and inhibition by endogenous inhibitors.(4) Cancer cells also make use of MMP for invasion and metastasis. The invading cells are forced to proliferate within an embedded dense three-dimensional matrix composed largely of type I collagen or cross-linked fibrin. Membrane type MMP-1 (MT1-MMP) has been thought to play a major role in this step. (5,6) Unique structure of MT1-MMP. Currently 23 MMP have been identified in humans and they are divided into two groups; secretory and membrane-type (Fig. 1).(7) While MT1-MMP has a common MMP domain structure with pre-, pro-, catalytic and hemopexin-like domains, it also has unique insertions. First there is an insertion of 11 amino-acids between the pro-peptide and the catalytic domains, which contains the recognition sequence for the Golgi-associated processing enzyme furin. Another unique insertion at the C-terminus contains a hydrophobic amino-acid sequence that acts as a transmembrane domain. Thus, unlike secretory MMP, MT1-MMP is expressed on the cell surface in an active form. Implication of MT1-MMP in tumor invasion and metastasis. MMP-2 has been suspected to be associated with tumor invasion because it can degrade the type IV collagen, which is a major component of the basement membrane. An active form of MMP-2 has frequently been detected in tumor tissues. (8,9) The expression of MT1-MMP has been demonstrated in tumor tissues, in which MMP-2 is always activated.(5,10 -12) Furthermore, the MMP-2 activation ratio correlates with the MT1-MMP expression level, suggesting that MT1-MMP is the MMP-2 activator in tumor tissues. An analysis of MT1-MMP-deficient mice, which had severe defects in bone formation and died within a few weeks of birth, clearly showed that MT1-MMP is the major activator of MMP-2 during tissue morphogenesis.(13) Interestingly MMP-2-deficient mice do not show such severe defects, indicating that MT1-MMP has critical functions in addition to MMP-2 activation. ECM macromolecules including type I collagen and various biologically important molecules are now known to serve as substrates for MT1-MMP, which will be discussed in the following sections (Table 1). (14 -23) Induction of MT1-MMP expression by transformation of epithelial cells. MT1-MMP is associated with not only tumor invasion and metastasis but also tissue morphogenesis, which is clearly demonstrated in vitro by the Madin-Darby canine kidney (MDCK) epithelial cell system (Fig. 2). MDCK cells are kidney-derived normal epithelial cells that show typical cobblestone morphology when cultured in a plastic dish. MDCK cells form cysts when cultured in three-dimensional type I collagen gel, and grow to form branching tubules in the presence of hepatocyte growth factor.(24) MT1-MMP expression is induced at a low level in tube-forming MDCK cells. Collageno...

MT1-MMP protects breast carcinoma cells against type I collagen-induced apoptosis

“…Many of the MMP-14 activities have been ascribed to its ability to bind and activate the MMP-2 zymogen (Sato et al, 2005). However, the protective function of MMP-14 against COL1-induced apoptosis demonstrated here is conserved in the absence of MMP-2, arguing for a direct implication of MMP-14 in this process.…”

“…MMP-14 is tethered to the cell surface by a transmembrane segment that terminates in a short cytoplasmic domain (Sato et al, 2005). The extracellular proteinase portion containing the zinc-containing catalytic domain endows this enzyme with the unique ability to modify the surrounding microenvironment by proteolysis as well as to interact with the intracellular transduction machinery involved in the cellular response to extracellular signals (Gingras and Be´liveau, 2010).…”

Vinculin negatively regulates transcription of MT1-MMP through MEK/ERK pathway

“…Membrane-type 1 matrix metalloproteinase (MT1-MMP) is considered to play a significant role in tumor progression, as its expression correlates most closely with the invasive phenotype of human tumors among MMPs and the inhibition of MT1-MMP suppresses tumor cell invasion both in vitro and in vivo [14]. MT1-MMP was originally identified as a tumor-specific MMP-2 activator [15].…”

MT1-MMP promotes cell growth and ERK activation through c-Src and paxillin in three-dimensional collagen matrix

“…Membrane-type 1 matrix metalloproteinase (MT1-MMP) was originally identified as a tumor-specific MMP-2 activator [9], and has been implicated in tumor progression [10]. It is now known to activate MMP-2 and -13 and degrade a wide range of ECM components including type I collagen, fibronectin, and laminins.…”

“…It is now known to activate MMP-2 and -13 and degrade a wide range of ECM components including type I collagen, fibronectin, and laminins. This enzyme also processes and interacts with membrane-tethered proteins, such as integrins and CD44, which is associated with the regulation of tumor cell invasion [10]. The inhibition of MT1-MMP suppresses tumor cell invasion both in vitro and in vivo [11][12][13].…”