Role of Matrix Metalloproteinases in Angiogenesis and Cancer

Abstract

During angiogenesis, new vessels emerge from existing endothelial lined vessels to promote the degradation of the vascular basement membrane and remodel the extracellular matrix (ECM), followed by endothelial cell migration, and proliferation and the new generation of matrix components. Matrix metalloproteinases (MMPs) participate in the disruption, tumor neovascularization, and subsequent metastasis while tissue inhibitors of metalloproteinases (TIMPs) downregulate the activity of these MMPs. Then, the angiogenic response can be directly or indirectly mediated by MMPs through the modulation of the balance between pro- and anti-angiogenic factors. This review analyzes recent knowledge on MMPs and their participation in angiogenesis.

Keywords: MMP; MT-MMP; angiogenesis and cancer; immune system; metalloproteinases.

Figure 1

Structure and architectures of MMPs. The selected Protein Data Bank (PDBs) structures are comprehensive (when possible) full-length peptides found in the available coordinates files, all structures were overlapped at similar positions. For every structure, the propeptide domain and triple-helical collagen peptide appear in yellow, while the catalytic domains (right) appear in black, and hemopexin domains (left) in white. (A) MMP-1 family (collagenases and stromelysins) is represented by the structure of the MMP-1 from Human (PDB: 4AUO) in complex with triple-helical collagen peptide. Family members: MMP-1, MMP-8, MMP-13, MMP-3, MMP-10, MMP-12, MMP-20, and MMP-27. (B) Gelatinases family is represented by the full-length structure of the inactive MMP-2 with propeptide from Human (PDB: 1CK7). The additional fibronectin type II domains appear in white and are located under the catalytic domain (black). Family members: MMP-2 and MMP-9. (C) MT-MMPs transmembrane type I family. Represented by two structures mixed in two models of MMP-14 (MT1-MMP) from Human (PDBs: 2MQS and 3MA2). Models were built by the superposition of the homologous structure of MMP-1 (PDB: 4AUO). 2MQS structure is a complex of the hemopexin domains with triple-helical collagen peptide; 3MA2 structure is a complex of the catalytic domain with TIMP-1 inhibitor. The models show the hypothetical MMP-14 with hemopexin and catalytic domains in complex with TIMP-1 and triple-helical collagen peptide. The structure of helical membranal fragment is unknown (542–562) and the structure of the cytoplasmatic tail of the C-terminal fragment (563–582) is available in a complex with the FERN domain from Radixin (PDB: 3X23, structure not represented). Family members: MMP-14 (MT1-MMP), MMP-15 (MT2-MMP), MMP-16 (MT3-MMP), and MMP-24 (MT5-MMP). (D) Matrilysin family (shortest MMPs). Represented by the full-length structure of the inactive MMP-7 with propeptide from Human (PDB: 2MZE). This family lacks hemopexin domains. Family members: MMP-7 and MMP-26. (E) Global MMPs architecture by families. Families (a–d) are represented from (A,D). (e) is the MMP stromelysins type 3 family (structures available but not complete); the architecture is similar to that of MMP-1 family. Family members: MMP-11 (stromelysin 3), MMP-21, MMP-28 and MMP-19 (evolutionary close to MMP-11 and MMP-7). (f) is the MT-MMP GPI (Glycosylphosphatidylinisotol) anchored family (structures not available), the architecture is similar to that of MMP-1 family and closely related to stromelysin type 3 family, but it is attached to the membrane by the GPI. Family members: MMP-17 (MT4-MMP), MMP-25 (MT6-MMP). The (g) family is represented by the MMP-23 (structures not available) and shares the catalytic domain with other families; the architecture is different on the N-terminal of the catalytic domain, containing a type II helical membrane fragment. On the C-terminal are an ShKT (Stichodactyla toxin) domain (with potential channel-modulatory activity) and an Ig-like (Immunoglobulin) C2-type domain that mediates protein-protein interactions. Cyt: cytoplasmatic domain, PD: Propeptide domain, TD: transmembrane helix, FD: Fibronectin type-II domains, CAT: zinc-dependent metalloproteinase domain, Ig: Ig-like C2-type domain and ShKT type domain. All figures were made with VMD (Visual Molecular Dynamics) (20).

Figure 2

Evolutionary relationship of the catalytically domain of MMP family. Additionally, the main substrates are mentioned. MMPs classification is based on a phylogenetic tree of the catalytic domains reported (23). The sequences are arranged in four groups: (1) Evolutionary group 1 (Figures 1A,B) mainly assembles collagenases, stromelysins, and gelatinases, but other MMPs with a broad range of activities appear grouped. (2) Evolutionary group 2 (Figures 1D,Ee,f) mainly include matrilysins, the GPI-anchored MMPs, and other metalloproteinases as MMP-11 (a stromelysin) and MMP-21 (an MMP with a specific function in embryogenesis). (3) Evolutionary group 3 (Figure 1C) includes the MT-MMP trans-membrane type I family (MT1-MMP, MT2-MMP, MT3-MMP, and MT5-MMP). All three groups share a basic architecture with PD-CAT-HD domains array with a few additions or deletions, as matrilysins. The shortest MMPs without HD domain (group 3) contain a transmembrane type I helix and cytoplasmic domains after the HD domain (Figure 1). (4) We added evolutionary group 4 that includes the MT-MMP transmembrane type II family (Figure 1E) with MMP-23A and MMP-23B proteins. MMP-23A gene is considered a pseudogene produced by duplication of the MMP-23B gene. Sources: “GeneCards: the human gene database” (24) and Uniprot databases (25).

Figure 3

MT1-MMP functions and mechanism. (A) MT1-MMP (MMP-14) participates in angiogenesis regulation and remodeling of the ECM. MT1-MMT interacts with cell surface molecules such as CD44, S1P₁ (G-protein coupled receptor coupled to the G(i) subclass of heteromeric G proteins) and receptors such as discoidin domain receptor (DDR1). S1P represents sphingosine-1-phosphate ligand of S1P₁ leading to the activation of RAC1. MT1-MMT cleaves collagen type I to prevent DDR1 recognition and the apoptotic cascade. MT1-MMT is a key effector in the production of pro-angiogenic factors such as VEGF and is able to degrade pro-TGF-β and endoglin (TGF-β receptor), suggesting a pivotal role in vessel maturation and angiogenesis, respectively. (B) MT1-MMP model of the interaction and activation of pro-MMP-2. MT1-MMP forms a homo-dimer in the membrane mediating the interaction of the hemopexin and the transmembrane domains, necessary conditions for the activation of pro-MMP-2. MT1-MMP dimer forms a complex with one TIMP-2 inhibitor, the interaction is not a symmetric array. TIMP-2 binds to a single MT1-MMP monomer by the catalytic domain mediated by the N-terminal. The C-terminal of TIMP-2 binds to the hemopexin domain of pro-MMP-2, thus allowing the prodomain of MMP-2 to access the catalytic domain of the second monomer of MT1-MMP.