Division of Cancer Prevention, Stony Brook University, Stony Brook, New York 11794, USA
I-) Activation of proMMPs and degradation of ECM Pro-MMP2 was the first identified substrate of MMP-14 and the trimolecular complex consisting of MMP-14 and proMMP2-TIMP2 has been investigated very well for many years. TIMP2 (tissue inhibitor of metalloproteinases-2) is actually the inhibitor of the MMPs. However, low concentrations of TIMP-2 aids in the activation of proMMP-2 by MMP-14 within this complex by binding to the catalytic domain of MMP-14 and the C-terminal domain of pro-MMP2. Following the formation of the triplex, a second MMP-14, which is free of TIMP-2, forms a dimer with the pre-existing MMP-14 on the cell membrane and cleaves the latent pro-MMP2 to produce active MMP2. Active MMP-2 can then participate in other events such as the degradation of collagen type-IV, a major protein component of the basement membrane, which is not cleaved by MMP-14 itself. Another substrate of MMP-14 within the MMP family is the pro-MMP-13, which also functions as a collagenase in the surrounding tissue after its activation. Besides activation of MMPs, especially pro-MMP-2, MMP-14 cleaves many proteins in the ECM and changes the composition of the matrix. Type I-Type II-Type III collagen, gelatin, fibronectin, laminin-1 and -5, fibrin and proteoglycans are the major direct targets of MMP-14 in the extracellular environment. Out of these substrates, collagen makes up a significant portion of the ECM and acts as a barrier for migratory cells. Within the collagenases, which includes MMP-1, MMP-2, MMP-8, MMP-13, only MMP-14 can stimulate invasion into collagen by epithelial cells, fibroblasts, and cancer cells. MMP-14 concentrates in the protrusions of the cells, called lamellipodia in normal cells and invadopodia in cancer cells, to induce a significant increase in cell migration and invasion by degrading components of the ECM and making a path in through the surrounding tissue. In this aspect, MMP-14 should be bound to the plasma membrane in vivo, as membrane-bound MMP-14 has been demonstrated to be more proteolytically active than the soluble recombinant MMP-14.
II-) Shedding of cell surface molecules Studies underlying the mechanism of the constitutive shedding of CD44 from the human melanoma cell surface implicated the necessity of MMP-14 with the presence of ADAM-10 for this process. Especially in the hyaluronan based matrix, cleavage of CD44 at the stem region by MMP-14 sheds these molecules from the cell surface and concurrently promotes the migration of the cells from the leading edge. Another cell adhesion molecule, E-cadherin, is also cleaved by MMP-14 to disrupt contact between cells. In the ischemia-induced ARF (acute renal failure), MMP-14 expression is required for the disruption of the cadherin/catenin complex. Syndecan-1 is another cell surface molecule which is cleaved by MMP-14.
III-) Cleavage of cytokines and growth factors MMP-14 indirectly plays a major role in cleavage of the cytokines and growth factors by activating pro-MMP-2 and pro-MMP13. It also makes direct contact with several chemokines and growth factors including; the neutrophil chemokine IL-8, secretory leukocyte protease inhibitor, pro-tumor necrosis factor, death receptor-6, and connective tissue growth factor.
IV-) Activation of ERK cascade by the cytoplasmic tail of MMP-14 In several studies, overexpression of MMP-14 has been reported to activate the ERK cascade. It is not yet clear how MMP-14 activates ERK signalling, but overexpression of the cytoplasmic-deleted form of MMP-14 has been shown to eradicate ERK activation. Within the cytoplasmic tail, the 573YCQR576 motif has been suggested to be involved in ERK activation. In addition to ERK activation, the role of MMP-14 in the p38 and JNK pathway has also been investigated.
V-) Inhibition of MMP-14 function Function of MMP-14 can be abolished either by TIMPs (Tissue Inhibitor of MetalloProteinases) or proteolytic degradation. TIMP-2, -3 and -4 but not TIMP-1 specifically inactivates the functions of MMP-14. Besides TIMPs, RECK and N-Tes can also block the activity of MMP-14 in a similar manner. For the proteolytic cleavage of MMP-14, membrane bound MMP-14 should be internalized by the clathrin-dependent and caveolae-dependent pathways. There is an AP-2 binding site in the cytoplasmic domain of MMP-14, 571LLY573 which is required for the incorporation of MMP-14 into clathrin-coated vesicles. The palmitoylation of the C574 right after the AP-2 binding site has also been demonstrated to be an essential modification for the internalization of MMP-14.
NCBI: 4323 MIM: 600754 HGNC: 7160 Ensembl: ENSG00000157227
dbSNP: 4323 ClinVar: 4323 TCGA: ENSG00000157227 COSMIC: MMP14
Cem Kuscu ; Nikki Evensen ; Jian Cao
MMP14 (matrix metallopeptidase 14 (membrane-inserted))
Atlas Genet Cytogenet Oncol Haematol. 2010-10-01
Online version: http://atlasgeneticsoncology.org/gene/41391/js/case-report-explorer/