title: Functional relationship between matrix metalloproteinase-11 and matrix metalloproteinase-14.
abstract: MMP-11 is a key factor in physiopathological tissue remodeling. As an active form is secreted, its activity must be tightly regulated to avoid detrimental effects. Although TIMP-1 and TIMP-2 reversibly inhibit MMP-11, another more drastic scenario, presumably via hydrolysis, could be hypothesized. In this context, we have investigated the possible implication of MMP-14, since it exhibits a spatiotemporal localization similar to MMP-11. Using native HFL1-produced MMP-11 and HT-1080-produced MMP-14 as well as recombinant proteins, we show that MMP-11 is a MMP-14 substrate. MMP-14 cleaves MMP-11 catalytic domain at the PGG(P1)-I(P1')LA and V/IQH(P1)-L(P1')YG scissile bonds, two new cleavage sites. Interestingly, a functional test showed a dramatical reduction in MMP-11 enzymatic activity when incubated with active MMP-14, whereas inactive point-mutated MMP-14 had no effect. This function is conserved between human and mouse. Thus, in addition to the canonical reversible TIMP-dependent inhibitory system, irreversible MMP proteolytic inactivation might occur by cleavage of the catalytic domain in a MMP-dependent manner. Since MMP-14 is produced by HT-1080 cancer cells, whereas MMP-11 is secreted by HFL1 stromal cells, our findings support the emerging importance of tumor-stroma interaction/cross-talk. Moreover, they highlight a Janus-faced MMP-14 function in the MMP cascade, favoring activation of several pro-MMPs, but limiting MMP-11 activity. Finally, both MMPs are active at the cell periphery. Since MMP-14 is present at the cell membrane, whereas MMP-11 is soluble into the cellular microenvironment, this MMP-14 function might represent one critical regulatory mechanism to control the extent of pericellular MMP-11 bioavailability and protect cells from excessive/inappropriate MMP-11 function.
authors: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Department of Functional Genomics and Cancer, CNRS UMR 7104, INSERM U964, Université de Strasbourg, Illkirch, France.
authors: Emilie
authors: E
authors: Buache
authors: Robert
authors: R
authors: Thai
authors: Corinne
authors: C
authors: Wendling
authors: Fabien
authors: F
authors: Alpy
authors: Adeline
authors: A
authors: Page
authors: Marie-Pierre
authors: MP
authors: Chenard
authors: Vincent
authors: V
authors: Dive
authors: Marc
authors: M
authors: Ruff
authors: Annick
authors: A
authors: Dejaegere
authors: Catherine
authors: C
authors: Tomasetto
authors: Marie-Christine
authors: MC
authors: Rio
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D015870:Gene Expression; D006801:Humans; D053507:Matrix Metalloproteinase 11 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D053511:Matrix Metalloproteinase 14 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011487:Protein Conformation; D059748:Proteolysis; D011994:Recombinant Proteins / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: D011994:Recombinant Proteins; D053507:Matrix Metalloproteinase 11; D053511:Matrix Metalloproteinase 14
keywords: Cell microenvironment; MMP inactivation; epithelial-stromal cell interaction; tissue remodeling