Functional relationship between matrix metalloproteinase-11 and matrix metalloproteinase-14

Cancer Med. 2014 Oct;3(5):1197-210. doi: 10.1002/cam4.290. Epub 2014 Aug 1.


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.

Keywords: Cell microenvironment; MMP inactivation; epithelial-stromal cell interaction; tissue remodeling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Catalytic Domain
  • Cell Line, Tumor
  • Enzyme Activation
  • Gene Expression
  • Humans
  • Matrix Metalloproteinase 11 / chemistry
  • Matrix Metalloproteinase 11 / genetics
  • Matrix Metalloproteinase 11 / metabolism*
  • Matrix Metalloproteinase 14 / chemistry
  • Matrix Metalloproteinase 14 / genetics
  • Matrix Metalloproteinase 14 / metabolism*
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Protein Conformation
  • Proteolysis
  • Recombinant Proteins / metabolism
  • Sequence Alignment


  • Recombinant Proteins
  • Matrix Metalloproteinase 11
  • Matrix Metalloproteinase 14