Membrane Type 4 Matrix Metalloproteinase (MMP17) Has Tumor Necrosis Factor-α Convertase Activity but Does Not Activate Pro-MMP2*

By W. English, Xose S. Puente, J. Freije, V. Knäuper, A. Amour, Ann Merryweather, C. López‐Otín, Gillian Murphy. 2000

233 citations recorded by the source corpus.

Membrane type 4 matrix metalloproteinase (MT4-MMP) shows the least sequence homology to the other MT-MMPs, suggesting a distinct function for this protein. We have isolated a complete cDNA corresponding to the mouse homologue which includes the signal peptide and a complete pro-domain, features that were lacking from the human form originally isolated. Mouse MT4-MMP (mMT4-MMP) expressed in COS-7 cells is located at the cell surface but does not show ability to activate pro-MMP2. The pro-catalytic domain was expressed in Escherichia coli as insoluble inclusions and active enzyme recovered after refolding. Activity of the isolated catalytic domain against synthetic peptides commonly used for MMP enzyme assays could be inhibited by TIMP1, -2, and -3. The recombinant mMT4-MMP catalytic domain was also unable to activate pro-MMP2 and was very poor at hydrolyzing components of the extracellular matrix with the exception of fibrinogen and fibrin. mMT4-MMP was able to hydrolyze efficiently a peptide consisting of the pro-tumor necrosis factor α (TNFα) cleavage site, a glutathioneS-transferase-pro-TNFα fusion protein, and was found to shed pro-TNFα when co-transfected in COS-7 cells. MT4-MMP was detected by Western blot in monocyte/macrophage cell lines which in combination with its fibrinolytic and TNFα-converting activity suggests a role in inflammation.

Subfields: Cancer Research, Hematology, Oncology

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In Cancer Research

1. Zena Werb
2. T. Klein
3. Rainer Bischoff
4. B. Bauer
5. A. Hartz
6. J. McGuire
7. A. Manicone
8. R. Rempe

In Hematology

1. Zena Werb
2. J. McGuire
3. A. Manicone

In Oncology

1. Zena Werb
2. B. Bauer
3. A. Hartz
4. J. McGuire
5. A. Manicone
6. R. Rempe
7. Pengfei Lu
8. M. Egeblad

Citations in the corpus

• Structure and function of matrix metalloproteinases and TIMPs. (2006, unknown): “MT-MMPs in mammals includes four type I transmembrane proteins (MMP-14, -15, -16, and -24) and two glycosylphosphatidylinositol-anchored proteins (MMP-17 and -25).”
• How matrix metalloproteinases regulate cell behavior. (2001, background): “In a co-culture model of herniated disk resorption, MMP3 from chondrocytes is required to generate a macrophage chemotactic factor (Haro et al. 2000a), whereas macrophage MMP7 is required to release soluble TNF-α from the macrophages, thereby enabling them to infiltrate the cultured intervertebral d”
• Matrix metalloproteinases in the brain and blood–brain barrier: Versatile breakers and makers (2016, background): “For example, MT4-MMP has TNF-a-convertase activity through which transmembrane TNF-a is proteolytically converted into soluble, active TNF-a (Figure 4(1)).(61,62) Second, MMPs themselves act as neuroinflammatory signaling molecules.”
• Matrix metalloproteinases as modulators of inflammation. (2008, background): “However, several MMPs also have TNF converting activity in vitro (including MMP1, -2, -3, -9, -12, -14, -15, and -17), and MMP-7 and MMP-12 have been shown to activate pro-TNF in isolated macrophages [31,32].”
• Physiology and pathophysiology of matrix metalloproteases (2010, background): “Interestingly, MMP-17 is not able to activate proMMP-2 even in vitro, making this the only MT-MMP that lacks this trait (English et al. 2000).”