30. Matrix metalloproteinases
Matrix metalloproteinases (MMPs) are calcium-dependent zinc-containing endopeptidases. They degrade proteins of the extracellular matrix, hence the name. They’re involved in converting structural matrix proteins to signaling molecules, changing the structure of matrix proteins, initiate cell proliferation, induce cell survival, activate signaling molecules and, more importantly, in cancer metastasis, angiogenesis and vasoconstriction.
Many subtypes of MMPs exist. They’re shown in the table below. The gelatinases are the most important.
| Subtype | Members | Function |
|---|---|---|
| Collagenases | MMP1 | Cleave type I, II and III collagens |
| Gelatinases | MMP2, MMP9 | Cleave gelatin and collagen type IV |
| Stromelysins | MMP3 | Activate other MMPs |
| Matrilysin | MMP7 | Cleave cell surface proteins, activate FasL |
| Membrane-type MMPs | Not important | Cleave type I, II and III collagens, activate other MMPs |
MMPs are ruthless. When they’re activated, they will degrade all ECM proteins around them and will be difficult to stop. Because of this the MMPs are only activated when needed, and the activation of them is very tightly regulated. If they’re underregulated there will be significant tissue damage.
Because of this, they’re regulated at the transcriptional, translational and secretional levels. Proteins called TIMPs (Tissue Inhibitors of MetalloProteinases) reversibly inhibit the MMPs. α2-macroglobulin, a protein in the blood irreversibly inhibit and degrade MMPs. Three responsive elements on the DNA are involved in the expression of MMPs. They’re summarized in the table below.
| Name of responsive element | Activate/inhibit MMP expression | Activated by |
|---|---|---|
| TIE | Inhibit | TGF-β (a cytokine) |
| PEA-3 | Activate | C-Ets (a transcription factor) |
| TRE (most important) | Activate | Inflammation (TNF-α, IL-1, Jun/Fos, LPS) |
MMPs are secreted as zymogens, enzymes that must be activated by other enzymes, like in the GI tract. After pro-MMPs have been secreted, plasmin, an enzyme in the blood, activate MMP3. MMP3 then activates the other MMPs.
In cancer
Because MMPs degrade the ECM, they are very important for cancers, which degrade the ECM to allow the tumor to grow, and to allow the cancer cells to migrate to other tissues in the body. Cancers wants more blood supply, so they try to increase the vascularization of the tumor. MMPs are needed for this, to degrade the ECM to give space for arteries to grow. The higher the expression of MMPs in cancers, the more aggressive the tumors are.