Matrix metalloproteinases: old dogs with new tricks

Abstract

The matrix metalloproteinase family in humans comprises 23 enzymes, which are involved in many biological processes and diseases. It was previously thought that these enzymes acted only to degrade components of the extracellular matrix, but this view has changed with the discovery that non-extracellular-matrix molecules are also substrates.

Figure 1

The domain composition and important structural features of the various subtypes of MMPs.

Figure 2

The 'cysteine-switch' mechanism regulating the MMP zymogen. The thiol group of a conserved cysteine (C) at the carboxyl terminus of the pro-domain acts as a fourth inactivating ligand for the catalytic zinc atom in the active site; this results in the exclusion of water and keeps the enzyme latent. Displacement of the pro-domain by conformational change or proteolysis disrupts this cysteine-zinc pairing and the thiol group is replaced by water. The enzyme can then cleave the peptide bonds of its substrates.

Figure 3

The locations of MT-MMPs. (a) The location of MT-MMPs lends them critical biological roles at the cell surface: they cleave components of the ECM, other MMPs and receptors for growth factors (which leads to shedding of the receptors from the cells). (b) Mobilization of MT-MMPs to the leading edge of cancer cells, where they remodel the ECM, facilitates cell migration and tumor invasion.

Figure 4

The phenotype of Mmp14-null mice, which is the most dramatic developmental phenotype of all MMP null transgenes. A rare example of an Mmp14-null mouse that has survived to 10 weeks of age is shown (front, alongside a normal littermate); note the severe dwarfism and craniofacial anomalies.