MT1-MMP (green) is inactive when associated with β1 integrin (red, left) between static cells, but active when associated with αvβ3 integrin (red, right) in migrating cells.

The extracellular matrix (ECM) orchestrates its own destruction, according to results by Gálvez et al. (page 509).

Many different proteins, such as collagen (COL), fibronectin (FN), and gelatin (GEL), make up the basement membranes and connective tissues of ECM-rich tissues. Their degradation by membrane-type matrix metalloprotease 1 (MT1-MMP) is required for cell migration. But it now appears that ECM proteins are not passive victims in this process—they influence the location and activity of the protease by recruiting the help of cell adhesion receptors.

Using MT1-MMP fused to GFP in endothelial cells, Gálvez et al. noted that the protease had an unusual association with β1 integrin at cell–cell contact sites on β1 integrin–dependent substrates (e.g., FN and COL). This association induced by ECM-mediated integrin clustering somehow blocked internalization of MT1-MMP, possibly through integrin signaling. Endocytosis of MT1-MMP was recently shown to be necessary for its activity, and, as expected, MT1-MMP activity at cell contact sites was indeed down-regulated.

In contrast, MMP remained active in cells in which MT1-MMP was not associated with β1 integrins at cell–cell contacts due to either growth on a different substrate (as on GEL) or wound-induced migration. In migrating cells, MT1-MMP relocalized to motility-associated (such as filopodia), where it associated with αvβ3 integrin. MT1-MMP internalization proceeded, thus allowing MMP activation. MT1-MMP activity and its association with integrins were both necessary for maximum cell migration.

The localization of MT1-MMP at cell contact sites indicates that it may have functions not previously considered. Although it is inactive at this site, the authors speculate that MMPs could be activated at the onset of cell migration and cleave adhesion receptors to ease the separation of the close-knit endothelial cells. Transmigrating leukocytes might also stimulate MMP activity at cell contacts to allow cell passage through the endothelium. ▪