Tissue Inhibitors of Metalloproteinases in Cell Signaling: Metalloproteinase-Independent Biological Activities

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Abstract
Over the past 20 years, the tissue inhibitors of metalloproteinases (TIMPs) have been implicated in direct regulation of cell growth and apoptosis. However, the mechanisms of these effects have been controversial. Recent work by several laboratories has identified specific signaling pathways and cell surface binding partners for members of the TIMP family. TIMP-2 binding to the integrin α3β1 is the first description of a cell surface receptor for a TIMP family member. TIMP-2 has been shown to induce gene expression, to promote G1 cell cycle arrest, and to inhibit cell migration. TIMP-1 binding to CD63 inhibits cell growth and apoptosis. These new findings suggest that TIMPs are multifunctional and can act either directly through cell surface receptors or indirectly through modulation of protease activity to direct cell fate. The emerging concept is that TIMPs function in a contextual fashion so that the mechanism of action depends on the tissue microenvironment.