Tissue Inhibitors of Metalloproteinases in Cell Signaling: Metalloproteinase-Independent Biological Activities
William G. Stetler-Stevenson*
Chief, Extracellular Matrix Pathology Section, Cell and Cancer Biology Branch, Vascular Biology Faculty, Center for Cancer Research, National Cancer Institute (NCI), NIH, Advanced Technology Center, 8717 Grovemont Circle, Room 115, Bethesda, MD 20892–4605, USA.
Gloss: The extracellular matrix influences cell behavior through interaction with various cell surface receptors. Cells also influence the structure and the composition of the extracellular matrix. Remodeling of the extracellular matrix is mediated by protease activity, which, in turn, is modulated by endogenous protease inhibitors. The tissue inhibitors of matrix metalloproteinases (TIMPs) were first identified as inhibitors of the matrix metalloproteinase (MMP) family, a class of proteases closely identified with cell growth and invasion during the process of tumor progression and metastasis. Over the past 20 years, TIMPs have been implicated in direct regulation of cell growth and apoptosis. However, these biological activities of the TIMP family have been controversial. Recent work by several laboratories has identified specific signaling pathways and cell surface binding partners for members of the TIMP family. These new findings suggest that TIMPs are pluripotent regulators of the extracellular matrix and can act either directly through cell surface receptors or indirectly through modulation of protease activity to direct cell fate.
*E-mail: sstevenw{at}mail.nih.gov
