CD44 is a transmembrane cell adhesion receptor that binds many components of the extracellular matrix (ECM). Kajita et al. show that when the transmembrane matrix metalloproteinases TM1-MMP or TM3-MMP are coexpressed (by transfection) with the H isoform of CD44, a soluble form of CD44 is shed into the culture medium. Such cells have a different morphology and enhanced motility relative to cells expressing CD44 alone. If the activity of the TM1-MMP was inhibited, then CD44 did not appear in the culture medium, and motility was decreased. In cells transfected to express only CD44 or when the TM1-MMP activity was inhibited, the cells formed small and large protrusions, which suggests that such cells had more substrate attachment sites than did cells in which CD44 was cleaved. The physiological importance of the cleavage of CD44 was investigated in a pancreatic tumor cell line that spontaneously sheds soluble CD44 in a manner dependent on the activity of TM1-MMP. Inhibition of CD44 cleavage and shedding decreased cell motility, as did expression of a mutant form of CD44 in which the cleavage site was eliminated. Thus, breaking the bonds that tether cells to the ECM (by disrupting the CD44 and ECM interaction) may represent one mechanism by which cell motility can be enhanced.
M. Kajita, T. Itoh, T. Chiba, H. Mori, A. Okada, H. Kinoh, M. Seiki, Membrane-type 1 matrix metalloproteinase cleaves CD44 and promotes cell migration. J. Cell Biol. 153, 893-904 (2001). [Abstract] [Full Text]