Translational regulation of membrane type 3‐matrix metalloproteinase (MT3‐MMP) expression

MT3‐MMP and MT1‐MMP are two closely related membrane‐anchored matrix metalloproteinases that promote pericellular proteolysis and tumor cell invasion. Like MT1‐MMP, recombinant MT3‐MMP accomplishes the surface activation of pro‐MMP‐2 in a TIMP‐2‐dependent manner. However, little is known about the expression and regulation of natural MT3‐MMP. We found that MT3‐MMP and MT1‐MMP mRNAs are readily detected in several human cell lines and primary cells by semiquantitative RT‐PCR. However, MT3‐MMP protein, in contrast to MT1‐MMP, was consistently undetectable, as determined by immunoblotting and immunoprecipitation of cell lysates and plasma membrane fractions. MT3‐MMP protein was also undetected after treatment of cells with proteasome or synthetic MMP inhibitors. HT1080 human fibrosarcoma, WPMY‐1 human prostate myofibroblast, and A2058 human melanoma cells exposed to TNF‐α, EGF, FGF, phorbol ester, collagen I and III or hypoxic conditions also showed a consistent lack of MT3‐MMP protein expression. Pulse chase analyses showed no evidence of MT3‐MMP protein synthesis or degradation in HT1080 and WPMY1 cells lines. In contrast, MT1‐MMP biosynthesis and processing were readily detected under the same condition. No difference in MT1‐ and MT3‐MMP mRNA stability was found in HT1080 cells after actinomycin D treatment. Taking together, these studies suggest that MT3‐MMP exhibits a unique mode of regulation at the translational level, which may play a key role in tightly controlling protein expression of MT3‐MMP during tumor cell invasion.