We have isolated and characterized the complete primary structure of a new member of the tissue inhibitor of metalloproteinase family (TIMP family) which we refer to as TIMP-2. TIMP-2 binds specifically to the latent form of the 72 kDa type IV collagenase. Recent studies have shown that all cells studied to date which secrete the 72 kDa type IV collagenase enzyme secrete this enzyme as a complex with TIMP-2. TGFbeta treatment of these cells results in a decrease in the TIMP-2 mRNA transcript levels. Along with induction of the 72 kDa type IV collagenase mRNA, this results in a shift in the enzyme inhibitor ratio in favor of proteolysis. These studies have also shown that TIMP-2 transcription is regulated independently of both TIMP-1 and the 72 kDa type Iv collagenase enzyme. We have also demonstrated that TIMP-2 is anti-angiogenic and that the mechanism for this effect is through inhibition of endothelial cell proliferation. Finally, we have shown that TIMP-2 inhibits tumor cell invasion through reconstituted basement membranes in vitro.
