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. Our studies have 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. The mechanism for this effect may be through inhibition of endothelial cell proliferation in addition to inhibiting endothelial cell mediated matrix proteolysis. We have shown that TIMP-2 inhibits tumor cell invasion through reconstituted basement membranes in vitro, and that this inhibitor demonstrates erythroid potentiating activity (EPA). Recent studies have been directed at cloning the human TIMP-2 gene and determining its chromosomal localization. Two human TIMP-2 genomic clones of approximately 9 and 12 kb have been obtained. The gene appears to be single copy and is localized on human chromosome 17q22-25. We have examined the TIMP-2 protein structure and have localized the metalloprotease inhibitory domain to the N-terminal half of the molecule. Further sublocalization has been attempted using a synthetic peptide approa .
