Tissue inhibitor of metalloproteinase‐2 (TIMP‐2) has erythroid‐potentiating activity

Abstract

Tissue inhibitor of metalloproteinase (TIMP) was purified and molecularly cloned on the basis of its erythroid.potentiating activity (EPA). TIMP/EPA appears to be a bifunctional molecule with both growth factor and anti-enzymatic activity. Recently, a ~g~ond TINlP-relatcd molecule was identified and we have investigated its possible erythroid-lmtentiating activity. Native, purified human TIMP-2 was assayed for erythroid. potentiating activity using an in vitro erythroid burst formation assay and was compared with that of previoasly characterized recombinant EPA/TIMP-I. The results demonstrate that both members of the tissue inhibitor of metalloproteinase family, TIMP-i and TIMP-2, pos~cs~d erythroid potentiating activity which was inhibited by antibodies developed to neutralize EPA. These restdt~ suggest that TIMP-2 shares a common structural domain with EPA/TIMP-I that is r¢sponsibl¢ for the erythroid-potentiating activity ofthe~ inhibitors. Therefore, TIMP-I and TIMP-2, with both anti-proteaae activity and growth factor activity, join a family of bifunctional molecules such as libroblast growth factor and thrombin which have both enzymatic and growth factor activity.

The matrix metalloproteinase stromelysin-1 acts as a natural mammary tumor promoter

“…Like TIMP-1, TIMP-2 promotes cell growth in culture (Hayakawa et al, 1994;Nemeth et al, 1996;Stetler-Stevenson et al, 1992) and appears to inhibit tumor growth in vivo (Imren et al, 1996). Although some studies indicate that TIMP-2 expression tends to be similar in tumors and matched normal tissues (Stetler-Stevenson et al, 1990), others have found a signi®cant correlation between TIMP-2 expression and the development of distant metastases (Ree et al, 1997).…”

Imbalance between serum matrix metalloproteinase-2 and its inhibitor as a predictor of recurrence of urothelial cancer

“…Many investigators have demonstrated that human and rodent metastatic malignant cells produce larger amounts of MMP-2 than do non-metastatic cells, both in vitro and in vivo (Liotta et al, 1980;. Tissue inhibitor of metalloproteinases-2 (TIMP-2), an unglycosylated protein of 21-kDa molecular weight, strongly inhibits the biological activity of MMP-2, and was shown to strongly inhibit cancer invasion, metastasis, growth and angiogenesis in some rodent and human tumours (Stetler-Stevenson et al, 1989;DeClerck et al, 1992). Therefore, it is likely that an imbalance in the MMP-2 and TIMP-2 ratio plays an important role in cancer invasion, metastasis and angiogenesis DeClerck et al, 1994).…”

Enhancing activity and phospholipase A2 activity: two independent activities present in the enhancing factor molecule

“…There are other reports of such bifunctional molecules. Tissue inhibitor of metalloproteinase is a molecule that has both anti-protease activity and growth-factor activity [32]. PLA # from bovine seminal plasma has been shown to be a platelet-activating factor acetylhydrolase [33].…”