TISSUE INHIBITORS OF METALLOPROTEINASES - STRUCTURE, REGULATION AND BIOLOGICAL FUNCTIONS

Four members of the tissue inhibitor of metalloproteinases (TIMP) fami ly have been characterized so far, designated as TIMP-1, TIMP-2, TIMP- 3, and TIMP-4. TIMP-1 and TIMP-2 are capable of inhibiting the activit ies of all known matrix metalloproteinases (MMPs) and as such play a k ey role in maintaining the balance between extracellular matrix (ECM) deposition and degradation in different physiological processes, Accel erated breakdown of ECM occurs in various pathological processes, incl uding inflammation, chronic degenerative diseases and tumor invasion. TIMP-1 and TIMP-2 can inhibit tumor growth, invasion, and metastasis i n experimental models which has been associated with their MMP inhibit ory activity, Recent developments in TIMP research suggest that TIMP-1 and TIMP-2 are multifunctional proteins with diverse actions, Both in hibitors exhibit growth factor-like activity and can inhibit angiogene sis. Structure-function studies have separated the MMP inhibitory acti vity of TIMP-1 from its growth promoting effect. TIMP-1 has also been implicated in gonadal steroidogenesis and as a cellular elongation fac tor. TIMP-3 is the only member of the TIMP family which is found exclu sively in the extracellular matrix (ECM). It is regulated in a cell cy cle-dependent fashion in certain cell types and may serve as a marker for terminal differentiation. The most recently discovered TIMP, TIMP- 4, may function in a tissue-specific fashion in extracellular matrix h emostasis, The main aim of this article is to review recent literature on TIMPs with special emphasis on their biological activities and the possibility that they may have paradoxical roles in tumor progression .