Accession Number:

ADA394512

Title:

Extracellular Matrix Regulations of Membrane Type 1-Matrix Metalloproteinasis (MT1-MMP) and Matrix Metalloproteinase-2 (MMP-2) in Human Breast Fibroblasts

Descriptive Note:

Annual summary rept. 1 Jul 1999-1 Jul 2000

Corporate Author:

WAYNE STATE UNIV DETROIT MI

Report Date:

2000-08-01

Pagination or Media Count:

18.0

Abstract:

Previous studies have shown that MT1-MMP MMP-14 initiates pro-MMP-2 activation in a process that is tightly regulated by the level of TIMP-2. However, given the difficulty in modulating TIMP-2 levels, the direct effect of TIMP-2 on MT1-MMP processing and on pro-MMP-2 activation in a cellular system could not be established. Here, recombinant vaccinia viruses encoding full-length MT1-MMP or TIMP-2 were used to express MT1-MMP alone or in combination with various levels of TIMP-2 in mammalian cells. We show that TIMP-2 regulates the amount of active MT1-MMP 57 kDa on the cell surface whereas in the absence of TIMP-2 MT1-MMP undergoes autocatalysis to a 44-kDa form, which displays a N-terminus starting at Gsup 285 and hence lacks the entire catalytic domain. Neither pro-MT1-MMP N terminus Ssup 24 nor the 44-kDa form bound TIMP-2. In contrast, active MT1-MMP N-terminus Ysup 112 formed a complex with TIMP-2 suggesting that regulation of MT1-MMP processing is mediated by a complex of TIMP-2 with the active enzyme. Consistently, TIMP-2 enhanced the activation of pro-MMP-2 by MT1-MMP. Thus, under controlled conditions, TIMP-2 may act as a positive regulator of MT1-MMP activity by promoting the availability of active MT1-MMP on the cell surface and consequently, may support pericellular proteolysis.

Subject Categories:

  • Biochemistry
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE