Differential Roles of TIMP-4 and TIMP-2 in Pro-MMP-2 Activation by MT1-MMP

Hernandez-Barrantes, Sonia; Shimura, Yoichiro; Soloway, Paul D.; Sang, Qing‐Xiang Amy; Fridman, Rafael

doi:10.1006/bbrc.2001.4323

Cited by 74 publications

(63 citation statements)

References 32 publications

(38 reference statements)

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“…Previous studies have shown that active MT1-MMP is autocatalytically processed on the cell surface to an inactive membrane-tethered ϳ44-kDa species lacking the entire catalytic domain (17). This processing is inhibited by TIMP-2, TIMP-4, and synthetic MMP inhibitors consistent with being an intermolecular autocatalytic event (19,20). Inhibition of MT1-MMP processing induces accumulation of the active enzyme on the cell surface, and, as a consequence, net MT1-MMP-dependent proteolysis is enhanced.…”

Section: Membrane Type 1 Matrix Metalloproteinase (Mt1-mentioning

confidence: 80%

“…The autocatalytic shedding is inhibited by the natural MT1-MMP inhibitors, TIMP-2 and TIMP-4, and high affinity synthetic MMP inhibitors like marimastat. Consequently, these inhibitors stabilize active MT1-MMP on the cell surface (16,17,19,21,62). In the non-autocatalytic shedding of MT1-MMP (on right side of figure), a yet unknown protease releases the ectodomain (ϳ50 kDa, no structural information yet), which possess catalytic activity (24).…”

mentioning

confidence: 99%

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Complex Pattern of Membrane Type 1 Matrix Metalloproteinase Shedding

Tóth¹,

Hernandez-Barrantes²,

Osenkowski³

et al. 2002

Journal of Biological Chemistry

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112

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Membrane type 1 matrix metalloproteinase (MT1-MMP 255 and Ile 256 residues near the conserved methionine turn, a structural feature of the catalytic domain of all MMPs. Consistently, a recombinant 18-kDa fragment had no catalytic activity and did not bind TIMP-2. Thus, autocatalytic shedding evolved as a specific mechanism to terminate MT1-MMP activity on the cell surface by disrupting enzyme integrity at a vital structural site. In contrast, functional data suggest that the non-autocatalytic shedding generates soluble active MT1-MMP species capable of binding TIMP-2. These studies suggest that ectodomain shedding regulates the pericellular and extracellular activities of MT1-MMP through a delicate balance of active and inactive enzyme-soluble fragments.Release of the extracellular portion of type I transmembrane proteins, referred to as ectodomain shedding, has been established as a major regulatory mechanism to control the activity of a variety of membrane-bound proteins on the cell surface (1). Recent evidence suggests that ectodomain shedding is also characteristic of the membrane type matrix metalloproteinases (MT-MMPs), 1 a subfamily of membrane-anchored MMPs by means of a transmembrane domain or a glycosylphosphatidylinositol anchor (2, 3). The MT-MMPs are major mediators of proteolytic events on the cell surface, including turnover of extracellular matrix components (4, 5), cleavage of various surface adhesion receptors (6 -8), and initiation of zymogen activation cascades (9, 10). Uncontrolled MT-MMP activity contributes to abnormal development (11) and is a key determinant in cancer metastasis and tumor angiogenesis (12)(13)(14). To control the extent of pericellular activity, the MT-MMPs are inhibited by the tissue inhibitors of metalloproteinases (TIMPs), a family of natural protein MMP inhibitors. In addition, MT-MMPs have a unique regulatory mechanism in which the active enzyme undergoes a series of processing steps, either autocatalytic (15-17) or mediated by other proteases (18), that regulate the activity and nature of the enzyme species at the cell surface and at the pericellular space. Previous studies have shown that active MT1-MMP is autocatalytically processed on the cell surface to an inactive membrane-tethered ϳ44-kDa species lacking the entire catalytic domain (17). This processing is inhibited by TIMP-2, TIMP-4, and synthetic MMP inhibitors consistent with being an intermolecular autocatalytic event (19,20). Inhibition of MT1-MMP processing induces accumulation of the active enzyme on the cell surface, and, as a consequence, net MT1-MMP-dependent proteolysis is enhanced. Indeed, we have shown that, under certain conditions, inhibition of MT1-MMP autocatalysis by synthetic MMP inhibitors enhances pro-MMP-2 activation by MT1-MMP in the presence of TIMP-2 (20, 21). Thus, although the presence of inhibitors will stabilize MT1-MMP on the cell surface, the absence or reduced levels of inhibitors will facilitate autocatalysis. As a membrane-anchored protein, the autocatalytic processing of ac...

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Section: Membrane Type 1 Matrix Metalloproteinase (Mt1-mentioning

confidence: 80%

mentioning

confidence: 99%

Complex Pattern of Membrane Type 1 Matrix Metalloproteinase Shedding

Tóth¹,

Hernandez-Barrantes²,

Osenkowski³

et al. 2002

Journal of Biological Chemistry

Self Cite

112

View full text Add to dashboard Cite

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“…These results suggest that the pericellular activity of MMP-2 is tightly regulated by membrane-bound TIMP-2 and surrounding extracellular matrix components. TIMP-4 and TIMP-3 can also bind to proMMP-2 with high a nity (Butler et al, 1999;Bigg et al, 1997), but do not promote MT1-MMP mediated activation of proMMP-2 (Hernandez- Barrantes et al, 2001).…”

Section: Paradox 2: Timps Regulate Pro-mmp Activation and Tumor Angiomentioning

confidence: 99%

Complex roles of tissue inhibitors of metalloproteinases in cancer

2002

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Matrix metalloproteinases (MMPs) is tightly associated with extracellular matrix (ECM) turnover, which plays a very active role in tumor invasion and metastasis. Tissue inhibitors of metalloproteinases (TIMPs) plays a critical role in the homeostasis of ECM by regulating the activity of MMPs. TIMPs are well-known for their ability to inhibit MMP activity thereby inhibiting tumor growth and metastasis. However, many evidences suggest that TIMPs are multifunctional proteins, which regulate cell proliferation, apoptosis, proMMP-2 activation, and angiogenesis. These e ects may be through MMPdependent or MMP-independent pathways. Recent data indicate that TIMPs have many paradoxical roles in tumorigenesis. In particular, both inhibitory e ect and stimulatory e ect on tumorigenesis have been demonstrated in many animal models in which TIMPs were overexpressed in cancer cells or in mice. Elevated TIMP levels are reported in association with cancer progression and identi®ed as poor prognostic indicators in several human tumor types. Herein, we review the complex roles of TIMPs in cancer growth and metastasis.

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“…Their activity is regulated by tissue inhibitors of metalloproteinases (TIMPs) [7,321, which are also present in most tissues and body fluids and which bind to MMPs to inhibit their action [3, 141. To be activated, proMMP-2 requires a ternary complex with membrane type 1 (MT1)-MMP [25] and TIMP-2 [13,17,18, 211 at the cell surface.…”

Section: Introductionmentioning

confidence: 99%

Modulation of matrix gelatinases and metalloproteinase-activating process in acute kidney rejection

et al. 2003

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Changes in matrix metalloproteinase (MMP) activities would contribute to the accumulation of extracellular matrix during acute kidney allograft rejection. MMP-2 and MMP-9 and other gelatinolytic activities were examined in the rejected graft and the urine of a rat model of acute kidney rejection (orthotopic allotransplantation from a Buffalo donor to a Wistar-Furth recipient) by either zymography or fluorescence assay. MMP-2, membrane type 1 (MT1)-MMP, and tissue inhibitor of metalloproteinase (T1MP)-2 were also examined by immunodetection. The proMMP-2 activity and protein level increased in the graft during rejection when compared with normal Buffalo kidney, whereas activated MMP-2 decreased. TIMP-2 protein levels were markedly decreased and MTI-MMP proteolytic fragments (4440 kDa) were undetectable. This suggests an altered MTl-MMP-dependent processing of proMMP-2 into active MMP-2 due to a diminished TIMP-2 level in acute kidney rejection. In the urine the overall gelatinolytic activity decreased considerably, although activity associated with an as yet unidentified 78-kDa protein appeared 6 days after transplantation.

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Differential Roles of TIMP-4 and TIMP-2 in Pro-MMP-2 Activation by MT1-MMP

Cited by 74 publications

References 32 publications

Complex Pattern of Membrane Type 1 Matrix Metalloproteinase Shedding

Complex Pattern of Membrane Type 1 Matrix Metalloproteinase Shedding

Complex roles of tissue inhibitors of metalloproteinases in cancer

Modulation of matrix gelatinases and metalloproteinase-activating process in acute kidney rejection

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