Plasma Membrane-bound Tissue Inhibitor of Metalloproteinases (TIMP)-2 Specifically Inhibits Matrix Metalloproteinase 2 (Gelatinase A) Activated on the Cell Surface

Itoh, Yoshifumi; Ito, Akira; Iwata, Kazushi; Tanzawa, Kazuhiko; Mori, Yo; Nagase, Hideaki

doi:10.1074/jbc.273.38.24360

Cited by 129 publications

(126 citation statements)

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“…In the current report, activation of TIMP-2-bound progelatinase A on the plasma membrane, presumably by a second MT1-MMP molecule (free of TIMP-2) (Butler et al, 1998;Zucker et al, 1998), was noted within 60 minutes after the addition of ConA. The appearance of mature gelatinase A in cell-conditioned media followed thereafter but may not be as relevant physiologically because of inactivation by excess soluble TIMP-2 (Itoh et al, 1998).…”

Section: Trafficking Of Mt1-mmp To the Cellmentioning

confidence: 46%

Rapid Trafficking of Membrane Type 1-Matrix Metalloproteinase to the Cell Surface Regulates Progelatinase A Activation

Zucker

Hymowitz

Conner

et al. 2002

Laboratory Investigation

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SUMMARY: Pericellular matrix degradation during cancer invasion and inflammation is dependent on activation of progelatinaseA by membrane type 1-matrix metalloproteinase (MT1-MMP); a stoichiometric concentration of tissue inhibitor of metalloproteinase-2 (TIMP-2) is required. Activation of progelatinase A has generally been considered to be a slow process occurring as a result of enhanced expression of MT1-MMP. We herein report that ConA treatment of HT1080 fibrosarcoma cells is followed by MT1-MMP-induced activation of progelatinase A on the cell surface within 1 hour. Cell surface biotinylation, immunohistochemistry, and 125 I-labeled TIMP-2 binding to cell surface MT1-MMP were used to characterize the appearance and function of MT1-MMP on the plasma membrane. Treatment of HT1080 cells with ConA resulted in increased specific binding of 125 I-labeled TIMP-2 to cell surface receptors within 5 minutes. TIMP-2 binds almost exclusively to activated MT1-MMP on the surface of HT1080 cells. MT1-MMP function at the cell surface was also accelerated by treatment of cells with cytochalasin D, an inhibitor of actin filaments, PMA, a stimulator of protein kinase C, and bafilomycin A 1 , an inhibitor of lysosome/endosome function. A functional pool of intracellular MT1-MMP available for trafficking to the cell surface was demonstrated by repetitive ConA stimulation. ConA-induced expression of MT1-MMP mRNA (Northern blot analysis) in HT1080 cells was a delayed event (Ͼ6 hours). These data suggest that presynthesized MT1-MMP is sorted to a transient storage compartment (trans-Golgi network/endosomes), where it is available for rapid trafficking to the plasma membrane and cell surface proteolytic activity. (Lab Invest 2002, 82:1673-1684.

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Section: Trafficking Of Mt1-mmp To the Cellmentioning

confidence: 46%

Rapid Trafficking of Membrane Type 1-Matrix Metalloproteinase to the Cell Surface Regulates Progelatinase A Activation

Zucker

Hymowitz

Conner

et al. 2002

Laboratory Investigation

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“…Fully functional TIMP-2 is essential for e cient activation of proMMP-2 both in vitro and in vivo (Caterina et al, 2000). However, the active 65-kDa MMP-2 can be inhibited by plasma membrane-bound TIMP-2 (Itoh et al, 1998). These results suggest that the pericellular activity of MMP-2 is tightly regulated by membrane-bound TIMP-2 and surrounding extracellular matrix components.…”

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

confidence: 95%

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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“…Activation is enhanced by MT1-MMP clustering, but the binding interactions that occur in the cell surface rafts of gelatinase A activation complexes are not resolved. Evidence indicates that cell surface-bound active gelatinase A, rather than soluble active enzyme, is needed to efficiently perform the final activation cleavage (11), but the extent of any intramolecular autolysis is not clear. Heparin binding is known to enhance activation in vitro (19,31,32), presumably by promoting the final cleavage event through localization of the gelatinase A activation intermediate with active gelatinase A. Clustering of MT1-MMP at the cell surface fulfills the same role as heparin in vitro by concentrating gelatinase A intermediate and active forms.…”

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confidence: 99%