Murine TIMP‐2 Gene‐Targeted Mutation

Caterina, John J.; Caterina, Nancy C.M.; Yamada, Satoru; Holmbäck, Kenn; Longenecker, Glenn; Shi, Joanne; Netzel‐Arnett, Sarah; Engler, Jeffrey A.; Yermovski, A.; Windsor, Jack; Birkedal‐Hansen, Henning

doi:10.1111/j.1749-6632.1999.tb07717.x

Cited by 11 publications

(16 citation statements)

References 2 publications

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“…Although TIMP-2 deficiency leads to severely impaired MMP-2 activation [22,23], MT1-MMP processing of pro-MMP-2 to the intermediate form has been demonstrated in TIMP-2 depleted cells [24], leading to speculation that TIMP-2 is required only for the second autocatalytic activation step.…”

Section: Discussionmentioning

confidence: 99%

MT1-MMP hemopexin domain exchange with MT4-MMP blocks enzyme maturation and trafficking to the plasma membrane in MCF7 cells

Atkinson

Roghi

Murphy

2006

Biochemical Journal

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The hemopexin-like domain of membrane-type matrix metalloproteinase-1 (MT1-MMP) enables MT1-MMP to form oligomers that facilitate the activation of pro-matrix metalloproteinase-2 (pro-MMP-2) at the cell surface. To investigate the role of the MT1-MMP hemopexin domain in the trafficking of MT1-MMP to the cell surface we have examined the activity of two MT1-MT4-MMP chimaeras in which the hemopexin domain of MT1-MMP has been replaced with that of human or mouse MT4-MMP. We show that MT1-MMP bearing the hemopexin domain of MT4-MMP was incapable of activating pro-MMP-2 or degrading gelatin in cell based assays. Furthermore, cell surface biotinylation and indirect immunofluorescence show that transiently expressed MT1-MT4-MMP chimaeras failed to reach the plasma membrane and were retained in the endoplasmic reticulum. Functional activity could be restored by replacing the MT4-MMP hemopexin domain with the wild-type MT1-MMP hemopexin domain. Subsequent analysis with an antibody specifically recognising the propeptide of MT1-MMP revealed that the propeptides of the MT1-MT4-MMP chimaeras failed to undergo proper processing. It has previously been suggested that the hemopexin domain of MT4-MMP could exert a regulatory mechanism that prevents MT4-MMP from activating pro-MMP-2. In this report, we demonstrate unambiguously that MT1-MT4-MMP chimaeras do not undergo normal trafficking and are not correctly processed to their fully active forms and, as a consequence, they are unable to activate pro-MMP-2 at the cell surface.

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Section: Discussionmentioning

confidence: 99%

MT1-MMP hemopexin domain exchange with MT4-MMP blocks enzyme maturation and trafficking to the plasma membrane in MCF7 cells

Atkinson

Roghi

Murphy

2006

Biochemical Journal

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Section: Discussionmentioning

confidence: 99%

“…In contrary, the MT1-MMP/MMP-2/TIMP-2 pathway, at least in the mesenchyme, does not seem to be under the direct control of TGF-␤3. This functional redundancy may explain why neither MMP-2, TIMP-2, nor MT1-MMP-deficient mice develop a cleft palate (Itoh et al, 1998;Caterina et al, 1999;Holmbeck et al, 1999).Currently, it is thought that during palatal fusion most of the MEE cells are removed from the midline seam mainly by EMT. It has been shown that MMPs can directly induce EMT in mammary gland epithelial cells during neoplastic progression (Lochter et al, 1997).…”

mentioning

confidence: 99%

TGF-β3-induced Palatogenesis Requires Matrix Metalloproteinases

Blavier¹,

Lazaryev²,

Groffen³

et al. 2001

MBoC

154

176

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Cleft lip and palate syndromes are among the most common congenital malformations in humans. Mammalian palatogenesis is a complex process involving highly regulated interactions between epithelial and mesenchymal cells of the palate to permit correct positioning of the palatal shelves, the remodeling of the extracellular matrix (ECM), and subsequent fusion of the palatal shelves. Here we show that several matrix metalloproteinases (MMPs), including a cell membraneassociated MMP (MT1-MMP) and tissue inhibitor of metalloproteinase-2 (TIMP-2) were highly expressed by the medial edge epithelium (MEE). MMP-13 was expressed both in MEE and in adjacent mesenchyme, whereas gelatinase A (MMP-2) was expressed by mesenchymal cells neighboring the MEE. Transforming growth factor (TGF)-␤3-deficient mice, which suffer from clefting of the secondary palate, showed complete absence of TIMP-2 in the midline and expressed significantly lower levels of MMP-13 and slightly reduced levels of MMP-2. In concordance with these findings, MMP-13 expression was strongly induced by TGF-␤3 in palatal fibroblasts. Finally, palatal shelves from prefusion wild-type mouse embryos cultured in the presence of a synthetic inhibitor of MMPs or excess of TIMP-2 failed to fuse and MEE cells did not transdifferentiate, phenocopying the defect of the TGF-␤3-deficient mice. Our observations indicate for the first time that the proteolytic degradation of the ECM by MMPs is a necessary step for palatal fusion. INTRODUCTIONThe formation of the palate is of critical importance to separate the oropharynx from the nasopharynx. A dysfunction in one of the regulators of this developmental process can lead to a cleft palate, one of the most common birth defects in humans (Chenevix-Trench et al., 1992). In the mouse embryo, the entire process of palatal formation takes place between day 12 and 15 (E12 and E15) of development (Ferguson, 1988). The fusion itself occurs over a relatively short period of time during which the medial edge epithelia (MEE) of the shelves form a midline seam, which is then disrupted to allow mesenchymal continuity (Pourtois, 1966;Smiley and Koch, 1971). Complete fusion of the secondary palate requires disappearance of the MEE from the midline, as well as the breakdown of their basement membrane.The molecular mechanisms controlling palatal fusion are complex and not fully understood. However, studies in the mouse have pointed to primary and secondary causes of defective palatogenesis. In mice deficient for the epidermal growth factor receptor or the platelet-derived growth factor receptor, a cleft palate is often associated with a primary defect in the development of the first branchial arch (Shiota et al., 1990;Brunet et al., 1993;Robbins et al., 1999). In these cases, delayed development of the lower jaw interferes with forward displacement of the tongue and prevents the elevation and subsequent fusion of the shelves (Robbins et al., 1999). In transforming growth factor (TGF)-␤3-deficient mice a cleft palate develops in all mice due to ...

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“…Aside from gross phenotype, TIMP‐1 null mice have also been shown to be robustly resistant to bacterial infection (Osiewicz et al, 1999), although the precise reason for this resilience is currently not clear. Although TIMP‐2 null mice have not been reported to have any notable phenotype, TIMP‐2 deficiency has been shown to result in reduced pro‐MMP‐2 activity (Caterina et al, 1999; Wang et al, 2000). This finding supports a physiological role for TIMP‐2 in the recruitment and activation of MT‐MMP‐2 through binding of the membrane‐bound zymogen (Strongin et al, 1995).…”

Section: Properties Of the Timpsmentioning

confidence: 99%

The TIMPs tango with MMPs and more in the central nervous system

Crocker

Pagenstecher²,

Campbell

2003

J of Neuroscience Research

122

107

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The matrix metalloproteinases (MMPs) are a family of zinc-dependent extracellular proteases that have been implicated in CNS development and disease. Crucial homeostatic regulation of MMPs is mediated through the expression and actions of the tissue inhibitors of metalloproteinases (TIMPs). Although the TIMPs are recognized inhibitors of the MMPs, recent studies have revealed that these proteins also can exhibit biological activities that are distinct from their interactions with or inhibition of the MMPs. With our understanding of the roles of the TIMPs in the CNS continuously emerging, this review examines the current state of knowledge regarding the multifarious and novel functions of this family of proteins, with particular attention to their increasing potential in the development, plasticity, and pathology of the CNS.

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Murine TIMP‐2 Gene‐Targeted Mutation

Cited by 11 publications

References 2 publications

MT1-MMP hemopexin domain exchange with MT4-MMP blocks enzyme maturation and trafficking to the plasma membrane in MCF7 cells

MT1-MMP hemopexin domain exchange with MT4-MMP blocks enzyme maturation and trafficking to the plasma membrane in MCF7 cells

TGF-β3-induced Palatogenesis Requires Matrix Metalloproteinases

The TIMPs tango with MMPs and more in the central nervous system

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