The metalloproteinase matrilysin proteolytically generates active soluble Fas ligand and potentiates epithelial cell apoptosis

Powell, William C.; Fingleton, Barbara; Wilson, Carole L.; Boothby, Mark; Matrisian, Lynn M.

doi:10.1016/s0960-9822(00)80113-x

Cited by 391 publications

(317 citation statements)

References 38 publications

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“…Over the past years, it became evident that FasL might also be released by protease cleavage to act as a soluble cytokine. 8 34 Several MMPs including MMP-3 (stromelysin-1) 35 and MMP-7 (matrilysin) 9,16 have been associated with FasL cleavage in different cellular systems. On the other hand, several other members of the TNF-family and TNF receptor family are proteolytically processed by ADAMs, suggesting that these proteases might also be involved in the FasL cleavage.…”

Section: Discussionmentioning

confidence: 99%

“…Depending on the availability and accessibility of respective cleavage sites, matrix metalloproteases (MMPs) like MMP-7 have been proposed as FasL sheddases in different cellular systems mostly using in vitro proteolysis assays. 15,16 On the basis of observation that MMP-inhibiting tissue inhibitors of metalloproteases (TIMPs) did not alter FasL shedding, it was suggested that members of the 'a disintegrin and metalloprotease' (ADAM) family are responsible for the generation of sFasL. 6 This family of zinc-dependent transmembrane proteases has been implicated in the ectodomain shedding of various membrane-bound proteins.…”

Section: For Review)mentioning

confidence: 99%

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ADAM10 regulates FasL cell surface expression and modulates FasL-induced cytotoxicity and activation-induced cell death

et al. 2007

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The apoptosis-inducing Fas ligand (FasL) is a type II transmembrane protein that is involved in the downregulation of immune reactions by activation-induced cell death (AICD) as well as in T cell-mediated cytotoxicity. Proteolytic cleavage leads to the generation of membrane-bound N-terminal fragments and a soluble FasL (sFasL) ectodomain. sFasL can be detected in the serum of patients with dysregulated inflammatory diseases and is discussed to affect Fas-FasL-mediated apoptosis. Using pharmacological approaches in 293T cells, in vitro cleavage assays as well as loss and gain of function studies in murine embryonic fibroblasts (MEFs), we demonstrate that the disintegrin and metalloprotease ADAM10 is critically involved in the shedding of FasL. In primary human T cells, FasL shedding is significantly reduced after inhibition of ADAM10. The resulting elevated FasL surface expression is associated with increased killing capacity and an increase of T cells undergoing AICD. Overall, our findings suggest that ADAM10 represents an important molecular modulator of FasL-mediated cell death.

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Section: Discussionmentioning

confidence: 99%

Section: For Review)mentioning

confidence: 99%

ADAM10 regulates FasL cell surface expression and modulates FasL-induced cytotoxicity and activation-induced cell death

et al. 2007

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“…Through proteolysis of various biologically active molecules, MMPs can positively or negatively regulate apoptosis in a context-dependent manner. MMP-7 releases membrane-bound Fas ligand, thereby triggering apoptosis upon binding with the Fas receptor (Powell et al, 1999). On the other hand, MMP-7 can inhibit apoptosis by proteolytic generation of mature HB-EGF that promotes cell survival by stimulating the ErbB4 tyrosine kinase receptor (Yu et al, 2002).…”

Section: Cell Deathmentioning

confidence: 99%

Matrix metalloproteinases and their tissue inhibitors direct cell fate during cancer development

2003

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Matrix metalloproteinases (MMPs) were initially recognised for their extracellular matrix (ECM)-degrading capability during tissue remodelling. Their importance was further highlighted by their role in metastasis. Clinical trials have since evaluated the potential of MMP inhibitors as anticancer therapeutics, but without success. These initial studies point to the complex, multifunctional capacity of MMPs in cancer as shown by their function, not only as strident mediators of advanced malignancies, but also as effectors of early stage tumorigenesis. Research now shows that MMPs, and their tissue inhibitors, affect tumour initiation and growth through loss of cell adhesion, evasion of apoptosis, and deregulation of cell division. The extracellular nature of the metalloproteinase axis situates it as a master regulator of cell fate.

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“…The MMPs, which are known as a family of zincdependent endopeptidases, are essential for normal tissue remodeling [29], and many studies have shown the involvement of MMPs in tumor growth [9], differentiation [12], apoptosis [24], migration, invasion [7], the regulation of tumor angiogenesis [23] and immune surveillance [lo]. One member of the MMP family, MMP-1, is capable of degrading type I, 11, 111, VII, X, gelatin, and aggrecan [8].…”

Section: Introductionmentioning

confidence: 99%

RNAi mediated MMP-1 silencing inhibits human chondrosarcoma invasion

2005

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Previous work indicates that matrix metalloproteinase-1 (MMP-1) gene expression is a prognostic factor for local recurrence and metastasis in human chondrosarcoma. The current study evaluates the effects of MMP-1 knock-down via RNA interference on chondrosarcoma metastasis in vitro. Of nine siRNA oligos tested, one showed a 90% inhibitory effect on MMP-1 gene expression. Stable attenuation of MMP-1 in chondrosarcoma cells was achieved by using a plasmid vector-based siRNA system. Propounced MMP-1 activity suppression was accompanied by marked inhibition of tumor cell invasion. Cells in which MMP-1 has been stably silenced are useful tools to elucidate the mechanism of MMP-1 mediated tumor metastasis.

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The metalloproteinase matrilysin proteolytically generates active soluble Fas ligand and potentiates epithelial cell apoptosis

Abstract: The results show that a functional form of sFasL was generated by the action of the metalloproteinase matrilysin, and suggest that matrilysin cleavage of FasL is an important mediator of epithelial cell apoptosis.

Cited by 391 publications

References 38 publications

ADAM10 regulates FasL cell surface expression and modulates FasL-induced cytotoxicity and activation-induced cell death

ADAM10 regulates FasL cell surface expression and modulates FasL-induced cytotoxicity and activation-induced cell death

Matrix metalloproteinases and their tissue inhibitors direct cell fate during cancer development

RNAi mediated MMP-1 silencing inhibits human chondrosarcoma invasion

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