Processing of tumor necrosis factor by the membrane‐bound TNF‐α‐converting enzyme, but not its truncated soluble form

Itai, Toshimitsu; Tanaka, Masato; Nagata, Shinji

doi:10.1046/j.1432-1327.2001.02085.x

Cited by 51 publications

(39 citation statements)

References 31 publications

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“…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. However, a recent report excluded the TNF-a convertase ADAM17 as a possible FasL secretase, 36 leaving the potential role of other ADAM family members open.…”

Section: Discussionmentioning

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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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%

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

et al. 2007

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“…Several of these studies have been done using cell lines into which a gene encoding noncleavable mTNF has been transfected. When tmTNF is transfected into cells, investigators take care to protect it from an enzyme that would otherwise cleave the TNF molecule, called TNFα-converting enzyme (TACE) [67]. At first the gene encoding tmTNF was transfected as a deletion mutant, but more recently, Harashima et al [68] developed a method of transfecting cells with a tmTNF rendered non-cleavable by site-directed mutagenesis.…”

Section: Limiting Factors Contributing To Disease Restriction In Thermentioning

confidence: 99%

TNFα blockade in human diseases: Mechanisms and future directions

Wong

Ziring

Korin

et al. 2008

Clinical Immunology

256

162

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Tumor necrosis factor-alpha (TNFα) antagonists have shown remarkable efficacy in a variety of immune-mediated inflammatory diseases (IMIDs). Therapeutic scope and limitations of these agents are reviewed in a recently published article in the Journal. In spite of their therapeutic popularity, little is known about their modes of action in vivo and factors that limit their scope of therapeutic use. Intriguingly, while all TNFα antagonists including blocking antibodies and soluble receptors are effective in certain IMIDs, only anti-TNFα antibodies are effective in other IMIDs. Early efforts at understanding how TNFα antagonists act in IMIDs centered on their ability to neutralize soluble TNFα or to block TNF receptors from binding to their ligands. Subsequent studies suggested a role of complement-mediated lysis or antibody-dependent cell cytotoxicity in their therapeutic effects. More recent models postulate that TNFα blockers may act by affecting intracellular signaling, with the end result being a hastened cell cycle arrest, apoptosis, suppression of cytokine production, or improved Treg cell function. TNFα antagonists can also modulate the functions of myofibroblasts and osteoclasts, which might explain how TNFα antagonists reduce tissue damage in chronic IMIDs. Focusing on the human therapeutic experience, this analytical review will review the biology of mechanisms of action, the limiting factors contributing to disease restriction in therapeutic efficacy, and the mechanism and frequency of treatment-limiting adverse responses of TNFα antagonists. It is hoped that the overview will address the needs of clinicians to decide on optimal use, spur clinical innovation, and incite translational researchers to set priorities for in vivo human investigations.

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“…An important feature of some of the ADAMs that do have a functional metalloproteinase domain is their ability to act as ectodomain sheddases of cell surface receptors or adhesion molecules. ADAM-17 (TNF-a-converting enzyme) processes membrane-bound pro-TNF-a and pro-TGF-a liberating the active ligands, 31 while ADAM-10 (Kuzbanian) releases a soluble form of the Notch ligand, Delta, thus facilitating Notch signaling. 29,30 The ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) are an ADAM-like group of proteins, with 19 members.…”

Section: Endogenous Inhibitors Of Metalloproteinasesmentioning

confidence: 99%

Metalloproteinases and their inhibitors in tumor angiogenesis

Handsley

Edwards

2005

Intl Journal of Cancer

260

211

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Angiogenesis is the process by which new blood vessels are formed from preexisting vasculature. It is an essential feature of the female reproductive cycle, embryonic development and wound repair. Angiogenesis has also been identified as a causal or contributing factor in several pathologies, including cancer, where it is a rate-limiting step during tumor progression. Matrix metalloproteinases (MMPs) are a family of soluble and membrane-anchored proteolytic enzymes that can degrade components of the extracellular matrix (ECM) as well as a growing number of modulators of cell function. Several of the MMPs, in particular the gelatinases and membrane-type 1 MMP (MT1-MMP), have been linked to angiogenesis. Potential roles for these proteases during the angiogenic process include degradation of the basement membrane and perivascular ECM components, unmasking of cryptic biologically relevant sites in ECM components, modulation of angiogenic factors and production of endogenous angiogenic inhibitors. This review brings together what is currently known about the functions of the MMPs and the closely related ADAM (a disintegrin and metalloproteinase domain) and ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) families in angiogenesis and considers how this information might be useful in manipulation of the angiogenic process, with a view to constraining tumor progression. ' 2005 Wiley-Liss, Inc.Key words: metalloproteinase; tumor; angiogenesis; tissue inhibitor of metalloproteinases; protease; extracellular matrix Angiogenesis is an essential feature of several physiologic processes such as the developmental growth of organs, wound healing and the female reproductive cycle. 1 It is also particularly significant in cancer progression, being a crucial step in the transition of a tumor from a hyperplastic but contained in situ state to a malignant phenotype. 2,3 To allow its growth beyond a certain critical size, a solid avascular tumor must develop its own blood supply in order to meet its growing metabolic requirements. 1 Vascularization of a tumor also provides a route for dissemination of the tumor cells to different sites around the body.Although angiogenesis appears to be the primary form of tumor vascularization, the malignant cells of a tumor can gain access to a blood supply through other means, such as via tumor-induced vasculogenesis, in which bone marrow-derived precursor endothelial cells contribute to the formation of tumor vessels. 4,5 Vasculogenic mimicry is another form of vessel formation that has been reported in certain tumor types, such as aggressive human uveal melanomas, prostate and breast tumors. [6][7][8] In these cases, networks of tumor cell-lined vascular channels were identified within the tumors. Finally, vessel co-option, implemented by tumor cells as a temporary means of gaining access to a blood supply, involves the tumor cells growing around and thus co-opting existing host vessels to form an initially well-vascularized tumor. 9 This review will highlight new insigh...

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Processing of tumor necrosis factor by the membrane‐bound TNF‐α‐converting enzyme, but not its truncated soluble form

Cited by 51 publications

References 31 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

TNFα blockade in human diseases: Mechanisms and future directions

Metalloproteinases and their inhibitors in tumor angiogenesis

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