Tumor necrosis factor-α converting enzyme

doi:10.1016/S1357-2725(01)00097-8

The International Journal of Biochemistry & Cell Biology

Volume 34, Issue 1, January 2002, Pages 1-5

https://doi.org/10.1016/S1357-2725(01)00097-8 Get rights and content

Abstract

Tumor necrosis factor-α converting enzyme (TACE/ADAM17/CD156q) is a member of the ‘A Disintegrin And Metalloprotease’, or ADAM, family. It is a multi-domain, type I transmembrane protein that includes an extracellular zinc-dependent protease domain. TACE expression is largely constitutive, but the surface pool is downregulated following cell activation. Cleavage by TACE generates the soluble forms of tumor necrosis factor, transforming growth factor-α, and other proteins from their membrane-bound precursors (a phenomenon termed ‘shedding’). The recognition of substrates by TACE is poorly understood, but sites distal to the active site are probably involved, and in at least some cases both enzyme and substrate must be membrane-anchored. Cell-activators increase the rate of shedding. Activator-induced shedding is mediated by intracellular kinase cascades, but how these cascades affect the shedding machinery is unknown. The pharmaceutical industry is attempting to design specific TACE inhibitors to treat inflammatory diseases.

Introduction

Tumor necrosis factor-α converting enzyme (TACE/ADAM17/CD156q) was identified by its ability to cleave the transmembrane form of tumor necrosis factor (TNF) at its physiological processing site. There are two forms of TNF: the full-length, type II membrane-bound form, and the soluble form resulting from a proteolytic cleavage that releases the active C-terminal portion from the cell surface. The role of TNF in pathological conditions such as rheumatoid arthritis stimulated an intense effort to identify the releasing enzyme. Various studies indicated that this enzyme is cell-associated, and two groups purified it in 1997 from detergent extracts of TNF-producing cells [1], [2].

Section snippets

Structure

The cloning of TACE revealed it to be a member of the ADAM family of proteins [3]. This family falls within the metzincin superfamily, which also includes the matrix metalloproteases [4]. Like most ADAMs, TACE is a multi-domain, type I transmembrane protein, which includes a zinc-dependent catalytic domain and a disintegrin-cysteine rich sequence. (Fig. 1a). As in other metzincins, the pro domain contains a cysteine that interacts with the active-site zinc of the catalytic domain and must be

Synthesis and degradation

TACE mRNA is found in most tissues, and expression of the protein is largely constitutive [1]. Removal of the pro domain also appears to occur constitutively, most likely by the action of furin or a related enzyme in a late Golgi compartment [6]. Only processed TACE appears on the cell-surface [1], [7]. In the absence of cell activators, the surface pool of the enzyme is long-lived, with a half-life of more than 8 h. Prolonged exposure of cells to a phorbol ester, however, causes the

Biological function

TACE's role in ‘shedding’ (Fig. 1b) TNF has been confirmed by observing the effects of deleting its zinc binding domain. Both T cells and monocytes derived from ‘tace^ΔZn/ΔZn’ transgenic mice are deficient in releasing TNF [1]. Most of the tace^ΔZn/ΔZn mice die at birth [8], however, preventing an in vivo assessment of TACE's role in TNF production.

An additional substrate for the enzyme was deduced from the failure of eyelids to fuse normally in tace^ΔZn/ΔZn embryos and from a number of hair and

Possible medical applications

TACE's role in the production of soluble TNF has stimulated major efforts to develop inhibitors. Peptide-hydroxamates, containing a hydroxamic acid group that chelates zinc, are potent inhibitors of TACE and other metzincins. The challenge for the pharmaceutical industry has been to develop specific inhibitors, and thus far no specific TACE inhibitors have been tested in the clinic. The developmental roles of TACE, and its action on multiple substrates, may complicate this therapeutic strategy.

References (15)

J.D. Buxbaum et al.
Evidence that tumor necrosis factor-α converting enzyme is involved in regulated α-secretase cleavage of the Alzheimer amyloid protein precursor
J. Biol. Chem.
(1998)
P. Reddy et al.
Functional analysis of the domain structure of tumor necrosis factor-α converting enzyme
J. Biol. Chem.
(2000)
A. Amour et al.
TNF-α converting enzyme (TACE) is inhibited by TIMP-3
FEBS Lett.
(1998)
R.A. Black et al.
A metalloproteinase disintegrin that releases tumour necrosis factor-α from cells
Nature
(1997)
M.L. Moss et al.
Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-α
Nature
(1997)
J. Schlondorff et al.
Metalloporotease-disintegrins: modular proteins capable of promoting cell–cell interactions and triggering signals by protein-ectodomain shedding
J. Cell Sci.
(1999)
W. Stocker et al.
The metzincins—topological and sequential relations between the astacins, adamalysins, serralysins, and matrixins (collagenases) define a superfamily of zinc-peptidases
Protein Sci.
(1995)

There are more references available in the full text version of this article.

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Molecules in focusTumor necrosis factor-α converting enzyme

Abstract

Introduction

Section snippets

Structure

Synthesis and degradation

Biological function

Possible medical applications

J. Biol. Chem.

J. Biol. Chem.

FEBS Lett.

A metalloproteinase disintegrin that releases tumour necrosis factor-α from cells

Nature

Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-α

Nature

Metalloporotease-disintegrins: modular proteins capable of promoting cell–cell interactions and triggering signals by protein-ectodomain shedding

J. Cell Sci.

The metzincins—topological and sequential relations between the astacins, adamalysins, serralysins, and matrixins (collagenases) define a superfamily of zinc-peptidases

Protein Sci.

Molecules in focus
Tumor necrosis factor-α converting enzyme