The metalloprotease ADAM17 in inflammation and cancer

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Abstract

Proteolytic cleavage of transmembrane proteins is an important post-translational modification that regulates the biological function of numerous transmembrane proteins. Among the 560 proteases encoded in the human genome, the metalloprotease A Disintegrin and Metalloprotease 17 (ADAM17) has gained much attention in recent years and has emerged as a central regulatory hub in inflammation, immunity and cancer development. In order to do so, ADAM17 cleaves a variety of substrates, among them the interleukin-6 receptor (IL-6R), the pro-inflammatory cytokine tumor necrosis factor α (TNFα) and most ligands of the epidermal growth factor receptor (EGFR). This review article provides an overview of the functions of ADAM17 with a special focus on its cellular regulation. It highlights the importance of ADAM17 to understand the biology of IL-6 and TNFα and their role in inflammatory diseases. Finally, the role of ADAM17 in the formation and progression of different tumor entities is discussed.

Introduction

The biological functions of proteins are critically regulated by post-translational modifications. Among those, proteolytic cleavage of transmembrane proteins at the cell surface by a variety of proteases has gained interest in recent years and has emerged as an important process in many physiological and pathophysiological states [1,2].

Protein cleavage at the cell surface serves several different purposes. First, the cleavage event generates a novel soluble ectodomain of the substrate (therefore, this process is often referred to as “ectodomain shedding”). Because the cleavage usually occurs close to the plasma membrane, these ectodomains often keep their binding sites for ligands or other interacting proteins and are therefore biologically active themselves. Thus, they can compete with their membrane-tethered counterparts for ligand binding and function as soluble decoy proteins, which act antagonistically. Other soluble ectodomains act agonistically in combination with their ligand and can thereby expand the biological functions of the ligand. Thus, proteolytic cleavage can be envisioned as a regulatory step that controls the amount of the soluble form of a transmembrane protein and thereby controls its biological functions [3]. At least for the TNF family, soluble receptors generated by proteolysis do not only act as decoys, but can also bind to their membrane-bound ligands and signal back into the ligand-expressing cell, a process known as “reverse signaling” [4,5].

Second, proteolytic cleavage reduces the amount of the substrate on the cell surface, which is often accompanied by a reduced biological activity of the protein. Is the substrate e.g. a signal-transducing receptor, the cell will be less susceptible to activation by the receptor’s ligand when the cell-surface amount of the receptor has been reduced by proteolytic cleavage. Thus, proteolysis is also a regulatory mechanism that controls the cell-surface amount of transmembrane proteins and thereby regulates the responsiveness of the cell towards extracellular stimuli [2].

The topic of this review article is the metalloprotease ADAM17, one of the best-studied shedding proteases. We will summarize current knowledge about the basic biology of ADAM17, including its regulation, highlight important substrates of the protease, and give an overview about its role in inflammation and tumorigenesis.

Section snippets

The metalloprotease ADAM17

ADAM17 is a member of the A Disintegrin and Metalloprotease (ADAM) family of proteases, which consist of 21 members, among them 13 active enzymes [6]. ADAM17 was first named TACE (TNFα converting enzyme), as it was originally cloned as the protease that cleaves membrane-bound TNFα [7,8]. However, it is clear nowadays that ADAM17 is not solely responsible for the release of soluble TNFα, but has a rather broad spectrum of more than 90 substrates, including ligands of the epidermal growth factor

Regulation of ADAM17 function

Given the high number of ADAM17 substrates, the regulation of its activity is crucial. Judging from transgenic ADAM17 overexpressing mice, which do not display enhanced shedding activity despite increased protein level [30], the main regulatory steps appear to be post-translationally. Indeed, several factors have been described to affect ADAM17 activity, making the deciphering of its regulation a rather complex topic (Fig. 2). In addition to the aforementioned phosphorylation of the

ADAM17 in inflammation: TNFα and IL-6

ADAM17 plays a decisive role in inflammation, as it can cleave and thereby activate cytokines and cytokine receptors. The most prominent examples are the cytokine Tumor Necrosis Factor α (TNFα) and the TNF receptors 1 and 2, which are all ADAM17 substrate, and the cytokine Interleukin-6 (IL-6), whose IL-6 receptor is also a substrate for ADAM17 (Fig. 1).

The cytokine TNFα is part of the TNF superfamily, which contains 19 ligands and 29 receptors [57]. TNFα is synthesized as a typical type-II

ADAM17 in tumor development

Since its discovery, ADAM17 has been implicated in the initiation and progression of practically all tumor entities, and it is thus not possible to cover all these topics within one article. This review focusses exemplarily on the role of ADAM17 in tumorigenesis of colon, breast, and gastric tumorigenesis as well as the Howel–Evans syndrome. Further information on the role of ADAM17 in cancer and pathophysiology can be found in other review articles, e.g. [41,91,92].

ADAM17 has a profound role

Acknowledgment

Work in the lab of C.G. is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – Projektnummer 125440785 – SFB 877 (projects A10 and A14).

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