Review
The “A Disintegrin And Metalloprotease” (ADAM) family of sheddases: Physiological and cellular functions

https://doi.org/10.1016/j.semcdb.2008.11.002Get rights and content

Abstract

There is an exciting increase of evidence that members of the disintegrin and metalloprotease (ADAM) family critically regulate cell adhesion, migration, development and signalling. ADAMs are involved in “ectodomain shedding” of various cell surface proteins such as growth factors, receptors and their ligands, cytokines, and cell adhesion molecules. The regulation of these proteases is complex and still poorly understood. Studies in ADAM knockout mice revealed their partially redundant roles in angiogenesis, neurogenesis, tissue development and cancer. ADAMs usually trigger the first step in regulated intramembrane proteolysis leading to activation of intracellular signalling pathways and the release of functional soluble ectodomains.

Introduction

Proteolytic ectodomain release, a process known as “shedding”, has emerged as a key mechanism for regulating the function of a diversity of cell surface proteins. Shedding of integral membrane proteins is to our knowledge limited to type I and type II transmembrane proteins or GPI-anchored molecules in which the cleavage site is generally located close to the membrane surface. A Disintegrin And Metalloproteases (ADAMs) have emerged as the major proteinase family that mediates ectodomain shedding. ADAM-mediated shedding and non-proteolyic ligand binding are important in a number of biological processes such as the interaction of sperm and egg, cell fate determination, cell migration, wound healing, neurite and axon guidance, heart development, immunity, cell proliferation and angiogenesis. This proteolytic event through a cut in the juxtamembrane region seems to be the rate-limiting step for further cleavage within the membrane plane, releasing an intracellular domain which in some cases might act as signal-transducing molecule. Dependent on the cell type a considerable percentage of the proteins on the cell surface undergo ectodomain shedding affecting functionally diverse proteins, such as cadherins, L-selectin, Fas ligand, TNFα, EGFR ligands, ErbB2, ErbB4, amyloid precursor protein (APP), Notch receptor and ligand, and many others (Table 1). ADAMs as proteins of about 750 amino acid length are characterised by a conserved domain structure (Fig. 1), consisting of an N-terminal signal sequence followed by a prodomain, a metalloprotease domain, a disintegrin domain with a cysteine-rich region, an EGF domain, a transmembrane domain and a cytoplasmic tail [1]. ADAM-mediated shedding is both constitutive and inducible dependent on G-protein coupled receptors, protein kinase C (PKC), intracellular Ca2+ levels, membrane lipid composition and other experimental and natural stimuli. Also modulation of ADAM activity by removal of the inhibitory prodomain, by changing their intracellular distribution and by interaction of proteins, and/or posttranslational modifications of their cytoplasmic tails are reported, which further complicates the understanding of the regulation of proteolysis through ADAMs. The role of ADAMs and their pathophysiological roles are also covered in a number of excellent recent reviews [2], [3], [4], [5].

Section snippets

History and phylogeny

ADAMs belong to the metzincin family of metalloproteases which also includes astacins and matrix metalloproteinases (MMPs). Together with snake venom metalloproteinases (SVMPs) and ADAMTS (ADAMs containing thrombospondin motifs), they form the adamalysin subfamily. The domain structure of ADAMs is responsible for their proteolytic, adhesive, and putative signalling activities [6].

Based upon similar structural features of the first cloned testicular ADAMs with snake venom disintegrin proteinases

ADAM shedding as a prerequisite for intracellular signalling

RIP has emerged as an unusual but important mechanism of signal transduction [66]. This sequential processing of transmembrane proteins in their extracellular domain and the subsequent further processing in the intramembrane region leads to the release of an intracellular domain (ICD), which might participate in signal transduction. Even though the extracellular processing may be mediated by several distinct ectodomain sheddases, the ADAMs play the most prominent role in this context. While the

Roles of ADAMs for health and disease revealed by studies from ADAM knockout mice

Knockout mice for a number of widely expressed ADAMs were generated. The phenotype of these mice revealed important information about functions and substrates of these proteases. The availability of these mice but also of cell lines derived from these mice allowed the in depth analysis of potential functions of these proteins under physiological and pathological conditions. Interestingly, whereas knockout strains for ADAM8,9,12,15 did not present overt phenotypes, mice lacking ADAM10,17,19 and

Aspects of regulation of ADAM proteases

Apart from the constitutive cleavage by ADAM proteases a number of stimuli for such shedding events are known. Serum factors, growth factors, changes in the intracellular calcium concentration, osmotic and mechanical stress, and PKC activation are known inducers for ADAM-mediated ectodomain shedding. Regulation of ADAM activity may happen at different levels such as transcriptional control, alternative splicing, post-translational modifications, changes in the stability of ADAM proteinases,

Conclusions

It is well recognised that ADAM-mediated ectodomain shedding is of major importance to regulate cell-cell interaction and cell communication. Dysregulation of ectodomain shedding is associated with autoimmune and cardiovascular diseases, infection, inflammation and cancer and ADAMs are attractive targets for novel therapies. It becomes increasingly clear that further research especially on the regulation and control of ADAM activity, ADAM redundancy in substrate processing, ADAM structure,

Acknowledgments

This work was supported by the Deutsche Forschungsgemeinschaft Sonderforschungsbereich 415 and 617 to P.S. and K.R., Interuniversity Attraction Poles Program IAP VI P6/43 of the Belgian Federal Science Policy Office and the Center of Excellence “Inflammation at Interfaces”.

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