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Review
. 2008 Oct;29(5):258-89.
doi: 10.1016/j.mam.2008.08.001. Epub 2008 Aug 15.

The ADAM metalloproteinases

Dylan R Edwards  1 , Madeleine M Handsley, Caroline J Pennington
Affiliations
Review

The ADAM metalloproteinases

Dylan R Edwards et al. Mol Aspects Med. 2008 Oct.

Abstract

The ADAMs (a disintegrin and metalloproteinase) are a fascinating family of transmembrane and secreted proteins with important roles in regulating cell phenotype via their effects on cell adhesion, migration, proteolysis and signalling. Though all ADAMs contain metalloproteinase domains, in humans only 13 of the 21 genes in the family encode functional proteases, indicating that at least for the other eight members, protein-protein interactions are critical aspects of their biological functions. The functional ADAM metalloproteinases are involved in "ectodomain shedding" of diverse growth factors, cytokines, receptors and adhesion molecules. The archetypal activity is shown by ADAM-17 (tumour necrosis factor-alpha convertase, TACE), which is the principal protease involved in the activation of pro-TNF-alpha, but whose sheddase functions cover a broad range of cell surface molecules. In particular, ADAM-17 is required for generation of the active forms of Epidermal Growth Factor Receptor (EGFR) ligands, and its function is essential for the development of epithelial tissues. Several other ADAMs have important sheddase functions in particular tissue contexts. Another major family member, ADAM-10, is a principal player in signalling via the Notch and Eph/ephrin pathways. For a growing number of substrates, foremost among them being Notch, cleavage by ADAM sheddases is essential for their subsequent "regulated intramembrane proteolysis" (RIP), which generates cleaved intracellular domains that translocate to the nucleus and regulate gene transcription. Several ADAMs play roles in spermatogenesis and sperm function, potentially by effecting maturation of sperm and their adhesion and migration in the uterus. Other non-catalytic ADAMs function in the CNS via effects on guidance mechanisms. The ADAM family are thus fundamental to many control processes in development and homeostasis, and unsurprisingly they are also linked to pathological states when their functions are dysregulated, including cancer, cardiovascular disease, asthma, Alzheimer's disease. This review will provide an overview of current knowledge of the human ADAMs, discussing their structure, function, regulation and disease involvement.

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Figures

Fig. 1
Fig. 1
Comparison of the domain structures of the ADAM, MMP, SVMP and ADAMTS metalloproteinases. The domain organization of the proteases is compared, and their membrane or secreted location is indicated. Domains are not drawn to scale.
Fig. 2
Fig. 2
The 21 members of the human ADAM family, in relation to their metalloproteinase activity and sites of expression.
Fig. 3
Fig. 3
Phylogenetic tree of human ADAMs based on the sequences of their metalloproteinase domains. Phylogenetic and molecular evolutionary analyses were conducted using MEGA version 4 (Tamura et al., 2007). The scale bar represents amino acid substitutions per site, such that 0.1 represents 10% of sites having a substitution.
Fig. 4
Fig. 4
Regulated intramembrane proteolysis of Notch and Amyloid Precursor Protein (APP).
Fig. 5
Fig. 5
Structure of the ADAM metalloproteinase domain. (A) The schematic depicts structural features determined by X-ray crystallographic analysis of the SVMP Adamalysin II (Gomis-Ruth, 2003). (B) Nomenclature for the amino acid sequence in the cleavage site of substrates and the corresponding sub-sites in the active site of the protease.
Fig. 6
Fig. 6
The disposition of the modular domains of ADAMs. The schematic shows a representation of the likely arrangement of ADAM domains based on the crystallographic data of Takeda et al., 2006, Igarashi et al., 2007.
Fig. 7
Fig. 7
ADAM metalloproteinases can influence autocrine, paracrine and juxtacrine signalling. The schematic depicts the potential actions of ADAMs (scissors) on receptor–ligand pairs, acting to release ligand that acts upon receptors on the cell of origin (autocrine), or on distant cells (paracrine). Juxtacrine signalling involving adjacent cells may involve ADAMs for correct presentation of the ligand, or for cleavage of the ligand following receptor engagement, or for receptor activation. Shed receptors may act as decoys, or cleavage of the receptor may itself activate or modulate signalling.
Fig. 8
Fig. 8
Triple membrane passing signal: involvement of ADAMs in the crosstalk between GPCR and EGFR signalling. The model proposed is based on studies reported in Zhang et al. (2006).
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