The ADAM metalloproteinases

By D. Edwards, M. Handsley, C. Pennington. 2008

1,171 citations recorded by the source corpus.

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-α convertase, TACE), which is the principal protease involved in the activation of pro-TNF-α, 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.

Subfields: Immunology and Allergy, Molecular Biology, Oncology

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology and Allergy

1. S. Takeda
2. Zena Werb

In Molecular Biology

1. S. Takeda
2. D. Edwards
3. V. Plaks
4. Hideaki Nagase
5. K. Brew
6. Zena Werb
7. K. Kessenbrock
8. Gillian Murphy

In Oncology

1. Zena Werb
2. V. Plaks
3. D. Edwards
4. Hideaki Nagase
5. K. Kessenbrock
6. Pengfei Lu
7. M. Egeblad
8. Gillian Murphy

Citations in the corpus

• ADAM and ADAMTS Family Proteins and Snake Venom Metalloproteinases: A Structural Overview (2016, background): “An increasing number of transmembrane proteins have been identified as the targets of ADAM-mediated proteolysis [1].”
• An Overview of APP Processing Enzymes and Products (2010, neutral): “APP is only one of many substrates for ADAM family proteins; others include N-cadherin (Kohutek et al., 2009), EGFR ligands, TNF-α, TGF-α, notch and ephrin (Edwards et al., 2008; Le Gall et al., 2009).”
• Matrix Metalloproteinases: Regulators of the Tumor Microenvironment (2010, background): “ADAMs fulfill a broad spectrum of functions with roles in fertilization, development, and cancer (Edwards et al., 2008).”
• Extracellular matrix structure. (2016, background): “They include two subgroups the membrane-bound ADAMs and the secreted ADAMTSs that are characterized by cell de-adhesion/adhesion and fusion motifs.”
• Proteolytically active ADAM10 and ADAM17 carried on membrane microvesicles in human abdominal aortic aneurysms (2015, background): “ADAM10 has also been shown to function as a gelatinase (15) and to target several matrix proteins, such as cadherins and collagen type XVII (16).”
• ADAM and ADAMTS gene expression in native and wound healing human lens epithelial cells (2010, background): “The ADAMs (a disintegrin and metalloproteinase) and the ADAMTSs (a disintegrin and metalloproteinase with thrombospondin-like motifs) are members of the M12 adamalysin family of the metzincin metalloproteinases, related to the matrix metalloproteinases (MMPs) [1,2].”
• A Disintegrin and Metalloprotease (ADAM): Historical Overview of Their Functions (2016, background): “The disintegri and the cyst ine-rich domains can also medi te cellul r interactions via binding not ly to integrins, but also t hepara ulfate pr te glycans, such as synd cans [20].”
• The tissue inhibitors of metalloproteinases (TIMPs): An ancient family with structural and functional diversity (2010, background): “ADAM metalloproteinases differ from the MMPs in domain structures and are highly divergent in catalytic domain sequences: ADAMs are membrane-bound enzymes containing disintegrin, cysteine-rich, EGF-like and transmembrane domains C-terminal to their catalytic domains [3]; and ADAMTS (disintegrinmetal”