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  • Review Article
  • Published:

The ADAMs: signalling scissors in the tumour microenvironment

Nature Reviews Cancer volume 8, pages 932–941 (2008)Cite this article

Key Points

  • ADAMs (a disintegrin and metalloproteinase) are membrane-associated metalloproteinases with a complex multi-domain structure. About half of the family have proteolytic potential, as well as domains with adhesive properties and a cytoplasmic domain involved in cell signalling.

  • The upregulation of proteolytic ADAMs has been documented for a number of cancers, with some correlation to parameters of disease progression.

  • The 'shedding' activities of ADAMs — cleaving transmembrane proteins and solubilizing the complete ectodomain of cytokines, growth factors, receptors and adhesion molecules — places them in pivotal positions in the extracellular regulation of cellular signalling. They can potentially regulate many activities within the tumour microenvironment, including inflammatory responses, immune regulation, angiogenesis, and cell migration and proliferation.

  • ADAM proteolysis has been implicated in key signalling pathways identified in many tumour cells. The generation of soluble ligands for the family of Erbb receptors, including in response to the activation of G-protein-coupled receptors and leading to epidermal growth factor receptor transactivation, have been described. ADAM sheddase activity appears to modulate the process of regulated intramembrane proteolysis (RIPping) by γ-secretase: the intracellular portions of transmembrane proteins are released either into proteasomal degradation pathways or into the cytosol prior to nuclear trafficking where they function as transcription factors.

  • ADAM activity is regulated in part by cellular trafficking and changes in the interaction with the membrane-bound substrate. Numerous protein adaptors and modulators that alter either enzyme activity or substrate availability have been documented and these may build specificity into ADAM sheddase activities in vivo.

  • The data from cell and animal models of cancer indicate that ADAM proteolytic activities could drive aspects of tumorigenesis. Before their consideration as therapeutic targets it will be necessary to further define the correlation of their expression in relation to different aspects of tumour development, and the mechanism by which they do this. Furthermore, the design of specific inhibitors, possibly targeting extracatalytic sites or adaptor proteins, will be essential.

Abstract

Over the last few years disintegrin metalloproteinases of the Adam (a disintegrin and metalloproteinase) family have been associated with the process of proteolytic 'shedding' of membrane-associated proteins and hence the rapid modulation of key cell signalling pathways in the tumour microenvironment. Furthermore, numerous members of the Adam family have been associated with tumorigenesis and tumour progression. The question now arises of whether pharmacological manipulation of their functions would be a useful adjunct to therapies targeting intercellular communications. To learn from the lessons of matrix metalloproteinase inhibitors as anticancer agents, there are many facets of the biological and clinical relevance of the ADAMs that need to be understood before embarking with confidence on such an approach.

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Figure 1: Zinc metalloproteinases.
Figure 2: Schematic diagram of the domain structure of the Adam (a disintegrin and metalloproteinase) family.
Figure 3: Shedding and RIPping.
Figure 4: ADAMs (a disintegrin and metalloproteinase): cellular interactions.

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Acknowledgements

This Review is not intended to be comprehensive and discusses only some of the major representative studies of ADAMs. Apologies to the many laboratories whose work has not been cited. Work in the author's laboratory is supported by Cancer Research UK, the Medical Research Council, UK, the Biotechnology and Biological Sciences Research Council, UK, the British Heart Foundation and the European Union Framework Programme 6 (LSH-2002-2). Thanks to H. Nagase and W. English and the external reviewers for their thoughtful contributions to the writing of this Review.

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    Gillian Murphy

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Glossary

Ectodomain

The portion of the structure of a membrane-associated protein that is outside the plasma membrane.

Furin-like

Enzymes of the proprotein convertase family that largely reside in the endoplasmic reticulum and are involved in post-translational processing of hormones and other proteins. The substrate cleavage specificity is carboxy-terminal to either single or paired basic residues, with the Lys–Arg motif being the most common.

RIPping

Regulated intramembrane proteolysis of the membrane-embedded portion of transmembrane proteins by the membrane-embedded presenilin-containing γ-secretase complex. This activity is central to Alzheimer disease and certain cancers and is therefore an important therapeutic target.

Phorbol esters

Polycyclic esters that are isolated from croton oil. The most common is phorbol myristoyl acetate (PMA, also known as 12,13-tetradecanoyl phorbol acetate or TPA). They are potent co-carcinogens or tumour promoters because they mimic diacylglycerol, thereby irreversibly activating protein kinase C.

Lipid rafts

Detergent-resistant membrane microdomains that are involved in a wide array of cellular processes including membrane trafficking and intracellular signalling.

Tissue inhibitors of metalloproteinases

(TIMPs). TIMPs are protein inhibitors of the matrix metalloproteinases, and some disintegrin metalloproteinases have a key role in the regulation of their activity in cancer and other diseases.

RECK

Reversion-inducing-cysteine-rich protein with kazal motifs is a membrane-associated regulator of matrix metalloproteinases, and possibly some disintegrin metalloproteinases, and is downregulated when the cells undergo malignant transformation.

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Murphy, G. The ADAMs: signalling scissors in the tumour microenvironment. Nat Rev Cancer 8, 932–941 (2008). https://doi.org/10.1038/nrc2459

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