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ADAMs: key components in EGFR signalling and development

Nature Reviews Molecular Cell Biology volume 6, pages 32–43 (2005)Cite this article

Key Points

  • ADAMs are a family of membrane-anchored glycoproteins that contain a metalloprotease and a disintegrin domain. They have been implicated in fertilization, heart development, angiogenesis, neurogenesis and cancer, and can function as post-translational regulators of other membrane proteins including growth factors such as transforming growth factor (TGF)α and heparin-bound epidermal growth factor (HB-EGF), cytokines such as tumour necrosis factor α (TNFα), and receptors such as Notch and TNF receptor-I.

  • About half of the currently known ADAMs have a catalytic-site consensus sequence (HEXXH), and many of these ADAMs have also been shown to possess catalytic activity. The remaining ADAMs lack a catalytic site in their otherwise conserved metalloprotease-like domain.

  • This review focuses on catalytically active ADAMs, which can function as molecular signalling switches by cleaving and releasing the ectodomain of other membrane proteins. This process, which is referred to as 'protein ectodomain shedding', might activate or inactivate the substrate protein, or dramatically change its functional properties.

  • The EGF-receptor ligands TGFα, HB-EGF and amphiregulin are excellent examples of membrane proteins that are regulated by ectodomain shedding. Biochemical and cell-biological studies, as well as the analysis of knockout mice, have uncovered a key role for ADAM17 (which is also referred to as TNFα-converting enzyme (TACE)) in activating these growth factors during mouse development and potentially also in diseases such as cancer.

  • The EGF receptor has an unusual mechanism of dimerizing compared with other tyrosine kinase receptors, which might explain why signalling through this receptor is particularly sensitive to proteolytic processing of its ligands.

  • ADAMs also have important roles in heart development, angiogenesis and pathological neovascularization. This raises questions about the role of shedding in regulating the function of membrane proteins that are involved in these processes, such as ErbB2, vascular endothelial growth factor receptor-2 (VEGFR2), TIE2, ephrinB2 or EphB2.

Abstract

ADAM (a disintegrin and metalloprotease) proteins are membrane-anchored metalloproteases that process and shed the ectodomains of membrane-anchored growth factors, cytokines and receptors. ADAMs also have essential roles in fertilization, angiogenesis, neurogenesis, heart development and cancer. Research on ADAMs and their role in protein ectodomain shedding is emerging as a fertile ground for gathering new insights into the functional regulation of membrane proteins.

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Figure 1: ADAM domain structure.
Figure 2: Protein ectodomain shedding.
Figure 3: EGFR dimerization and shedding.
Figure 4: Juxtacrine signalling through TNFα.
Figure 5: Is shedding essential for signalling through all EGFR ligands?

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Acknowledgements

I wish to thank G. Weskamp, T. Ludwig, D. Lee and my cousin G. A. Blobel for their suggestions and comments during the preparation of this manuscript.

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Authors and Affiliations

  1. Arthritis and Tissue Degeneration Program and Cell Biology Program, Hospital for Special Surgery, Weill Medical College of Cornell University, 535 East 70th Street, New York, 10021, New York, USA

    Carl P. Blobel

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DATABASES

Entrez

Adam17

Adam19

Swiss-Prot

ADAM10

ADAM15

ADAM17

ADAM19

ADAM23

amphiregulin

CD9

EGFR

HB-EGF

PACSIN2

PACSIN3

TGFα

TNFR1

FURTHER INFORMATION

Carl Blobel's laboratory

White Laboratory

Glossary

METALLOPROTEASE

A peptidase that depends on a coordinated metal ion (Zn2+) for its catalytic mechanism.

ANGIOGENESIS

The process of forming new blood vessels by sprouting from pre-existing ones.

EGF-LIKE DOMAIN

A motif with ∼50 amino acids, including six cysteine residues and a mainly β-sheet structure, found in all ErbB-binding growth factors and in extracellular matrix proteins.

PRO-PROTEIN CONVERTASE

Member of the family of Ca2+-dependent, subtilisin-like serine endoproteases that are structurally related to KEX2 and furin and that cleave pro-protein substrates at the C-terminal side of doublets or clusters of basic amino acids.

TRANS-GOLGI NETWORK

Membranous compartment from which vesicles bud to deliver proteins and other materials to the cell surface or to the late endosomes for delivery to lysosomes.

SRC-HOMOLOGY-3 (SH3) DOMAIN

A protein–protein interaction domain that recognizes a unique proline-rich peptide motif. This domain is found in many proteins that are involved in signal transduction and membrane–cytoskeleton interactions.

NEOVASCULARIZATION

De novo stimulation of new blood supplies to a growing tumour.

G-PROTEIN-COUPLED RECEPTOR

A seven-helix membrane-spanning cell-surface receptor that signals through heterotrimeric GTP-binding and -hydrolysing G-proteins to stimulate or inhibit the activity of a downstream enzyme.

ENDOCARDIAL CUSHION

Discrete cushion-like swelling that forms in the developing heart and that gives rise to mature heart valves and to the membranous part of the ventricular septum. The ventricular septum is a wall that separates the left and right ventricles of the heart.

GRAM-POSITIVE BACTERIA

The cell walls of these bacteria retain a basic blue dye during the Gram-stain procedure. These cell walls are relatively thick (15–80 nm) and consist of a network of peptidoglycans.

TETRASPANIN FAMILY

The tetraspanin family contains proteins that span the membrane four times with two exoplasmic loops, and that can be found at the cell surface. Whereas some are highly restricted to specific tissues, others are widely distributed. Members of this family have been implicated in cell activation and proliferation, adhesion, motility, differentiation and cancer.

PHORBOL ESTER

A polycyclic ester that is isolated from croton oil. The most common are phorbol-12-myristate-13-acetate (PMA) and 12-O-tetradecanoyl-phorbol-13-acetate (TPA). These are potent carcinogens or tumour promoters because they mimic diacylglycerol, and thereby irreversibly activate protein kinase C.

YEAST TWO-HYBRID SCREEN

A technique used to test if two proteins physically interact with each other. One protein is fused to the GAL4 activation domain and the other to the GAL4 DNA-binding domain, and both fusion proteins are introduced into yeast. Expression of a GAL4-regulated reporter gene indicates that the two proteins physically interact.

ORTHOLOGUES

Functionally related genes with extensive sequence similarity, which indicates a common ancestor. The term orthologues is often used to indicate the most closely related members of larger gene families in different species.

RETINOPATHY

A non-inflammatory degenerative disease of the retina, commonly found as a complication of diabetes.

RNA INTERFERENCE

A form of post-transcriptional gene silencing in which expression or transfection of double-stranded RNA induces degradation, by nucleases, of the homologous endogenous transcripts, mimicking the effect of the reduction, or loss, of gene activity.

COS CELLS

Cells from the monkey CV1 cell line that have an integrated SV40 genome that lacks an origin of replication. Plasmids with an SV40 origin of replication are replicated to a high copy number when transfected.

ISOTOPE-CODED-AFFINITY-TAG MASS SPECTROMETRY

A method to identify candidate protease substrates by comparing the relative levels of proteins in two samples, such as a supernatant of cells that overexpress a protease and a supernatant of control cells. It relies on marking proteins in each sample with chemically identical affinity tags (such as biotin) of different isotopic composition and mass.

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Blobel, C. ADAMs: key components in EGFR signalling and development. Nat Rev Mol Cell Biol 6, 32–43 (2005). https://doi.org/10.1038/nrm1548

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  • DOI: https://doi.org/10.1038/nrm1548

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