ReviewThe “A Disintegrin And Metalloprotease” (ADAM) family of sheddases: Physiological and cellular functions
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”.
References (184)
- et al.
Breaking up the tie: disintegrin-like metalloproteinases as regulators of cell migration in inflammation and invasion
Pharmacol Ther
(2006) - et al.
Shedding light on ADAM metalloproteinases
Trends Biochem Sci
(2005) - et al.
ADAM, a widely distributed and developmentally regulated gene family encoding membrane proteins with a disintegrin and metalloprotease domain
Dev Biol
(1995) - et al.
Astacins, serralysins, snake venom and matrix metalloproteinases exhibit identical zinc-binding environments (HEXXHXXGXXH and Met-turn) and topologies and should be grouped into a common family, the ‘metzincins’
FEBS Lett
(1993) - et al.
Kuzbanian controls proteolytic processing of Notch and mediates lateral inhibition during Drosophila and vertebrate neurogenesis
Cell
(1997) - et al.
The ADAM10 prodomain is a specific inhibitor of ADAM10 proteolytic activity and inhibits cellular shedding events
J Biol Chem
(2007) - et al.
Inhibition of the tumor necrosis factor-alpha-converting enzyme by its pro domain
J Biol Chem
(2004) - et al.
Crystal structure of the catalytic domain of human ADAM33
J Mol Biol
(2004) ADAMs: modulators of cell-cell and cell-matrix interactions
Curr Opin Cell Biol
(2003)- et al.
Functional analysis of the domain structure of tumor necrosis factor-alpha converting enzyme
J Biol Chem
(2000)
Adam meets Eph: an ADAM substrate recognition module acts as a molecular switch for ephrin cleavage in trans
Cell
Specific sequence elements are required for the expression of functional tumor necrosis factor-alpha-converting enzyme (TACE)
J Biol Chem
Disintegrin-like/cysteine-rich region of ADAM 12 is an active cell adhesion domain
Exp Cell Res
Interaction of the metalloprotease disintegrins MDC9 and MDC15 with two SH3 domain-containing proteins, endophilin I and SH3PX1
J Biol Chem
ADAM binding protein Eve-1 is required for ectodomain shedding of epidermal growth factor receptor ligands
J Biol Chem
Regulation of ADAM12 cell-surface expression by protein kinase C epsilon
J Biol Chem
PACSIN3 binds ADAM12/meltrin alpha and up-regulates ectodomain shedding of heparin-binding epidermal growth factor-like growth factor
J Biol Chem
A basolateral sorting signal directs ADAM10 to adherens junctions and is required for its function in cell migration
J Biol Chem
Analysis of loss of adhesive function in sperm lacking cyritestin or fertilin beta
Dev Biol
Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans
Cell
Regulated ADAM10-dependent ectodomain shedding of {gamma}-protocadherin C3 modulates cell-cell adhesion
J Biol Chem
A CBP binding transcriptional repressor produced by the PS1/epsilon-cleavage of N-cadherin is inhibited by PS1 FAD mutations
Cell
ADAM10-mediated E-cadherin release is regulated by proinflammatory cytokines and modulates keratinocyte cohesion in eczematous dermatitis
J Invest Dermatol
Mammalian cadherins and protocadherins: about cell death, synapses and processing
Curr Opin Cell Biol
Presenilin-dependent processing and nuclear function of gamma-protocadherins
J Biol Chem
Stimulated shedding of vascular cell adhesion molecule 1 (VCAM-1) is mediated by tumor necrosis factor-alpha-converting enzyme (ADAM 17)
J Biol Chem
Tumor necrosis factor-alpha-converting enzyme (TACE/ADAM-17) mediates the ectodomain cleavage of intercellular adhesion molecule-1 (ICAM-1)
J Biol Chem
Sequential processing of the transmembrane chemokines CX3CL1 and CXCL16 by alpha- and gamma-secretases
Biochem Biophys Res Commun
Structure-function relationship and role of tumor necrosis factor-alpha-converting enzyme in the down-regulation of L-selectin by non-steroidal anti-inflammatory drugs
J Biol Chem
The status and role of ErbB receptors in human cancer
Exp Mol Pathol
Ectodomain shedding of the EGF-receptor ligand epigen is mediated by ADAM17
FEBS Lett
A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE
Mol Cell
A ligand-induced extracellular cleavage regulates gamma-secretase-like proteolytic activation of Notch1
Mol Cell
The Notch ligands, Delta1 and Jagged2, are substrates for presenilin-dependent “gamma-secretase” cleavage
J Biol Chem
Proteolytic processing of delta-like 1 by ADAM proteases
J Biol Chem
The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner
J Biol Chem
A dominant role for FE65 (APBB1) in nuclear signaling
J Biol Chem
Dissection of amyloid-beta precursor protein-dependent transcriptional transactivation
J Biol Chem
Metalloprotease-disintegrin (ADAM) genes are widely and differentially expressed in the adult CNS
Mol Cell Neurosci
Ectodomain shedding of the neural recognition molecule CHL1 by the metalloprotease-disintegrin ADAM8 promotes neurite outgrowth and suppresses neuronal cell death
J Biol Chem
Evaluation of the contributions of ADAMs 9, 12, 15, 17, and 19 to heart development and ectodomain shedding of neuregulins beta1 and beta2
Dev Biol
The ADAMs family of metalloproteases: multidomain proteins with multiple functions
Genes Dev
ADAMs: key components in EGFR signalling and development
Nat Rev Mol Cell Biol
(Make) stick and cut loose—disintegrin metalloproteases in development and disease
Birth Defects Res C Embryo Today
Part-time alpha-secretases: the functional biology of ADAM 9, 10 and 17
Curr Alzheimer Res
A genomic analysis of rat proteases and protease inhibitors
Genome Res
UNC-71, a disintegrin and metalloprotease (ADAM) protein, regulates motor axon guidance and sex myoblast migration in C. elegans
Development
ADAM family protein Mde10 is essential for development of spore envelopes in the fission yeast Schizosaccharomyces pombe
Eukaryot Cell
Tumor necrosis factor-alpha converting enzyme is processed by proprotein-convertases to its mature form which is degraded upon phorbol ester stimulation
Eur J Biochem
Regulation of the alpha-secretase ADAM10 by its prodomain and proprotein convertases
FASEB J
Cited by (342)
C-terminal amino acids in the type I transmembrane domain of L-type lectin VIP36 affect γ-secretase susceptibility
2024, Biochemical and Biophysical Research CommunicationsNewfound Coding Potential of Transcripts Unveils Missing Members of Human Protein Communities
2023, Genomics, Proteomics and BioinformaticsThe clinical utility of CD163 in viral diseases
2023, Clinica Chimica ActaMetzincin metalloproteases in PGC migration and gonadal sex conversion
2023, General and Comparative EndocrinologyQuantitative Proteomics Identifies Proteins Enriched in Large and Small Extracellular Vesicles
2022, Molecular and Cellular Proteomics