Trends in Biochemical Sciences
Shedding light on ADAM metalloproteinases
Section snippets
ADAM metalloproteinases comprise the major sheddase family
Cellular membrane proteins can be proteolytically cleaved at their juxta-membrane region in a process called ectodomain shedding, which results in detachment of their extracellular region (the ectodomain). Shedding can release cytokines, growth factors or other mediators from their membrane-bound precursors or, conversely, down-regulate receptors and other proteins from the cell surface. Members of the ADAM (a metalloprotease and disintegrin) family have been identified as proteinases that
ADAM-17, the prototype sheddase
ADAM-17 was the first ADAM implicated in ectodomain shedding by its identification as the tumour necrosis factor-α (TNFα) convertase 5, 7. Since then, ADAM-17 has been established as an essential sheddase in mammalian development 8, 9, 10, 11. However, in addition to this role in development, the number and variety of other substrates (e.g. TNF receptors and other cytokines and cytokine receptors; Table 1) indicate a wider role for ADAM-17 in adults [5].
The major contribution of ADAM-17 to the
From MADM to ADAM-10
A membrane proteinase, originally isolated as a myelin basic protein-degrading enzyme from bovine brain, was subsequently identified as an ADAM and termed MADM (mammalian disintegrin metalloproteinase). It was later shown to be identical with ADAM-10 and, its orthologue, Kuzbanian, was implicated in early neural development in Drosophila by its proteolytic activation of Notch signalling [17]. The severe phenotype of adam10−/− embryos (see later; Table 2) suggests that ADAM-10 is also involved
Lessons from gene knockout experiments
Mice lacking functional ADAM-8, ADAM-9, ADAM-12 or ADAM-15 largely develop normally, although some adam12−/− mice show minor defects during development 24, 25, 26, 27. As indication of these ADAMs in diverse shedding events in cell-based assays (Table 1), corroborated by their wide expression in mammalian tissues, suggests that they function as physiological sheddases, Sahin et al. [13] generated adam9−/−, adam12−/− and adam15−/− mice, all of which also showed apparently normal phenotype.
Substrate selectivity and potential mechanisms for regulation of ADAM sheddases
To understand how individual sheddase ADAMs might cleave different substrates and several substrates can be cleaved by different ADAMs, it is important to understand how ADAMs recognize their substrates and how their sheddase activity might be regulated.
Intrinsic substrate selectivity at the active site of some ADAMs is indicated by the preference for residues flanking the scissile bond in a subset of substrates 3, 5, 31. By contrast, the variability of the cleavage-site sequences and their
MAP kinase pathways signal the activation of ADAM-mediated shedding
Accumulating studies have informed the view that mitogen-activated protein kinases (MAPKs) Erk and p38 mediate most, albeit not all, of the shedding-activation signals triggered by growth factors, stress and commonly used non-physiological drugs 46, 47, 48, 49. An emerging theme is that regulated shedding is often activated via the Mek/Erk pathway, whereas the constitutive basal shedding seems to be dependent on signals via p38 3, 5 (Figure 2). For example, both the muscarine-stimulated and the
ADAM sheddases in the processing of APP and Notch
ADAMs have been implicated in several processes during central nervous system (CNS) development, and their wide expression also indicates diverse roles in the adult CNS [50]. Recent studies provide strong evidence for ADAMs in the physiological processing of APP and Notch 3, 17.
β-Amyloid plaques are a hallmark diagnostic of Alzheimer's disease (AD). APP is normally processed by the α-secretase pathway, which does not lead to deposition of the β-amyloid fragments that are generated by the
Emerging roles of ADAM-mediated ectodomain shedding in human disease
GPCR-induced transactivation of EGFR signalling (Figure 3b) has emerged as an important mechanism that regulates normal cellular responses, but it has also been implicated in pathologies such as cancers 2, 7, 15, 54. As discussed, ADAMs are key regulators of EGFR signalling via shedding of EGFR ligands. ADAM-10, ADAM-15 and ADAM-17 were recently shown to contribute to tumourigenesis, migration and invasion by GPCR–EGFR transactivation in different tumours and cell lines 7, 15, 54.
ADAM-mediated
Identification of novel ADAM metalloproteinase substrates
Because all the ADAMs with an intact active-site sequence that have been studied so far show metalloproteinase activity 1, 2, it is plausible that physiological substrates also exist for those ADAMs not yet investigated. Furthermore, there are several shed membrane proteins, such as angiotensin-converting enzyme, without identified sheddase(s) [52].
Identification of the particular ADAM that cleaves a specific protein substrate in vivo or in vitro has proved problematic. Although the ability of
Concluding remarks
Although gene knockout experiments have shown that particular ADAMs are indispensable during mammalian development, functional redundancy among at least a subset of ADAMs is increasingly evident. Besides, alternative splicing is emerging as a mechanism by which functional complexity can be increased. This undoubtedly complicates both identification of the shedding-machinery components and the development of specific inhibitors against particular shedding events. Nevertheless, recent advances
Note added in proof
The recent study by Böhm et al. [83] shows that the development of osteoarthritic lesions is accelerated in aging adam15−/− mice.
Acknowledgements
We apologize to colleagues whose original work could not be cited owing to space limitations. This work was supported by the INTAS grant 2001–245 (A.J.T. and A-P.J.H.) and grants from the Medical Research Council of Great Britain (A.J.T.), the Wellcome Trust (A.J.T.), British Heart Foundation (A.J.T.), and the Medical Research Fund of Tampere University Hospital (A-P.J.H. and M.P.).
References (83)
ADAMs: modulators of cell–cell and cell–matrix interactions
Curr. Opin. Cell Biol.
(2003)- et al.
Biochemical properties and functions of membrane-anchored metalloprotease-disintegrin proteins (ADAMs)
Curr. Top. Dev. Biol.
(2003) Pulmonary hypoplasia in mice lacking tumor necrosis factor-α converting enzyme indicates an indispensable role for cell surface protein shedding during embryonic lung branching morphogenesis
Dev. Biol.
(2001)TACE is required for fetal murine cardiac development and modeling
Dev. Biol.
(2003)Selective roles for tumor necrosis factor α-converting enzyme/ADAM17 in the shedding of the epidermal growth factor receptor ligand family: the juxtamembrane stalk determines cleavage efficiency
J. Biol. Chem.
(2004)Distinct ADAM metalloproteinases regulate G protein-coupled receptor-induced cell proliferation and survival
J. Biol. Chem.
(2004)The function of leak and kuzbanian during growth cone and cell migration
Mech. Dev.
(2001)- et al.
Alzheimer's and prion diseases: distinct pathologies, common proteolytic denominators
Trends Neurosci.
(2002) Dual mechanisms for shedding of the cellular prion protein
J. Biol. Chem.
(2004)Essential roles of Meltrin β (ADAM19) in heart development
Dev. Biol.
(2004)
Catalytic activity of human ADAM33
J. Biol. Chem.
Evaluation of the contribution of different ADAMs to tumor necrosis factor α (TNFα) shedding and of the function of the TNFα ectodomain in ensuring selective stimulated shedding by the TNFα convertase (TACE/ADAM17)
J. Biol. Chem.
The enzymatic activity of ADAM8 and ADAM9 is not regulated by TIMPs
FEBS Lett.
Structure and expression of the murine ADAM 15 gene and its splice variants, and difference of interaction between their cytoplasmic domains and Src family proteins
Biochem. Biophys. Res. Commun.
Cellular cholesterol depletion triggers shedding of the human interleukin-6 receptor by ADAM10 and ADAM17 (TACE)
J. Biol. Chem.
Regulation of membrane metalloproteolytic cleavage of L-selectin (CD62l) by the epidermal growth factor domain
J. Biol. Chem.
Characterization of growth factor-induced serine phosphorylation of tumor necrosis factor-α converting enzyme and of an alternatively translated polypeptide
J. Biol. Chem.
Evidence for a critical role of the tumor necrosis factor α convertase (TACE) in ectodomain shedding of the p75 neurotrophin receptor (p75NTR)
J. Biol. Chem.
Muscarine enhances soluble amyloid precursor protein secretion in human neuroblastoma SH-SY5Y by a pathway dependent on protein kinase Cα, src-tyrosine kinase and extracellular signal-regulated kinase but not phospholipase C
Brain Res. Mol. Brain Res.
Metalloprotease-disintegrin (ADAM) genes are widely and differentially expressed in the adult CNS
Mol. Cell. Neurosci.
Putative function of ADAM9, ADAM10, and ADAM17 as APP α-secretase
Biochem. Biophys. Res. Commun.
The disintegrin-like metalloproteinase ADAM10 is involved in constitutive cleavage of CX3CL1 (fractalkine) and regulates CX3CL1-mediated cell–cell adhesion
Blood
Tumor necrosis factor-α-converting enzyme (ADAM17) mediates the cleavage and shedding of fractalkine (CX3CL1)
J. Biol. Chem.
Differential shedding of transmembrane neuregulin isoforms by the tumor necrosis factor-α-converting enzyme
Mol. Cell. Neurosci.
Catalytic activity of ADAM8, ADAM15, and MDC-L (ADAM28) on synthetic peptide substrates and in ectodomain cleavage of CD23
J. Biol. Chem.
Membrane-anchored CD40 is processed by the tumor necrosis factor-α-converting enzyme. Implications for CD40 signaling
J. Biol. Chem.
Tumor necrosis factor-α-converting enzyme controls surface expression of c-Kit and survival of embryonic stem cell-derived mast cells
J. Biol. Chem.
Tumor necrosis factor-α-converting enzyme is required for cleavage of erbB4/HER4
J. Biol. Chem.
Natural soluble IL-15Rα is generated by cleavage that involves the tumor necrosis factor-α-converting enzyme (TACE/ADAM17)
J. Biol. Chem.
Engagement of CD44 promotes Rac activation and CD44 cleavage during tumor cell migration
J. Biol. Chem.
Ectodomain shedding of the neural recognition molecule CHL1 by the metalloprotease-disintegrin ADAM8 promotes neurite outgrowth and suppresses neuronal cell death
J. Biol. Chem.
Structure–function relationship and role of tumor necrosis factor-α-converting enzyme in the down-regulation of L-selectin by non-steroidal anti-inflammatory drugs
J. Biol. Chem.
Stimulated shedding of vascular cell adhesion molecule 1 (VCAM-1) is mediated by tumor necrosis factor-α-converting enzyme (ADAM 17)
J. Biol. Chem.
Characterization of the ectodomain shedding of the β-site amyloid precursor protein-cleaving enzyme 1 (BACE1)
J. Biol. Chem.
Phorbol 12-myristate 13-acetate-induced ectodomain shedding and phosphorylation of the human meprinbeta metalloprotease
J. Biol. Chem.
ADAMs, a disintegrin and metalloproteinases, mediate shedding of oxytocinase
Biochem. Biophys. Res. Commun.
Notch-induced proteolysis and nuclear localization of the Delta ligand
J. Biol. Chem.
The Notch ligands, Jagged and Delta, are sequentially processed by α-secretase and presenilin/γ-secretase and release signaling fragments
J. Biol. Chem.
Tumor necrosis factor-α converting enzyme/ADAM 17 mediates MUC1 shedding
J. Biol. Chem.
ADAMs: key components in EGFR signalling and development
Nat. Rev. Mol. Cell Biol.
The ADAMs family of metalloproteases: multidomain proteins with multiple functions
Genes Dev.
Cited by (390)
Posttranslational modifications of platelet adhesion receptors
2022, Pharmacological ResearchEctodomain shedding by ADAM proteases as a central regulator in kidney physiology and disease
2022, Biochimica et Biophysica Acta - Molecular Cell ResearchThe water extracts of Euonymus alatus (Thunb.) Siebold attenuate diabetic retinopathy by mediating angiogenesis
2022, Journal of Ethnopharmacology