Shedding light on ADAM metalloproteinases

doi:10.1016/j.tibs.2005.05.006

Trends in Biochemical Sciences

Volume 30, Issue 7, July 2005, Pages 413-422

https://doi.org/10.1016/j.tibs.2005.05.006 Get rights and content

ADAM metalloproteinase disintegrins have emerged as the major proteinase family that mediates ectodomain shedding, the proteolytic release of extracellular domains from their membrane-bound precursors. Recent gene-manipulation studies have established the role of ADAM-mediated shedding in mammalian physiology and, in addition, raised the issue of functional redundancy among ADAM sheddases. ADAM sheddases activate, for example, growth factors and cytokines, thus regulating signalling pathways that are important in development and pathological processes such as cancer. The recent studies have also begun to elucidate the substrate specificity and the mechanisms that control ADAM-mediated shedding events that regulate, for example, growth-factor and Notch signalling, and the processing of the amyloid precursor protein.

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.).

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Significant differences (p = 0.004) in the frequencies of the ADAM33 mutant allele carriers between patients and controls were found OR = 1.62 (95% CI 1.16–2.27). This association was significant in individuals who carried homozygous (GG) or heterozygous (AG) variant type genotypes in a reference with carriers of wild-type (AA) genotypes. The odds ratios were 1.70 (95% CI 1.11–2.60, p = 0.013), 2.97 (95% CI 1.00–8.75, p = 0.047), 1.79 (95% CI 1.18–2.71 p = 0.005) for those who carried (wt/vt), (vt/vt), and (wt/vt + vt/vt), respectively. Correlation based on gender shows the presence of a significant association (p = 0.01a) for female mutant allele carriers OR = 1.96 (95% CI 1.15–3.36), but not in the case of male. Significant difference (p = 0.02) in the frequencies of mutant G allele carrier compared to wild A allele carrier was also found correlated in patients with severe asthma than moderate or mild asthma, OR = 1.78 (95% CI 1.10–2.89). Serum total IgE level in patients with GG genotype (219.37 ± 108.49) was significantly higher than in patients with AG and AA genotypes, respectively (193.22 ± 85.83), (157.11 ± 92.10), (P = 0.001).
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Although liver is rich in peroxisome proliferator-activated receptor α (PPARα), recently we have described the presence of PPARα in hippocampus where it is involved in non-amyloidogenic metabolism of amyloid precursor protein (APP) via ADAM10, decreasing amyloid plaques and improving memory and learning. However, mechanisms to upregulate PPARα in vivo in the hippocampus are poorly understood. Regular exercise has multiple beneficial effects on human health and here, we describe the importance of regular mild treadmill exercise in upregulating PPARα in vivo in the hippocampus of 5XFAD mouse model of Alzheimer’s disease. We also demonstrate that treadmill exercise remained unable to stimulate ADAM10, reduce plaque pathology and improve cognitive functions in 5XFAD^ΔPPARα mice (5XFAD mice lacking PPARα). On the other hand, treadmill workout increased ADAM10, decreased plaque pathology and protected memory and learning in 5XFAD^ΔPPARβ mice (5XFAD mice lacking PPARβ). Moreover, the other PPAR (PPARγ) also did not play any role in the transcription of ADAM10 in vivo in the hippocampus of treadmill exercised 5XFAD mice. These results underline an important role of PPARα in which treadmill exercise remains unable to exhibit neuroprotection in the hippocampus in the absence of PPARα.
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Trends in Biochemical Sciences

Shedding light on ADAM metalloproteinases

Section snippets

ADAM metalloproteinases comprise the major sheddase family

ADAM-17, the prototype sheddase

From MADM to ADAM-10

Lessons from gene knockout experiments

Substrate selectivity and potential mechanisms for regulation of ADAM sheddases

MAP kinase pathways signal the activation of ADAM-mediated shedding

ADAM sheddases in the processing of APP and Notch

Emerging roles of ADAM-mediated ectodomain shedding in human disease

Identification of novel ADAM metalloproteinase substrates

Concluding remarks

Note added in proof

Acknowledgements

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