Regulation of the proteolytic disintegrin metalloproteinases, the ‘Sheddases’

Seminars in Cell & Developmental Biology 20 (2009) 138–145

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Review

Regulation of the proteolytic disintegrin metalloproteinases, the ‘Sheddases’ Gillian Murphy ∗ Dept of Oncology, University of Cambridge, UK

a r t i c l e

i n f o

Article history: Available online 18 September 2008 Keywords: ADAM Disintegrin metalloproteinase Sheddase Review

a b s t r a c t The proteolytically functional ADAMs, of which there are 13 in the human, play key roles in the way that many different types of cells respond to their environment. They act as ‘signalling scissors’ within various membrane environments, including at the cell surface, orchestrating rapid changes in the status of their transmembrane protein substrates. The elucidation of the mode of regulation of these ‘shedding’ activities is consequently of pivotal importance in the understanding their roles, but is still rather understudied, with large gaps in our knowledge. This review will consider the major regulatory mechanisms that are known which indicate where further research is needed. © 2008 Elsevier Ltd. All rights reserved.

Contents 1. 2. 3. 4. 5. 6. 7.

Gene regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Post-translational regulation and trafficking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Intracellular signalling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Protein modulators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The role of ADAM structure in regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ADAM inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Gene regulation Regulation of the genes coding for ADAMs has been documented in a small number of instances during development (Alfandari chapter, this issue). In pathological situations the overexpression of many ADAMs has been observed, both at the mRNA and protein level [1]. Cancer is a case in point where increased levels of ADAM8, 9, 10, 12, 15, 17, 19, and 28 have been reported [2,3]. ADAM8, 9 and 12 mRNAs are significantly elevated in the sputum of asthma patients relative to normal controls [4] and ADAM33 has specific SNPs associated with asthma susceptibility [5]. Many ADAM genes undergo alternative splicing to generate various transmembrane or soluble forms [1], but there is little information on the implications for their function. Soluble forms of the ADAMs are likely to be less efficient in membrane protein ‘sheddase’ activities, but

∗ Correspondence address: Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre Robinson Way, Cambridge CB2 0RE, UK. Tel.: +44 1223 404470; fax: +44 1223 404573. E-mail address: [email protected]. 1084-9521/$ – see front matter © 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.semcdb.2008.09.004

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could still have some undefined role in the extracellular environment. The splicing events often give rise to different cytoplasmic domain sequences, potentially modifying interactions with intracellular proteins. For example, human ADAM15 has a number of variants within its cytosolic tail which show differential associations with prognosis in breast cancer [6]. There are few ADAM gene promoter studies to date, but human ADAM10 has been shown to harbour Sp1, USF and retinoic acidresponsive elements [7]. Sequence analysis of the promoter of ADAM19 (MADDAM) revealed putative binding sites for several transcription factors including Sp1, Sp3, NF-kappaB, and VDR and a role for histone acetylation as a level of regulation in some cells [8]. Experimental studies have defined a number of effectors of ADAM gene expression, including cytokines. In mouse primary astrocytes and cerebellar neurons, and in mouse motor neuronlike NSC19 cells, ADAM8 expression was induced up to 15-fold by mouse TNF-alpha [9], IL-l␤ upregulated ADAM17 mRNA in neuroblastoma cells [10]. ADAM15 expression level was increased in human umbilical vein endothelial cells by treatment with vascular endothelial growth factor (VEGF)165 [11]. TGF␤ upreg-

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ulates several ADAM activities, but, as discussed later, this is not necessarily at the level of gene transcription. ADAM19 increases were shown in alveolar epithelial cells treated with TGF␤ [12] and ADAM12 was elevated in TGF␤ activated hepatic stellate cells [13]. 2. Post-translational regulation and trafficking Studies so far have indicated that ADAMs may be most significantly regulated at the post-translational level. This fits with the concept of their role as ‘rapid response’ features of cellular events, such as inflammatory responses, that allows efficient and timely adaptation to changes in circumstances. ADAMs are synthesised in the endoplasmic reticulum (ER) and mature in a late Golgi compartment. Protein folding and disulphide bonding depend on the presence of the N-terminal propeptide, which acts as a chaperone (Fig. 1) [14]. Extensive glycosylation occurs post-translationally and the glycoprotein specific oxidoreductase and chaperone ERp57, in conjunction with the ER proteins calnexin and calreticulin, may also be involved in folding, at least in the cases of ADAM10 and ADAM17 [15]. Due to interactions of the propeptide with the catalytic domain, the ADAMs are in an inactive form in the Golgi. The inhibitory properties of the ADAM17 propeptide differs from the cysteine switch mechanism of the MMP propeptide in that the cysteine is not necessary for propeptide function [16]. It is thought that ADAM maturation, i.e. activation by the cleavage of the propeptide, is effected by proprotein convertases (PCs), such as furin, where the cleavage recognition sequence RXR/KR is present. ADAM9, 10, 12 and 17 are activated by this route, whilst ADAM8 and ADAM28 may auto-activate. It is thought that ADAM28 may also be activated by MMP7. Although the ADAM processing is most likely to take place in the trans Golgi network, TGN [17], it is possible that activation can occur in compartments closer to the cell surface. Studies to date show that many ADAM proteins are stored in membranous structures around the nucleus, with small amounts at or near the cell surface [17], but some variation according to cell type and ADAM occurs. The pro domains of ADAM12, 17 and 33 can remain non-covalently attached to the metalloproteinase domain and may still act as an inhibitor which needs to be displaced prior to substrate cleavage [18]. Interestingly, the PCs themselves undergo regulated proteolysis which leaves the cleaved propeptide bound to the enzyme requiring activation by its dissociation, e.g. by heparan sulphate proteoglycans [19]. Potential ADAM substrates have been localised to various subcellular compartments so it his hard to identify a definitive site of ectodomain shedding. It is clear, however, that the trafficking and compartmentalization of substrates and other components of the shedding machinery may provide spatial and temporal control of ADAM functions. It seems logical that relevant shedding of adhesion receptors such as CD44, the cadherins and L-selectin will occur at the cell surface where they are engaged

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in interactions with the cell environment [20]. ADAM17 was found to undergo redistribution to the trailing edge of neutrophils rolling on purified E-selectin when activated by a chemoattractant under shear flow. ADAM17 and L-selectin also redistributed in the same manner in neutrophils attached to endothelium under shear flow [21]. Location at specific membrane sites such as lipid rafts may also be important. It has been shown that mature, activated ADAM17 is enriched in lipid rafts in a number of cell lines and tissues, compared to proADAM17 [22]. Mature ADAM17 co-localises with caveolin-1, flotillin-1 and actin. Active ADAM17 has been demonstrated at the surface of cells by labelling studies [17]. Cholesterol depletion of cell membranes leads to enhanced TNF␣ shedding, an observation corroborated for many other ADAM substrates, including the TNF receptors I and II (TNFRI, II) [22], the IL-6 receptor, CD3, collagen XVII and amyloid precursor protein, APP. It has been suggested that PMA stimulates shedding of TNF␣ by ADAM17 by increasing the amount of TNF␣ in rafts [22]. In a study of the receptor ErbB4 shedding in breast cancer cells it was found that active ADAM17, which is the principal sheddase, was present in all membrane fractions. This localisation was not modified by the effect of the ligand heregulin binding to ErbB4 which caused its translocation to a flotillin-1 lipid raft fraction [23]. The processing enzyme furin is also located in lipid rafts within the medial Golgi. In comparison, the route for biosynthetic trafficking of the ADAM17 substrate, membrane bound proTNF␣ has been described as involving tubulo-vesicular structures of the Golgi, from where it is loaded into recycling endosomes [24]. Delivery of TNF␣ to the cell surface for secretion is modulated by the availability of the SNARE complexes that facilitate vesicle fusion. Evidence for intracellular activity of ADAM10/17 in APP ‘␣secretase’ processing has also been presented using an APP mutant construct targeted specifically to the TGN [25]. However, more recently, inhibition of endocytosis by overexpression of the mutant dynamin (dyn I K44A) was found to result in increased shedding of the APP ectodomain by ADAM17. Levels of mature APP on the cell surface were increased in cells expressing dyn I K44A, and internalization of surface-immunolabeled APP was inhibited. Dynamin is a substrate for protein kinase C (PKC), and it was hypothesized that activators of PKC, which are known to stimulate ADAM17mediated cleavage of APP, might exert their effects by inhibiting dynamin-dependent endocytosis. However, the internalization of surface-biotinylated APP was unaffected by treatment of cells with PMA in the presence of the alpha-secretase inhibitor TAPI-1 [26]. It has been proposed that ADAM19 may function exclusively within the cell [27]. Both ADAM19 and its neuregulin substrate need to be in lipid rafts for shedding to occur [28]. Surprisingly, intracellular proteolysis of mature Kitl1 by ADAM19 decreases PMA-stimulated Kitl1 ectodomain shedding by ADAM17 cleavage [29]. Since ADAM19 can release other substrates into the

Fig. 1. Regulatory roles of ADAM domains. There are data from a number of studies that suggest that the proteolytsic functions of the ADAMs are modulated by interactions between their domains, as well as with other extracellular and intracellular proteins. PRO, propeptide; CAT, catalyic domain; DIS/CYS, disintegrin and cysteine rich domains; TM, transmembrane region; CYTO, cytoplasmic (intracellular) domain.

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supernatant when it is overexpressed, including TNF and TNFrelated activation-induced cytokine (TRANCE, OPGL) [30,31], it was suggested that overexpressed ADAM19 processes Kitl1 in a different subcellular location within the secretory pathway compared with other ADAM19 substrates [29]. ADAM10 substrates have been found at adherens junctions of polarized epithelial cells and are apparently involved in cell–cell interaction and cell migration. Intracellular trafficking of ADAM10 critically required a Src homology 3, SH3-binding domain within its cytoplasmic domain. Targetting of ADAM10 to adherens junctions is required for ADAM10 function in E-cadherin processing and cell migration [32].

3. Intracellular signalling Although cellular trafficking of the ADAMs and their substrates can be identified as key mechanisms for the control of shedding activities, the way that these events are orchestrated has yet to be fully addressed. Since the cytoplasmic domains of many of the ADAMs contain putative proline-rich Src homology3 (SH3) binding sites, as well as Tyr and Ser/Thr phosphorylation sites [33], it seemed logical that these would be major players in the regulation of signalling to and from the ADAMs and the regulation of their functions. Although the cytoplasmic domain of ADAM17 has many putative-binding partners, as discussed below (Table 1), it has been shown that it is not required for its activation by PMA (phorbol myristate acetate) [69]. The observation that PMA could stimulate ADAM17 shedding of many of its known substrates, including TNF␣, EGF receptor ligands and APP, implicated protein kinase C (PKC) in its regulation. ADAM17 cleavage of an exogenous peptide substrate was also upregulated by PMA which suggested that the release of an inhibitor or the enhanced binding of an activator might be involved [34]. Recent gain of function studies using cells from ADAM gene ablated mice have shown that many ADAMs can cleave EGFR ligands such as proTGF␣ and proHB-EGF in isolated cells but that ADAM17 is the only ADAM upregulated significantly by PMA in this situation. This response can be attributed to the ecto domain of ADAM17 and not the transmembrane or cytoplasmic domains [35]. PMA does not enhance the maturation (prodomain processing) of ADAM17, or the levels at the cell surface. Furthermore it only stimulates the shedding of EGFR ligands that have already moved out of the medial Golgi compartment [35]. It is possible that an accessory protein interacting with the ADAM17 ectodomain regulates the PMA response [34,35]. Despite these clearcut data, the situation in other cell types/for other substrates can still differ. ADAM17 can also shed EGF but PMA has no effect on this activity. In monkey kidney Vero cells PMA stimulation of ADAM9 mediated proHB-EGF proteolysis [36] and PKC ␦ was implicated in phosphorylation of the ADAM9 cytoplasmic domain, but details of the mechanism are not known. PMA has also been shown to induce ADAM12 translocation from a perinuclear vesicular location to the cell surface via PKC ␧ in a human RD rhabdomyosarcoma cell. This PKC isoform was found to bind to ADAM12 and was critical for its relocation [37]. The cytoplasmic domain of ADAM12 is involved in its trafficking, but is not necessary for PKC binding. The SH3-domain containing protein PACSIN3 which is involved in endocytosis, interacting with dynamin and N-WASP, binds to the cytoplasmic domain of ADAM12 and was shown to be functionally important for PMA-stimulated ADAM12 shedding of HB-EGF [38]. Since PACSIN3 interacts with ADAM9, 10 and 19 this could be a general regulator of ADAM-mediated shedding events. Similarly, Eve-1 is an SH3 adaptor protein that interacts with the cytoplasmic domain of ADAM12 and is required for the activa-

Table 1 Proteolytic ADAM trafficking and signalling partners. ADAM9 Src PKC␦ SH3PX1 Endophilin MAD2␤ PACSIN3 Eve-1

[95] [36] [96] [96] [97] [38] [39]

ADAM10 MAD2 Lck PACSIN3 Eve-1 SAP-97

[98] [98] [38] [39] [99]

ADAM12 MAD2␤ Src Yes Grb2 ␣-Actinin-2 ␣-Actinin-1 PI-3K p85 PKC␦ Tks5 PACSIN3 Eve-1 PKC␧

[97] [41,100] [100] [100] [101] [102] [41] [103] [40] [38] [39] [37]

ADAM15 SH3PX1 Endophilin MAD2␤ Src family Grb2 Tks5 Lck SNX30 Hck

[96] [93] [97] [98] [98] [40] [104] [105] [106]

ADAM17 MAD2␤ PTPH1 ERK SAP-97 Eve-1 PDK1 FHL2

[97] [43] [56] [44] [39] [107] [108]

ADAM19 Endophilin ArgBP1 Tks5 PACSIN3

[96] [109] [40] [38]

tion of its activity, and also associates with other ADAMs [39]. The scaffolding protein Tks5 interacts with ADAM12, 15 and 19. In Src-transformed cells Tks5 co-localizes with ADAM12 in actin-rich podosomes/invadopodia. ADAM12 binds to the SH3 domain of Src kinase and activates it, hence potentially activating Tks5 [40,41]. In differentiating myoblasts ADAM12, binds the p85alpha domain of phosphatidyl inositol-3-kinase (PI3K), mediating its recruitment to the membrane. Since PI3K is critical for terminal differentiation of myoblasts, and the expression of ADAM12 is upregulated at the onset of the differentiation process, ADAM12-mediated activation may constitute one of the regulatory mechanisms for PI3K during myoblast differentiation [42]. Protein tyrosine phosphatase1 (PTPH-1) binds to the cytoplasmic domain of ADAM17 through its PDZ domain and acts as an inhibitor of ADAM17 responses to PMA in terms of TNF␣ cleavage, but further details of the mechanism are not known [43]. The Synapse Associated Protein, SAP-97 binds to the cytoplasmic domain of ADAM10 and is required for

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correct positioning in synaptic membranes [99]. SAP-97 also interacts with ADAM17; the PDZ3 domain of SAP-97 and the extreme C-terminal amino-acid sequence of ADAM17 are involved and this was proposed to have a functional implication for the regulation of ADAM17 shedding activity [44]. A list of the known ADAM cytoplasmic domain interactants is given in Table 1, but the role of some is not known at this stage. Other signalling pathways have been found to regulate ADAM function. Ionomycin stimulation of Ca++ influx seems to upregulate ADAM10 activity in the shedding of the chemokines CX3CL1 and CXCL16 [45] and the adhesion molecules VE cadherin [46] and CD44 [47]. Ionomycin or the Ca++ /calmodulin inhibitor trifluoperazine caused ADAM10-mediated shedding of EGF receptor ligands and required the ADAM cytoplasmic domain to be present. However, no change in ADAM10 maturation could be detected [35]. Ionomycin does not appear to regulate ADAM17, but calmodulin has been implicated in platelet ADAM17 shedding of GPV [48], Lselectin and other membrane proteins [49]. Since calmodulin binds to these receptors it may play a role in bridging the interaction between the ADAM and its potential substrates. The role of the cytoplasmic domain of ADAM17 in stimulated shedding by other routes than PMA/PKC remains to be evaluated. Studies of other known signalling pathway roles in ADAM activation have established that constitutive shedding of TGF␣ and other substrates is p38 mitogen activated protein kinase (MAPK) regulated [50]. PMA/PKC activity may also involve p38 MAPK [51]. Interleukin-1alpha (IL-1␣) stimulates non-amyloidogenic pathway by ␣-secretase (ADAM10 and ADAM17) cleavage of APP in human astrocytic cells involving p38 MAPK [52]. The solubilisation of membrane proHB-EGF in response to osmotic or oxidative stress was found to involve not only ADAM17 but ADAM9, 10 and 12, via a p38 MAPK signalling pathway and does not involve Src [53]. The p75 neurotrophic receptor is constitutively shed by a p38 MAPK pathway whilst pervanadate stimulated shedding requires MEK/ERK activation [54]. The stimulation of CD44 proteolysis by ADAM10 in EGF treated glioblastoma cells is mediated by Rac1 and ERK MAPK [55]. The ERK MAPK pathway mediates many of the activation signals for ADAM17, such as those from growth factors [50] and from G protein coupled receptors (GPCR). ADAM17 can associate with ERK MAPK which phosphorylates Thr 735 [56] and this is thought to regulate trafficking of ADAM17 [57]. Carbachol treatment of cells led to the phosphorylation of Thr 735 of the ADAM17 cytoplasmic domain which was essential for its activation [58]. The ADAM17 cytoplasmic domain appears to be involved in these cases and it may be postulated that intracellular adaptors/interactions are of more relevance. The role of ADAMs in the regulation of EGFR ligands is critical, not least because they appear to mediate the crosstalk between other receptors and EGFR signalling. A number of GPCRs seem to signal in part through the EGFR via ADAM10, 12, 15 or 17-mediated generation of soluble EGFR ligands [59,60]. The mechanism of ADAM activation downstream of GPCR ligation is not fully understood. Studies are complicated by the multiple signalling pathways modulated by GPCRs and the additional signalling downstream of ADAM activation through the consequent EGFR activation [61]. In several studies the ‘sheddase’ activity involved has not been definitively identified and, in some cases, it has been claimed that an MMP rather than an ADAM is involved in the solubilisation of the EGFR ligand. The G protein subunit G␤, signalling through c-Src, has been shown to work downstream of ␣2A adrenergic receptor activation [62]. Since pertussis toxin inhibits ADAM17 activation after LPA or S1P stimulation of their respective GPCRs, this indicates that the G protein Gi may be involved. PKC, Ca++ and ROS have also found to be involved in the pathway between GPCRs and ADAMs [63]. Neurotensin binding to the neurotensin recep-

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tor1 (NTR1) transactivates the EGFR via a PKC-dependent pathway in prostate PC3 cells [64]. The cellular prion protein PrPc can be proteolytically released from the cell membrane by ADAM17 and it has been found that agonists of the muscarinic receptors M1 and M3 can enhance this activity. The PrPc-binding protein, the receptor NCAM can also be shed by ADAM17 [65], but these processes have not yet been monitored simultaneously. Besides GPCR signalling through the EGFR system, Caccamo et al. found that an agonist of the M1 muscarinic receptor modulated APP ␣-secretase processing (ADAM10/17) through the activation of both ERK1/2 and PKC pathways [66]. 4. Protein modulators Other levels of regulation of the ADAMs’ proteolytic functions have been suggested in a number of early studies of the involvement of protein interactants which might be considered to function as modulators. In some cases the modulators appear to be binding to the substrate and even to bind to both the ADAM and the substrate to promote cleavage rates. The tetraspanin CD9, which is involved in the biosynthesis and cellular localisation of TGF␣ [67], was originally shown to bind to the membrane form, decreasing the growth factor and PMA-induced proteolytic conversions of transmembrane to soluble TGF␣ [68]. The ADAM involved was not identified but ADAM17 has subsequently been shown to be the major TGF␣ sheddase [69,70]. Yan et al. found that bombesin stimulation of its GPCR activated ADAM10 cleavage of HB-EGF in part by promoting binding of ADAM10 to a CD9-HB-EGF complex [71]. An example of an adaptor binding to a membrane protein to promote its shedding is that of ARTS-1 (aminopeptidase regulator of TNFR1 shedding), a type II integral membrane protein that binds to the TNFR1 extracellular domain. It is thought to be essential for TNFR1 constitutive shedding and also promotes ADAM17 mediated inducible shedding, but has no effects on the solubilisation of TNFRII [72]. Cellular release of the soluble forms of the type II IL-1 decoy receptor (IL-1RII) and the IL-6 receptor by ADAM activity are also enhanced by ARTS-1 [73,74]. Thiol isomerases have been proposed to regulate some shedding activities by modulation of the redox status of the substrate. L-selectin shedding by ADAM17 is sensitive to reducing agents and is promoted by inhibitors of protein disulphide isomerase (PDI), hence it was suggested that modification of the disulphide bonding pattern of an essential EGF-like domain by PDI activity might be involved [75]. The thiol isomerase ERp5 was found to be important for the shedding of the tumour antigen MICA, promoting immune evasion [76]. It has been suggested that ERp5 modulates the structure of MICA at the cell surface such that it is amenable to ADAM10 and ADAM17 cleavage [77]. Nardilysin (N-arginine dibasic convertase (NRDc), is a peptidase that specifically binds HB-EGF [78] and enhances ectodomain shedding of HB-EGF by ADAM17. NRDc also formed a complex with ADAM17 and enhanced ADAM17 activity in a peptide cleavage assay, indicating that the interaction with NRDc potentiates the catalytic activity of TACE. The metalloendopeptidase activity of NRDc was not required for the enhancement of HB-EGF shedding. Notably, a reduction in the expression of NRDc caused by RNA interference was accompanied by a decrease in ectodomain shedding of HB-EGF [79]. Furthermore TNF␣ shedding by ADAM17 was enhanced by co-expression of NRDc. Curiously, overexpression of NRDc in ADAM17-deficient fibroblasts resulted in an increase in the amount of TNF-alpha released and it was suggested that NRDc enhances TNF-alpha shedding through activation of not only ADAM17 but ADAM10 [80]. NRDc also enhanced the ␣-secretase activity of ADAMs against APP and reduced the amount of A␤ peptide generated [81].

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There are a number of examples where ligand binding to receptors can initiate ADAM sheddase activity. Collagen binding to the platelet glycoprotein receptor GPVI induces ADAM-dependent shedding of the GPVI, generating an approximately 55 kDa soluble ectodomain fragment and an approximately 10 kDa membraneassociated remnant. Rapid formation of a high molecular weight GPVI complex occurs prior to shedding and involves changes in disulphide bond arrangements [82]. The Eph family of receptor tyrosine kinases and their ephrin ligands are mediators of cell–cell communication. Cleavage of ephrin-A2 by ADAM10 enables contact repulsion between Eph- and ephrin-expressing cells. A mechanism for regulating ADAM10-mediated ephrin proteolysis has been proposed which ensures that only Eph bound ephrins are recognized and cleaved. ADAM10 constitutively associates with EphA3 within the same cell. The formation of a functional EphA3/ephrin-A5 complex between two cells then creates a new molecular recognition motif for the ADAM10 cysteine-rich domain that positions the proteinase domain for effective ephrin-A5 cleavage. The cleavage occurs in trans, with ADAM10 and its substrate being on the membranes of opposing cells [83]. In the case of the receptor Notch, which can be shed by either ADAM10 or ADAM17 in mammalian cells, ligand (Delta or Jagged) binding in trans and its subsequent endocytosis is thought to generate sufficient force to modify the Notch structure such that ADAM cleavage and Notch ‘release’ can occur. In fact ADAM10 and 17 overexpression can effect Notch cleavage without ligand binding but this is likely to be less efficient [84]. It seems likely that cellular proteins specifically regulating the trafficking and location of membrane proteins that can be shed are also important levels of regulation. For instance, the low-density lipoprotein receptor-related protein (LRP) promotes APP trafficking to lipid rafts which expose it more to ␤- and ␥-secretase cleavages rather than ␣ cleavage by the ADAMs [26].

5. The role of ADAM structure in regulation The complex domain structure of the proteolytic ADAMs clearly plays roles in regulation of their catalytic activity (Fig. 1). Takeda et al. originally proposed that the hypervariable region of the cysteine rich domain was a likely determinant of substrate specificity [85]. Truncations and chimeric constructs of ADAM17 (with ADAM10) were originally studied to look at their role in determining substrate specificity by Reddy et al. In some cases the catalytic domain alone could efficiently shed a number of receptor substrates, but IL1RII shedding required the presence of the ADAM17 cysteine-rich domain [86]. A later study has shown that the intact structure of this domain may be needed for TNF␣ and TGF␣ solubilisation by ADAM17. Mutation of Cys600 located within the cysteine rich has been found to lead to a loss of activity [87]. A focus on the conformational properties of ADAM17 catalytic domain has shown that this enzyme has extraordinary conformational flexibility during substrate binding [88]. The dynamic charge transitions executed mean that in vitro, soluble ADAM17 is very sensitive to the ionic environment. In vivo in the cell membrane complexes associated with shedding larger molecules may act as structure/function modulators, e.g. NRDc was found to protect ADAM17 from the inhibitory activity of NaCl [79]. As discussed above, the regulatory function of the prodomain of the proteolytic ADAMs stems not only from their chaperone activities during folding, but their ability to remain associated with the ADAM ectodomain subsequent to furin, etc. cleavage [14,16]. Li et al. proposed that the transmembrane domain of ADAM17 may play a role in substrate specificity [89]. Domain exchange experiments between ADAM10 and 17 indicated that the intact ectodomain of ADAM17 is crucial for PMA-stimulated shedding of TGF [35]. It was proposed that this was either because a

membrane-anchored accessory protein(s) must interact with the ectodomain of ADAM17 to regulate the PMA response [90], or an intact ectodomain is necessary for proper presentation of the catalytic domain. The cysteine-rich domain of ADAM13 has also been shown to interact with the ADAM13 metalloprotease domain to regulate its function in vivo during Xenopus laevis development. When expressed in embryos, ADAM13 induces hyperplasia of the cement gland, whereas ADAM10 does not. Using chimeric constructs the metalloproteinase domain of ADAM10 could substitute for that of ADAM13, but the specificity for cement gland expansion requires the cysteine-rich domain, with a supporting role for the disintegrin domain [91]. 6. ADAM inhibitors The tissue inhibitors of metalloproteinases (TIMPs) appear to be the major potential natural inhibitors of the proteolytic functions of the ADAMs. Each of the 4 TIMPs have been found to have some activity against one or more ADAMs at physiologically relevant concentrations. TIMP-3, a heparan sulphate associated TIMP has activity against ADAM10, 12, 17, 28 and 33. TIMP-1 inhibits ADAM10 and TIMP-2 inhibits ADAM12 and 33. TIMP-4 inhibits ADAM28 and 33 [92]. Many studies have been carried out using soluble ADAM catalytic domains and peptide substrates and the TIMP activity for cell-based sheddases appears to be rather different. However, the potential relevance of TIMP-3 regulation of ADAM17 in vivo was shown by Smookler et al. who found that ablation of the Timp-3 gene in mice leads to dysregulation of ADAM17 cleavage of TNF␣ and its receptors. The altered kinetics of ligand and receptor shedding enhanced TNF signalling in timp3−/− mice, indicated by elevated serum IL-6 and greater susceptibility to LPS-induced mortality [93]. The membrane protein reversion-inducing cysteine-rich protein with Kazal motifs (RECK) is thought to be a physiological inhibitor of ADAM10 and regulates the ectodomain shedding of Notch ligands by directly inhibiting the proteolytic activity of ADAM10 in the embryonic brain. Notch shedding appeared to be essential for Notch ligands to properly induce Notch signalling and RECK thus acts as an upstream regulator and a critical modulator of brain development. RECK [94]. 7. Conclusions The importance of the proteolytic ADAMs at the cutting edge of cell biology, from proliferation, differentiation, migration and to apoptosis is not in dispute. As a consequence of their pivotal roles in so many events their regulation is complex and multi-layered. A major question, given that most ADAMs can potentially cleave many substrates, is how specificity is achieved in vivo? There is a good possibility that substrate concentration and localisation are key determining features and this aspect requires further examination. There are several exciting challenges at the molecular level, considering the role of the ADAM domains in their function. It is clear that the disintegrin/cysteine-rich domains can modulate the catalytic domain activity and the binding of the propeptide. At the cellular level, the role of trafficking of both ADAMs and their substrates will be a major focus of study. The nature of other interactants and the specificity that they confer, as well as the involvement of potential cell membrane signalling complexes, e.g. GPCR/EGFR, adhesion complexes and the cytoskeleton also need to be further unravelled. Acknowledgements The author would like to thank Dylan Edwards and colleagues for their generous provision of a review in press and Neil Taylor

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for advice on presentation. Work in the author’s laboratory is supported by Cancer Research UK, MRC UK, BBSRC UK and the British Heart Foundation.

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