Active Metalloproteases of the A Disintegrin And Metalloprotease (ADAM) Family: Biological Function and Structure Theo Klein and Rainer Bischoff* Analytical Biochemistry, Department of Pharmacy, University of Groningen, Groningen, The Netherlands 9700 AD Groningen, The Netherlands Received June 4, 2010
The “a disintegrin and metalloproteases” (ADAMs) are membrane-anchored metzincins of the adamalysin subfamily. This review gives an overview over the biological function and structure of ADAMs focusing on members of the family that display proteolytic activity. ADAMs are involved in a range of human diseases such as cancer metastasis, inflammatory disorders, neurological disease or asthma. It is, however, often difficult to assign a definitive role to a specific member of the ADAM family in a given disease mechanism due to overlapping activities and redundancy in function, as shown in various knock-out studies. The review discusses the structural domains that are not directly linked to protease activity followed by a more detailed overview over the role of the metalloprotease domain. Different family members are critically reviewed with respect to their role in biological processes with particular emphasis on disease-relevant functions. Keywords: metalloprotease • integrin • ADAM-17 • function • proteolysis
Introduction The “a disintegrin and metalloproteases” (ADAMs) or MDCs (metalloprotease-like, disintegrin-like, cysteine-rich proteins) are membrane-anchored metzincins of the adamalysin subfamily, which also contains the interesting class III snake venom metalloproteases as close relatives.1 ADAMs have a similar domain structure as the membrane-type matrix metalloproteases with two distinct differences (Figure 1). ADAM proteases do not contain the characteristic hemopexin-like domain but instead have three additional domains, the cysteine-rich domain, the Epidermal Growth Factor (EGF)-like repeat domain and the disintegrin domain from which the family derives its name. While the biological function of the EGF-like domain has not been fully elucidated, the cysteine-rich and disintegrin domains enable the cell surface bound ADAMs to interact with ECM proteins and ligands on neighboring cells. This important function in intercellular interaction was already obvious after identification of the first members of the ADAM family as key players in the fertilization process, specifically in the binding and fusion between egg and sperm cells. The first adamalysins described in mammalia were found on guinea pig sperm and dubbed fertilin R and β (or PH-30 R and β),2-4 which were later renamed ADAM-1 and -2 after identification of several other homologous genes.5 Disintegrin-Integrin Binding. The presence of a disintegrin domain in ADAMs is unique among cell-surface proteins, and can mediate cell-cell and cell-matrix interaction by binding integrins. The major integrin involved in interaction with ADAMs has been identified as R9β1, which can interact with a * To whom correspondence should be addressed. Prof. Dr. Rainer Bischoff, Antonius Deusinglaan 1, Postbus 196. Tel: +31 50 3633338. Fax: +31 50 3637582. E-Mail:
[email protected]. 10.1021/pr100556z
2011 American Chemical Society
conserved RX6DEVF sequence in the disintegrin domain.1 Although structural modeling of a snake venom disintegrinmetalloprotease has demonstrated that this motif is shielded by the cysteine-rich domain and may be inaccessible for integrin binding,6 other integrins are capable of binding the disintegrin domain.7 The consensus recognition site of disintegrins, first identified as integrin antagonists in snake venom, is dependent on the presence of RGD or KGD sequences, but surprisingly only ADAM-15 contains the RGD sequence in its disintegrin domain. Presence of this recognition site enables interaction with a broader range of integrins such as Rvβ3, Rvβ5 and R5β1.8,9 Other ADAMs (e.g., ADAM-9 and -23) are capable of binding these integrins through interaction with an ECD sequence in the disintegrin domain, an observation that corroborates the pivotal importance of especially the aspartic acid residue in the disintegrin-integrin interaction site.10 Although the binding of ADAMs to integrins is relatively well characterized, the biological relevance and scope is not yet clear.10 The only physiological process where the functionality is well documented remains the fertilization process, with the two fertilin-ADAMs forming a heterodimer capable of binding integrin R6β1 on the surface of the egg,11 but this model is under debate.12 The fact that the fertilin R/ADAM-1 gene encodes a nonfunctional protein in humans is a strong indication that this model for ADAM involvement in egg-sperm fusion in mammalia may need to be reconsidered.13 Gene deletion experiments have demonstrated an important role for ADAM-2 in fertilization since fertilin β null mice are infertile.14 ADAM-2 is, however, not indispensable in the sperm-egg fusion process since sperm from these knockout mice can still fuse with oocytes, albeit at a ∼50% decreased fusion rate. The observed sterility of fertilin β -/- mice is Journal of Proteome Research 2011, 10, 17–33 17 Published on Web 09/17/2010
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Figure 1. Schematic representation of the domain structure of metzincin proteases. (A) Signal peptide; (B) prodomain; (C) catalytic domain; (D) hemopexin-like domain; (E) fibronectin type II insert; (F) transmembrane domain; (G) cytoplasmic tail; (H) disintegrin domain; (I) cysteine-rich domain; (J) EGF-like domain; (K) thrombospondin type I-like repeat; (L) spacer region (reproduced from Klein and Bischoff, Amino Acids, in press).
postulated to be due to disruption of transit of the sperm through the female reproductive tract,15 which may be an indication that ADAM function during fertilization is based on a hitherto unknown mechanism.12 Interaction via the Cysteine-Rich Domain. ADAMs are capable of binding several ECM constituents independent of the disintegrin-integrin interaction. The cysteine-rich domain may have an important function in binding proteoglycans of the heparan sulfate class, such as syndecans, as described for ADAM-12.16 Studies involving the Xenopus-specific ADAM-13 protein have further revealed an important role for the cysteinerich domain in the interaction with fibronectin.17 An early observation revealed the presence of a hydrophobic stretch in the cysteine-rich domain of several ADAMs, which shows high sequence similarity to viral fusion peptides,18 which may indicate a role for the cysteine-rich domain in membrane fusion. This hypothesis has, however, not been confirmed by experimental data.1 Function of the Cytoplasmic Domain. The cytoplasmic domain of the individual ADAM proteases is highly variable in length (40-250 amino acids) and sequence, but the majority of ADAMs contain cytoplasmic tails with PxxP motifs, which indicates binding sites for Src-homology 3 (SH3) domain containing proteins.19 This structural feature enables interaction of the cytoplasmic domain with a large range of intracellular proteins and may be important in regulation of ADAM localization by interaction with cytoskeletal proteins such as R-actinin-2.20 ADAM function may also be regulated by interaction of the cytoplasmic tail with intracellular signaling proteins, as demonstrated by the activation of ADAM-9 by phorbol esters via interaction with PKC δ.21 The cytoplasmic domain of some ADAMs further contains putative phosphorylation sites for serine-threonine or tyrosine kinases, which may be involved in regulation of ADAM function, or supply binding sites for SH2 domain containing proteins.1 ADAM Metalloprotease Function. Perhaps the best studied function of the ADAM proteins is the catalytic activity exhibited by the metalloprotease domain, which is highly homologous to that of the Matrix MetalloProteases (MMPs). Interestingly not all ADAMs contain the consensus HExxHxxGxxH zincbinding metalloprotease active site motif, which leads to the conclusion that from the 22 known human ADAMs only 12 are equipped to exert endopeptidase activity (Table 1). Interest18
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Klein and Bischoff ingly, in mice an additional subfamily of possibly catalytically active ADAMs (ADAM-24-26, -34 and 36-40) has been described and named testases, referring to the testis-specific expression pattern.22 No orthologues of the testases have been identified in human to date. The ADAM metalloprotease domain is shielded by a prodomain in the inactive zymogens involving the so-called “cysteine switch mechanism” in a similar manner as in MMPs. The primary activation pathway of the ADAM zymogens involves removal of the prodomain by proprotein convertases (PCs) such as furin in the trans-Golgi network as demonstrated by strongly diminished activation of ADAM-9 and -15 in the presence of the early secretory pathway inhibitors brefeldin A and monensin, increased activation of ADAM-10 after overexpression of PC-7 and no activation of proADAM-10, -12, and -19 after mutational modification of the furin Rx(R/K)R recognition site (discussed in ref 1). Some ADAMs may require autoproteolytic processing for activation, as demonstrated for ADAM-823 and -28.24 Interestingly, the prodomain acts as a chaperone and is required for proper folding, especially of the metalloprotease domain. Removal of the prodomain prior to folding yields an inactive form of ADAM-17.25 For ADAM-10 a similar effect has been observed in cells expressing the protease without the prodomain, an effect that could be reversed by cotransfection of the prodomain.26 Although, similar to the MMPs, catalytically active ADAMs are capable of degrading ECM proteins such as collagens and fibronectin in vitro, the physiological relevance of this observation is not clear. The endopeptidase activity for which ADAMs are best known is the so-called shedding or liberation of biologically active proteins from their membrane-anchored proforms. This function of the ADAMs was first described simultaneously by two groups in 1997, identifying a disintegrinmetalloprotease as an important contributor to the production of soluble Tumor Necrosis Factor (TNFR) from the membranebound precursor.27,28 The responsible protease was named TACE (TNF-alpha converting enzyme), and gene-silencing experiments demonstrated a dominant, but not exclusive, role for TACE, since TNFR production was significantly diminished but not completely abolished in the knockout mice. In this review, ADAMs containing the metalloprotease active site will be discussed in further detail. ADAM-8. ADAM-8 (CD156) was first described in 1990 as antigen MS2 in mice29 and was later confirmed as a member of the human ADAM family in 1997.30 ADAM-8 is a transmembrane glycoprotein primarily expressed as a 120 kDa zymogen by immune cells but is also found in neurons and oligodendrocytes in the central nervous system. The promoter region of the adam-8 gene contains response elements for lipopolysaccharide (LPS) and cytokines such as interferon γ, interleukin6, and TNF R.31 ProADAM-8 does not contain a recognition site for cleavage by furins and depends on autoproteolytic removal of the prodomain for activation, yielding a 90 kDa mature enzyme. This process likely involves catalytic preprocessing of the prodomain which is dependent on interactions with the disintegrin, cysteine-rich and EGF-like domains.32 The mature cell-surface-bound ADAM-8 may be further processed by autoproteolytic shedding yielding a 60 kDa soluble form missing the metalloprotease domain.23 ADAM-8 may also exist as a soluble, catalytically active form that is presumably also released from the cell by autoproteolytic shedding.33 Contrary to the MMP and MT-MMP families, ADAM-8 catalytic activity
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Active Metalloproteases of the ADAM Family a
Table 1. Overview of the 22 Identified Human ADAM Proteases ADAM
MP active site?
activated by
1
Fertilin R, PH-30 R
yes
2
Fertilin β, PH-30 β Cancer/testis antigen 15 Cyritestin, tMDC I
no
n/a
no
n/a
no no yes yes yes no yes yes yes
n/a n/a Auto PC PC n/a PC PC PC
no yes
n/a PC Auto Unknown n/a n/a Auto MMP-7 n/a Unknown n/a PC
3 6 7 8 9 10 11 12 15 17 18 19 20 21 22 28 29 30 32 33 b
alternative names
tMDC IV EAP-1, Sperm maturation-related glycoprotein GP-83 Cell surface antigen MS2, CD156a MDC9, Meltrin γ Myeloma cell metalloprotease Kuzbanian protein homologue, CD156c MDC Meltrin R Metargidin, MDC-15 TACE, CD156b Snake venom-like protease tMDC III, ADAM-27 Meltrin β, MADDAM Metalloprotease and disintegrin dendritic antigen marker ADAM-31 MDC 2 MDC-L, ADAM-23 Cancer/testis antigen 73
yes no no yes no yes no yes
b
n/a
remarks
Nonfunctional pseudogene Testis specific Testis specific Nonfunctional pseudogene Testis specific Testis specific
Brain specific Soluble species exists
Testis specific
Testis specific Testis specific
Testis specific Testis specific Testis specific
a (t)MDC, (transmembrane) metalloprotease-like, disintegrin-like, cysteine-rich protein; Auto, autocatalytic processing; PC, Proprotein convertase.4 Although full length ADAM-1 contains a metalloprotease domain with a Zn2+ recognition motif, this domain is removed in the mature, processed form.
is not inhibited by any of the four known Tissue Inhibitors of MetalloProteases (TIMPs) in vitro.34 The biological function of ADAM-8 is far from clear, but the protein has been associated with neuron-glia interactions in the central nervous system,35 cell-cell fusion in osteoclast differentiation (an effect presumably mediated by the remnant form)33 and a possible role in the ovulation process involving hormonal regulation of ADAM-8 as recently shown.36 ADAM-8 sheddase activity in vivo is still rather poorly characterized, but in vitro experiments using cleavage assays of 10-amino acid peptide sequences containing known recognition sites for ectodomain shedding have revealed multiple possible substrates such as β-amyloid precursor protein (APP), low affinity IgG (CD16) and IgE (CD23) receptors, L-selectin, P-selectin glycoprotein ligand, transforming growth factor R (TGF R) and TNF R.37 ADAM-8 has also been implicated in shedding of the neural adhesion molecule CHL-1 (close homologue of L-1), yielding a biologically active fragment that enhances neurite outgrowth and suppresses neuronal cell death, indicating an important role in the development of the central nervous system.38 Knockout experiments in mice have identified ADAM-8 as a nonessential protein during development since ADAM-8 null mice show no pathological defects.39 This finding may be explained by a rather large redundancy with other ADAM proteases or by a specific role for ADAM-8 not in development but rather in processes such as inflammation, a hypothesis that seems to be substantiated by the responsiveness of ADAM-8 expression to cytokine stimulation. ADAM-8 has been associated with the development of asthma following the observation that ADAM-8 is highly
upregulated in an experimental ovalbumin-induced, allergic asthma model in mice, showing strong induction in peribronchial and perivascular inflammatory cells, airway smooth muscle and bronchiolar epithelial cells.40,41 Recent research demonstrated that the presence of ADAM-8 is indeed pivotal, since null mice show a greatly attenuated response to the ovalbumin challenge. This observation may be linked to decreased mobility of ADAM-8-deficient T-cells.42 Interestingly, in an asthma model with transgenic mice producing a soluble form of ADAM-8 a protective effect of sADAM-8 was found, presumably related to suppressed leukocyte migration,43 which may be mediated by shedding of vascular cell adhesion molecule 1 (VCAM-1) by ADAM-8.44 The amount of clinical evidence linking ADAM-8 to development of pulmonary disease is limited, but soluble ADAM-8 and VCAM-1 are increased in Bronchoalveolar Lavage (BAL) fluid of patients suffering from eosinophilic pneumonia45 and ADAM-8 mRNA is increased in asthma patients with a positive correlation to disease severity.46 ADAM-8 is expressed in human neutrophils, where it is stored in granules and transported to the cell surface upon stimulation. Cell surface exposed ADAM-8 is then rapidly released into the extracellular space by a metalloprotease activity-dependent process. These in vitro findings have been confirmed in neutrophils from synovial fluid from rheumatoid arthritis patients indicating another possible role for ADAM-8 activity in inflammatory processes.47 This hypothesis is corroborated by recent findings that show a diminished response during experimental autoimmune arthritis in mice expressing an inactive mutant of ADAM-8.48 ADAM-8 expression is increased in neutrophils that are in contact with endothelial cells. Since L-selectin is a possible substrate for ADAM-8, and Journal of Proteome Research • Vol. 10, No. 1, 2011 19
reviews since ADAM-8 colocalizes with L-selectin on the surface of neutrophils, it is conceivable that ADAM-8 mediated L-selectin shedding plays an important role in regulation of neutrophil rolling and trans-endothelial extravasation.47 Since ADAM-8 is involved in osteoclast differentiation it is not surprising that several studies have focused on the role of this protease in the development of pathological bone destruction. ADAM-8 expression is positively associated with tissue destruction in rheumatoid arthritis with the protein mainly localized at the edge of the eroded cartilage and bone (the socalled pannus).49 A similar induction of ADAM-8 at the edge of healthy and eroded tissue has been described in loosening hip replacements.50 ADAM-8, as most metzincins, has been associated with various malignant processes. ADAM-8 expression and protein level are correlated with the invasiveness of the tumor and with reduced survival rate, for example, in pancreatic duct adenocarcinoma,51 a phenomenon that may involve tumor hypoxia.52 A similar correlation has been shown in primary brain tumors between ADAM-8 activity, as measured by conversion of a peptide substrate, and the invasive potential of cells obtained from gliomas.53 Overexpression of ADAM-8 has also been associated with poor prognosis in lung cancer, with high expression significantly more common in stage IIIb/IV adenocarcinomas compared to lower stages. Truncated forms of ADAM-8 may be of importance in the occurrence of bone metastasis from primary lung cancer, again giving rise to the possible use of ADAM-8 as a marker for aggressiveness of the tumor and poor prognosis.54 The soluble protein species has thus been suggested as a useful diagnostic serum marker for lung cancer.55 ADAM-8 overexpression has also been described in prostate cancer56 and renal cell carcinoma.57,58 ADAM-9. ADAM-9 or meltrin γ was first identified in 1996 as MDC-9 from breast carcinoma59 and as myeloma cell metalloprotease in myeloma.60 ADAM-9 is ubiquitously produced as a 110 kDa glycosylated zymogen, which can be activated in the medial Golgi apparatus by proprotein convertase activity to the 84 kDa mature form that is found on the cell surface after removal of the prodomain. The cell membrane anchored form can be further truncated by proteolytic processing to a 47 kDa soluble form which contains the metalloprotease domain and retains catalytic activity as demonstrated by the ability to cleave insulin B-chain in vitro. Purified soluble ADAM-9 is further capable of cleaving peptides containing the membrane-proximal cleavage region of β-APP, proTNFR, the p75 TNF receptor and c-kit ligand-1 (KL-1), but not IL-6 receptor, the p55 TNF receptor, transforming growth factor R and L-selectin.61 Recombinant ADAM-9 is capable of degradation of fibronectin in vitro, but the physiological relevance is not proven.62 Like ADAM-8, ADAM-9 activity is not inhibited by any of the four TIMPs.34 As with ADAM-8, knockout models have demonstrated that ADAM-9 is not vital for development and survival, since deletion of ADAM-9 is not lethal,63 but that later in life these mice develop retinal degeneration and anomalies in the junctions between the retinal epithelium and photoreceptors.64 ADAM-9 is capable of processing β-APP and widely considered to be one of the three alpha-secretases from the ADAM family (next to ADAM-10 and -17).65 ADAM-9 knockout mice, however, do not show aberrant APP processing, indicating functional compensation by or redundancy with other proteases. Similarly, shedding of HB-EGF, which is known to be decreased 20
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Klein and Bischoff in cells overexpressing a mutant form of ADAM-9,21 is unaffected by the ADAM-9 knockout. In rat kidney, ADAM-9 is mainly found on the basolateral surface of the tubular cells. The expression in glomerular epithelium is restricted to areas that are in contact with the underlying basement membrane indicating an important role in cell-cell and cell-matrix interaction.66 This may be mediated by binding of the disintegrin domain to β1 integrins, which colocalize with ADAM-9 in glomerular epithelium.67 The soluble isoform of ADAM-9 has been reported as an important player in tumor metastasis in the liver. After shedding from the cell surface of activated hepatic stellate cells, sADAM-9 is hypothesized to bind to R6β4 and R2β1 integrins on the surface of carcinoma cells and to promote stroma-tumor interaction. Addition of soluble ADAM-9 to Matrigel invasion assays showed an increased invasive potential in several cancer cell lines. This effect is blocked by the broad-range metalloprotease inhibitor 1,10-phenantroline, indicating a possible role for an active metalloprotease, although it remains unclear whether this is related to ADAM-9. Histological examination of tumor sections obtained from liver metastases revealed that ADAM-9 expression was highest at the invasive front and in contact regions between tumor and stroma, whereas tumor cells and hepatocytes themselves were negative for ADAM-9.68 ADAM-9 expression is higher in malignant prostate tumors and expression in carcinoma cell culture is increased in response to oxidative stress. This effect is likely mediated by an androgen receptor (AR)-dependent mechanism, since ARnegative prostate cancer cells do not exhibit increased expression after exposure to reactive oxygen species (ROS) and since preincubation with the antiandrogen bicalutamide abrogates increased expression of ADAM-9.69 Blocking ADAM-9 production induced apoptotic cell death in cultured prostate cancer cells, indicating a role for ADAM-9 in tumor survival.70 Concurrently, high expression of ADAM-9 in tumors has been identified as a significant prognostic marker for relapse in prostate cancer71 and as a marker for poor prognosis in renal cancer.72 Since ADAM-9 is a putative R-secretase of β-APP, it has attracted some interest from the Alzheimer’s disease research field (although less than the two other R-secretases in the ADAM family). Alpha secretases supposedly have a protective effect toward development of Alzheimer’s disease, which is among others characterized by an accumulation of neurotoxic amyloid-beta peptides (Aβ) and plaque formation in the brain. These peptide fragments are the result of sequential β- and γ-secretase processing of APP, while R-secretases have a cleavage site within Aβ leading to degradation of the neurotoxic peptides. Decreased sheddase activity of the ADAM R-secretases may therefore play an important role in the development of the disease.73 The physiological relevance of ADAM-9 as an R-secretase has, however, been debated in recent years, especially after findings that APP cleavage is unaltered in ADAM-9 knockout models, and the consensus seems to point to a minor role of ADAM-9 in β-APP processing in vivo.74,75 Recent results from a genetic screen in sporadic Alzheimer’s disease patients has, however, shown that increased transcription of ADAM-9 caused by promoter polymorphisms is associated with a lower incidence of the disease.76 ADAM-10. ADAM-10 was first isolated in 1995 as a membrane-bound metalloprotease capable of cleaving myelin basic protein,77 It was later found to be expressed by various cell types and named MADM (mammalian disintegrin-metalloprotease) and to have significant sequence homology with several
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Active Metalloproteases of the ADAM Family other mammalian disintegrin-metalloproteases such as meltrin-R (ADAM-12) and MS2 (ADAM-8).78 MADM/ADAM-10 is the mammalian counterpart of the Drosophila protein Kuzbanian, which plays an important role in neurological development by proteolytic activation of the Notch-receptor and shedding of the Notch receptor ligand delta.79 ADAM-10 is produced as an inactive zymogen which is activated by proprotein convertases in the trans-Golgi network to its 56-58 kDa glycosylated mature form.80 Contrary to most other metzincins, the cysteine switch mechanism, which normally links the prodomain to the catalytic center thus keeping the enzyme inactive, seems to be nonfunctional in ADAM-10.81 ADAM-10 catalytic activity is inhibited by TIMP-1 and -3.82 ADAM-10 is one of the better characterized enzymes of this protein family with many studies focusing on its proteolytic function. ADAM-10 is capable of degrading type IV collagen in vitro83 and has been identified as a possible sheddase of the cell-surface bound proteins such as the epidermal growth factor receptor ligands EGF and betacellulin,84 ephrin-A2,85 cellular prion precursor protein,86 chemokines CX3CL1 and CXCL16,87,88 adhesion molecule L189 and many others, although some caution has to be exercised in interpreting these results, since most target substrates have been identified in vitro, and many ADAM-10 mediated shedding events in cell lines are validated by incubation with supposedly ADAM-10/ ADAM-17 selective hydroxamate-based inhibitors (e.g., TAPI, TNF alpha protease inhibitor) that were later shown to be broad-range metzincin inhibitors. ADAM-10 is believed to be primarily involved in the constitutive shedding of cytokines, chemokines and their receptors, while ADAM-17 mediated shedding is more responsive to stimuli.90 The release of TNFR from cells was originally thought to be (partially) mediated by ADAM-10 but recent insights demonstrated that ADAM-10 plays probably a minor role.91 The best studied shedding activity mediated by ADAM-10 relates to the Notch signaling pathway. Notch signaling is a highly conserved, ancient pathway that is essential in intercellular contact and cell fate determination at all stages of neural development. The membrane-bound Notch receptor is activated by either membrane-bound ligands on adjacent cells leading to an intracellular signaling cascade that involves a series of proteolytic cleavages (S1-3), internalization of the processed Notch receptor, transport to the nucleus and finally activation of gene transcription. The precise outcome of Notch receptor activation is highly dependent on other extra- and intracellular signals and can lead to inhibition of neuronal cell and oligodendrocyte differentiation, or to promotion of differentiation of glial progenitor cells (reviewed in ref 92). Although the role of the invertebrate ADAM-10 homologues Kuzbanian (Drosophila) and Sup-17 (C. elegans) in Notch signaling is clear,93,94 involving proteolytic activation of the Notch receptor-ligand complex (stage S2), attempts to identify ADAM-10 as a key player in mammalian Notch signaling have yielded variable results. Some studies point to ADAM-17 as the essential protease for Notch processing, based on proteolytic cleavage assays using ADAM-17 in vitro95 and on cotransfection of DTACE (the Drosophila ADAM-17 homologue) in deltaexpressing Drosophila S2 cells, but ADAM-17 knockout models show little similarity to Notch knockouts while ADAM-10 deficient mice die early in embryogenesis showing major defects in development of the central nervous and the vascular system with similar histological abnormalities as observed in
96,97
Notch deficiency induced in mice. Conditional knockout experiments of ADAM-10 in mice have demonstrated a pivotal role in the formation of the brain cortex with aberrant neuronal differentiation in the null mice.98 This apparent discrepancy between in vitro substrate specificity and biological relevance is also apparent from the unclear role of ADAM-10 as an APP R-secretase. ADAM-10 is widely expressed in neurons in the CNS,99 is capable of cleaving APPderived peptides in vitro and overexpression of ADAM-10 increases the release of cleaved APP from HEK 293 cells, while transfection with a nonfunctional ADAM-10 mutant inhibited APP processing.100 On the other hand, most preserved embryonic fibroblast cell lines obtained from ADAM-10 knockout mice show no decreased or altered APP processing compared to control, although two out of 17 lines do have severe APP processing defiencies96 and transgenic mice expressing a nonfunctional form of ADAM-10 show decreased performance in behavioral experiments testing learning and memory.101 Several shedding events possibly mediated by ADAM-10 have been associated with cancer. Proteolytic removal of the extracellular domain of neuronal cell adhesion receptor L1-CAM by ADAM-10 promotes metastasis in colon cancer.102 ADAM10 may also be involved in metastasis by shedding of CD44 promoting migration of cancer cells through the ECM by interaction with hyaluronic acid103 and by ADAM-10 mediated shedding of EGF receptor ligands, which may promote tumor growth. In melanoma, metastases show higher expression of ADAM-10 compared to the primary tumor, and overexpression of ADAM-10 induces migration in melanoma cells in vitro.104 ADAM-10 activity may be associated with poor prognosis in breast cancer by shedding of the membrane-anchored HER2 receptor leaving a fragment with constitutive kinase activity, which results in ligand independent cell growth and resistance to apoptotic signals.105 ADAM-10 may further be involved in tumor resistance to the immune response by shedding MHC class I-related chain A (MICA) and thereby inhibiting the response of natural killer cells toward the malignant cells.106 ADAM-10 proteolytic activity has been associated with a protective effect in inflammatory processes by shedding of the receptor for advance glycation endproducts (RAGE), yielding a soluble form which acts as a decoy receptor for RAGE ligands.107 ADAM-10 may on the other hand stimulate inflammatory processes during an allergic response by shedding of the low affinity IgE receptor CD23 yielding the soluble form, that has been described to stimulate differentiation of germinal B-cells into plasma cells, cytokine release by monocytes and IgE production by B-cells.108 ADAM-10 is furthermore involved in shedding of FAS ligand resulting in a soluble form which can have both pro- and antiapoptotic effects, depending on the microenvironment. The sFAS-L concentration in serum correlates with progression of inflammatory diseases such as arthritis and colitis indicating a possible role for ADAM-10 activity in these diseases.109,110 ADAM-12. ADAM-12 was first described in mouse in 1995 under the name of meltrin R as a disintegrin-metalloprotease involved in myoblast fusion.111 The human homologue was cloned 3 years later and experiments revealed a peculiarity of this ADAM compared to most other members of the family with respect to the existence of an alternative splicing variant yielding a soluble form of the enzyme (ADAM12-S)112 while for most other ADAMs soluble forms have been described as a result of autoproteolytic ectodomain shedding. The biological relevance of most of the proteolytically released proteins is Journal of Proteome Research • Vol. 10, No. 1, 2011 21
reviews unclear, since many experiments demonstrating these soluble forms have been performed with cell lines expressing recombinant ADAMs. Soluble ADAM-12 has a very similar ectodomain structure compared to the membrane-anchored form but lacks the transmembrane and cytoplasmic domains, which is replaced by a unique 33 amino acid C-terminus. Both membraneanchored and soluble ADAM-12 are expressed as inactive zymogens that are activated by proprotein convertase cleavage of the prodomain.113 Interestingly, the prodomain remains attached to the enzyme after activation, giving sADAM-12 a four-leaf clover like structure.114 ADAM-12 expression is relatively independent of transcriptional upregulation. Only TGFβ has been reported as an inducer in hepatic stellate cells.115,116 Interaction of the disintegrin domain of ADAM-12 and integrins R9β1 and R7β1 may be involved in cell differentiation during muscle development.117 ADAM-12 has been suggested to modulate the cytoskeleton by altering β1 integrins on the ECM, which causes reorganization of actin-integrin binding between cytoskeleton and ECM.118 A second mechanism by which ADAM-12 can reorganize the cytoskeleton is mediated by interaction with actinin-1 and -2.20 That ADAM-12 knockout mice show only limited abnormal muscular development indicates that ADAM-12 function overlaps with and can be compensated for by other (ADAM) proteins.119 Overexpression of ADAM-12 improves muscle regeneration after injury,120 and induces adipogenesis due to enhanced adipocyte proliferation. ADAM-12 deficient mice are resistant against high-fat dietinduced obesity.121 ADAM-12 is capable of degrading several ECM proteins such as fibronectin, type IV collagen and gelatin in vitro,122 but the physiological relevance of these activities is probably minor.123 The membrane-bound isoform of ADAM-12 was reported in ectodomain shedding of several substrates such as insulin-like growth factor binding proteins (IGFBP) 3 and 5 in vitro,124 HBEGF,125 the oxytocinase placental leucine aminopeptidase,126 EGF and betacellulin127 and Notch ligand delta-like 1.128 ADAM-12 is highly expressed in placenta, and sADAM-12 levels in serum are markedly increased during pregnancy. Interestingly, this rise in serum sADAM-12 is not observed in women carrying trisomy-18 and -21 fetuses, making ADAM12 a possible prenatal marker for Down syndrome,129 but recent findings cast a shadow of doubt on the usefulness of serum ADAM-12 as a marker for chromosomal defects, since the added value over traditional markers such as beta hCG and PAPP-A could not be proven.130,131 ADAM-12 has been associated with various other pathological states related to the development of musculoskeletal disorders. Although ADAM-12 seems to play a role in muscle regeneration, prolonged high expression of ADAM-12 is associated with muscular dystrophy.132 In heart muscle tissue ADAM-12 levels are increased in patients with hypertrophic cardiomyopathy, and ADAM-12 may contribute to tissue remodeling observed in heart failure by shedding of HBEGF.125,133 Polymorphisms in ADAM-12 have also been associated with susceptibility to osteoarthritis.134 The role of ADAM-12 in cancer has been extensively reviewed.135 ADAM-12 overexpression was observed in many tumors, ranging from breast and lung cancer to glioblastoma and osteoclastoma. An interesting difference between ADAM12 and the majority of MMPs and ADAMs is that the cancerous cells themselves and not the stroma are the main source of ADAM-12 in most tumors.136 ADAM-12 is often hypothesized to stimulate tumor growth, as demonstrated by a strongly 22
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Klein and Bischoff reduced tumor progression in ADAM-12 deficient mice with experimental prostate cancer,137 but anti-ADAM-12 antibodies have a stimulating effect on breast and gastric carcinoma cell proliferation.138,139 The latter effect may be effectuated by ADAM-12 induced apoptosis-resistance in tumor cells.140 Adam12 is a candidate breast cancer gene, with two possibly functional polymorphisms in the metalloprotease and disintegrin domains showing strong association with the development of breast cancer.141 The existence of a soluble variant makes ADAM-12 a possibly interesting biomarker, since sADAM-12 can be found in a functional form in biofluids such as serum and urine. A positive correlation has been demonstrated between breast cancer progression and urinary levels of sADAM-12122 as well as in patients with bladder cancer.142 The role of ADAM-12 in different diseases has recently been reviewed.143 ADAM-15. ADAM-15 was first described in 1996 as metargidin, referring to its RGD-motif in the disintegrin domain, which is unique among ADAM proteases.144 ADAM-15 is produced by many cell types as an inactive glycosylated zymogen with the prodomain linked to the catalytic domain via a cysteine switch. The prodomain contains a proprotein convertase recognition site, so the activation process is presumed to involve PC mediated removal of the prodomain, yielding the 85 kDa mature protease. ADAM-15 deficient mice are viable and fertile, but show reduced neovascularization after hypoxia-induced retinopathy. While growth of an implanted melanoma is reduced in ADAM15 null mice compared to wild type, which could indicate inhibited tumor angiogenesis, histological examination of the tumors revealed no difference in vascularization.145 The consensus integrin binding site containing an RGD motif was first found in a snake venom-derived disintegrin but there was no such motif in any of the ADAM proteases until the discovery of ADAM-15. The presence of this binding motif in ADAM-15 is expected to confer a much broader range of binding partners and thus to allow for adhesion to different kinds of neighboring cells and the ECM than for other ADAMs, where interaction is preferentially mediated through integrin R9β1 in an RGD-independent manner.146 The ADAM-15 disintegrin domain containing the RGD sequence was found to have a strong affinity toward integrin Rvβ3 after expression as a recombinant fusion protein with glutathione S-transferase.8 Recombinant ADAM-15 is capable of binding Rvβ3 integrin on a monocytic cell line and R5β1 on a T-cell line.147 The putative role of ADAM-15 in intercellular adhesion was substantiated by the observation that overexpression of ADAM-15 lead to increased adhesion of cultured NIH3T3 cells.148 In concurrence with this result is the observation that overexpression of ADAM15 inhibits wound healing in monolayers of intestinal epithelial cells by increasing cellular adhesion and inhibition of migration.149 RGD-mediated integrin Rvβ3 binding has been postulated to RGD-mediated integrin Rvβ3 binding has been postulated to inhibit cellular motility by blocking integrin Rvβ3 so contact with ECM proteins such as vitronectin, as demonstrated by reduced migration of ovarian cancer cells when overexpressing ADAM-15.250 This anti-invasive function of ADAM15 was also found in melanoma cells and is possibly linked to p38 kinase activation.150 The pro-adhesive properties of ADAM-15 may protect against degenerative diseases such as osteoarthritis, since ADAM-15 deficiency accelerates cartilage destruction while overexpression has a protective effect.151 The disintegrin domain of
Active Metalloproteases of the ADAM Family ADAM-15 has further been demonstrated to inhibit migration of airway smooth muscle cells through binding to β1-integrins.152 Integrin binding mediated by ADAM-15 is a possible player in inflammatory processes such as inflammatory bowel disease. ADAM-15 expression is higher in diseased areas and histological examination shows binding of ADAM-15 expressing endothelium and crypt epithelium to leukocytes. Interestingly, immunohistochemistry shows mainly the mature form to be present in these cells. In regenerating tissue, ADAM-15 positive epithelial cells are in close contact with integrin-positive myofibroblasts, which indicates a role for ADAM-15 in tissue remodelling.153 ADAM-15 may also play a role in cardiovascular disease. ADAM-15 is expressed in endothelium and is capable of binding to platelets by interaction with integrin R(IIb)β3. Platelets are activated by binding to ADAM-15 indicating a role in thrombotic disease.154 ADAM-15 expression in arterial cells is markedly higher in atherosclerotic tissue than in healthy control. ADAM-15-integrin binding may thus play a modulating role in formation of the neo-initima.155 Although most interest in the biological function of ADAM15 has been directed toward integrin binding, the metalloprotease domain does contain the consensus zinc-binding sequence and is active as a protease, since purified ADAM-15 is capable of proteolytic degradation of type IV collagen and gelatin.156 Experiments with recombinant ADAM-15 and a peptide library have demonstrated a broad substrate specificity in vitro, with a pattern similar to that of ADAM-8. Experiments in HEK 293 cells exposed to recombinant ADAM-15 revealed cleavage of the low affinity IgE receptor CD23.157 Only recently the first report of a possible biologically relevant substrate for ADAM-15 was published, since the enzyme was found to be the sheddase responsible for E-cadherin release yielding a soluble form that interacts with and stabilizes HER2 and HER3 receptors. This finding may be a first clue of a role for ADAM15 in the development of breast cancer.158 ADAM-17. ADAM-17 or TNF alpha converting enzyme (TACE) is undoubtedly the ADAM that has attracted most research ever since its discovery as the protease responsible for the release of soluble TNFR from cells in 1997.27,28 The shedding of TNFR had already been described earlier and was reported to be inhibited by metalloprotease inhibitors,159,160 but with the identification of ADAM-17 as the principle TNFR sheddase, the first physiological substrate for ADAM-mediated shedding was discovered. TACE is constitutively produced by many cell types as an inactive zymogen with a cysteine switch motif, and is activated by prodomain removal by proprotein convertase proteolysis. The prodomain of ADAM-17 appears to be essential for correct folding of the metalloprotease domain in proADAM-17 and may have a chaperone function in intracellular transport.25 After activation in the late Golgi apparatus, active ADAM-17 may be sequestered in lipid rafts, an observation supported by the increased processing of TNFR after cholesterol depletion and after incubation of ADAM-17 expressing cells with high-density lipoproteins.161,162 One interesting observation is that recombinant soluble ADAM-17 is highly sensitive to NaCl, with complete inhibition at concentrations where no structural or conformational changes in the protein can be detected. This effect has been attributed to disturbance of the electrostatic interaction between protease and substrate, but the physiological relevance
reviews of this phenomenon remains unclear. Perhaps this effect is a safety precaution regulating the proteolytic activity of TACE after its shedding from the cell surface, but experimental proof for this hypothesis is lacking.25 ADAM-17 activity is inhibited by the endogenous metalloprotease inhibitor TIMP-3, but not by TIMP-1, -2 and -4.163 ADAM-17 proteolytic activity is essential during embryonic development. Mice with a targeted deletion lacking the zincbinding region in the catalytic domain are subject to substantial perinatal mortality, an effect that seems independent of decreased TNFR processing. The mice exhibit abnormalities like open eyelids, a missing conjuctival sac and attenuated corneas. Surviving mice display lower body weight due to hypermetabolism,164 epithelial dysgenesis in many tissues, perturbed hair coats caused by disorganization of the hair follicles, and irregular pigmentation.165 ADAM-17 (together with the closely related ADAM-10) is not a typical member of the ADAM family when examining the catalytic domain: the catalytic domain is much longer than in most adamalysins, leading to two unique protuberances in the structure of the catalytic pocket. The S’3 pocket is very deep and merges with the S’1 pocket, and the characteristic Ca2+ binding motif is not found in TACE.166 ADAM-17 sheddase activity is a well-studied phenomenon, with the liberation of soluble TNFR being the first identified substrate. ADAM-17 (as ADAM-10) cleaves proTNF at Ala76Val77 and is the dominant TNFR sheddase, since genetic deletion of the zinc-binding sequence in mice results in monocytes that are incapable of releasing soluble TNFR27. Other ADAMs may compensate for decreased ADAM-17 activity, since ADAM-9, -10, and -19 are capable of processing of proTNF in vitro, but the physiological relevance of these activities seems limited, especially when cells are stimulated.91 ADAM-10 has been postulated to be responsible for the constitutive release of TNFR, while ADAM-17 is the major sheddase after stimulation.90 De novo production of proTNFR in monocytes can be induced with lipopolysaccharide (LPS) but for TNFR release (a measure for enhanced ADAM-17 activity) stimulation by phorbol esters is necessary, indicating a PKCδ-mediated mechanism involving phosphorylation of the cytoplasmic tail of TACE leading to activation or translocation of the enzyme.25 Another study found that the cytoplasmic tail is not necessary for phorbol ester induced TNFR shedding167 contradicting a possible role for intracellular phosphorylation. The effect of phorbol ester stimulation on ADAM-17 mediated shedding is intriguing: shedding is induced within minutes after exposure, but prolonged stimulation results in downregulation of ADAM17 due to internalization of the cell surface bound TACE, a process that appears to be dependent on metalloprotease activity.168 Besides TNFR, ADAM-17 is also capable of shedding soluble TNF receptors p55 and p75 TNF-R.165 Shedding of p55 TNF-R is inducible by hydrogen peroxide.169 ADAM-17 is also implicated in shedding of L-selectin,165 and ADAM-17 colocalizes with L-selectin on the cell surface of neutrophils after interaction with endothelial E-selectin.170 ADAM-17 is probably the main protease responsible for L-selectin shedding in neutrophils due to early death-receptor-mediated apoptosis, but in later stages of controlled cell death alternative enzymes are also able to liberate soluble L-selectin.171 ADAM-17 may function as an R secretase,172 but as with ADAM-9 and -10 the physiological relevance and role in the Journal of Proteome Research • Vol. 10, No. 1, 2011 23
reviews development of Alzheimer’s disease is under debate. There is some additional evidence identifying ADAM-17 as a relevant R secretase, since ADAM-17 activation downstream of muscarinic receptor 1 stimulation has been described to decrease the accumulation of neurotoxic Aβ peptides, a hallmark of R secretase activity.173 The activation pathway of ADAM-17 via muscarinic receptor activation is also implicated in processing of the cellular prion protein.174 The adam17 δZn/δZn mouse model bears striking similarity to a transforming growth factor R (TGFR) deficient phenotype. The role of ADAM-17 in TGFR shedding was confirmed by a strong decrease in soluble TGFR production in the ADAM-17 mutant mice.165 The anatomical abnormalities in heart valves observed in ADAM-17 deficient mice may also arise from decreased shedding of another EGFR ligand, HB-EGF which has also been described as a possible substrate for ADAM-17.175,176 ADAM-17-dependent shedding of TGFR is assumed to play an important role in the pathology of chronic inflammatory airway disease such as chronic bronchitis, COPD and cystic fibrosis.177 Liberation of soluble TGFR leads to mucus hyperproduction via EGF-receptor phosphorylation and overproduction of the MUC5AC mucin, a major constituent of airway mucus. This effect may be linked to cigarette smoke exposure which activates ADAM-17, and upregulates muc5ac gene expression, an observation supported by an apparent correlation of ADAM-17-mediated mucin production with generation of reactive oxygen species via dual oxidase-1 and neutrophil elastase.178-180 Since TNFR is an important proinflammatory mediator, ADAM-17 activity has been implicated in many diseases involving inflammation such as rheumatoid arthritis, Crohn’s disease and inflammatory bowel disorder. An interesting finding is that inhibition of ADAM-17 by conditional knockout has a strong protective effect in endotoxin shock in mice, and significantly reduces mortality. This observation may find use in the clinic where septic shock is still a condition with high mortality.181 ADAM-17 mediated TNFR processing may be important in atherosclerosis, since atherosclerotic plaques express both ADAM-17 and the substrates TNFR and p55 TNF-R. Shedding is stimulated by microparticles, small vesicles that are present in atherosclerotic lesions as a result of cellular apoptosis.182 ADAM-17 expression is upregulated in many tumors.183 ADAM-17 mediated shedding of EGFR ligand, TGFR and amphiregulin may be involved in invasion of breast cancer cells and high expression of both ADAM-17 and TGFR correlates with poor prognosis.184 Experiments with renal carcinoma cells have demonstrated that ADAM-17 may be an essential factor in tumor formation, since cells are unable to form solid tumors and loose their invasive potential after ADAM-17 silencing.185 ADAM-17 (and -10) may be involved in the early steps of malignant transformation and tumor growth. As ADAM-10, ADAM-17 was shown to be a major sheddase of the natural killer cell receptor ligand MICA, thereby inhibiting the immunological clearance of transformed cells.186,187 ADAM-19. Human ADAM-19 or meltrin β was first cloned in 2000 as a disintegrin-metalloprotease involved in 1R,25dihydroxy vitamin D3 induced differentiation in primary monocytes and named MADDAM (metalloprotease and disintegrin dendritic antigen marker). Expression was found to be maintained in monocytes differentiating to dendritic cells, while macrophages do not produce MADDAM.188 The authors also identified the novel protein as a human homologue of the 24
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Klein and Bischoff earlier discovered murine meltrin β (ADAM-19).111,189 ADAM19 is closely related to ADAM-12 (meltrin R) and both proteins appear to be implicated in the development of mesenchymal cells, with ADAM-19 expression observed mainly in areas where peripheral neural cell lineages are formed. ADAM-19 expression is also found in the developing lung, intestine, heart and skeletal muscle, while ADAM-12 gene activity is found mainly in mesenchymal cells giving rise to bone, visceral organs and skeletal muscle.190 Knockout experiments revealed that ADAM19 is essential for heart development with ADAM-19 null mice dying perinatally with severe cardial abnormalities, mainly in the ventricular septum and the heart valves.191 ADAM-19 may exist as an alternative splice variant missing the disintegrin and metalloprotease domain, dubbed meltrin β mini. This isoform is capable of initiating neural outgrowth in mouse neuronal cells, implicating a possible role for this alternative form in the development of the nervous system.192 ADAM-19 is widely expressed in adult mammals, with high expression in bone, lung and heart. ADAM-19 is expressed as an inactive zymogen, which is activated by cleavage of either one of two furin-recognition sites locate between the pro- and metalloprotease domain.193 Indications exist that autoproteolytic truncation of ADAM-19 by cleavage within the cysteinerich domain is necessary for proteolytic activity.194 ADAM-19 is catalytically active and is capable of cleaving R2-macroglobulin in vitro, but was not able to cleave proteins such as type I and IV collagen, gelatin, casein and laminin, nor was cleavage of tested synthetic fluorogenic MMP and TACE substrates observed.195 Later studies using a soluble recombinant ADAM-19 revealed a wide substrate specificity with potential targets for proteolysis including myelin basic protein, insulin B-chain, TNFR, TRANCE (TNF related activation induced cytokine) and kit ligand-1, but not p55 or p75 TNF-R or the IL6-receptor. The proteolytic activity of recombinant ADAM-19 is not inhibited by TIMP-1, -2, and -3. Cell-based shedding assays show increased release of TRANCE (TNF related activation induced cytokine) in COS-7 cells overexpressing ADAM-19 and kit ligand-1 shedding seems to be negatively regulated by ADAM-19.196 The proteolytic activity toward TRANCE, a member of the TNF family, is interesting because TRANCE signaling is associated with dendritic cell survival by inhibiting apoptosis.197 ADAM-19 has been implicated in shedding of neuregulin (NRG) with a preference for the beta-isoform with observed shedding of NRG β1 and β4 but not R2. Shedding of NRGs is in line with the essential role of ADAM-19 in the development of the heart and the central nervous system.198 The sheddase activity of ADAM-19 toward NRG has been attributed to the presence of the protease in lipid rafts within neurons, a localization which is not common for ADAMs, which are mostly membrane-anchored.199 Recently, the NRG-processing activity of ADAM-19 has been demonstrated to occur within the Golgi apparatus and not the cell surface, again hinting at a unique localization of ADAM-19 mediated proteolysis.200 The role of ADAM-19 in the developing heart and the shedding of NRG β is not exclusive and may be compensated for by other members of the ADAM family, as demonstrated in a study investigating the role of individual ADAM proteases. Apparently there is significant redundancy between the individual family members, which may complicate interpretation of results of individual knockout models.201 ADAM-19 has recently been described having R-secretase activity toward APP, since overexpression increased release of the cleaved APP fragment while RNA
Active Metalloproteases of the ADAM Family interference decreased shedding. This may implicate a (partial) role for ADAM-19 in the processing of APP the physiological relevance of which remains to be established.202 High ADAM-19 expression has been associated with the invasive potential of primary brain tumors, with detectable proteolytic activity present on tumors with the highest expression.53 ADAM-19 expression is high in renal cell carcinoma57 and ADAM-19 expression is significantly higher in patients with chronic allograft nephropathy compared to healthy graft recipients, but is also increased in acute rejection and in nonallograft related diseases. Interestingly, ADAM-19 colocalizes with CD4+ T-cells (T-helper cells) indicating a role in the allograft rejection process.203 ADAM-19 may be involved in development of fibrotic lesions in kidney disease. Expression is markedly higher in many renal structures in patients compared to healthy adults, and may be related to the infiltration of macrophages.204 ADAM-20 and -30. These two proteins are interesting with respect to being the only human testis-specific ADAMs that contain the metalloprotease active site sequence. Unfortunately, almost no research has been aimed at elucidating the biological roles of these proteases. ADAM-20 was first described in 1998 and has high sequence similarity to the fertilins (ADAM-1 and -2) and surprisingly, ADAM-9.205 Since mature ADAM-1 loses its metalloprotease domain during processing and is considered nonfunctional in humans, ADAM-20 was hypothesized to be the functional equivalent of ADAM-1. ADAM-30 was cloned in 1999,206 but the publication describing the cDNA sequence remains the only study published to date. Considering the expression pattern these two ADAMs may be functional homologues of the murine testases, although no evidence for this has been published. ADAM-28. ADAM-28 was first described in 1999 as eMDC II207 in human and macaque epididymis, and as MDC-L in human lymphocytes.208 There is some confusion with respect to ADAM-23 and ADAM-28, although there is consensus that they correspond to different forms of the same protein. Why the annotation ADAM-28 is preferred is unclear. ADAM-23 was described as a disintegrin-metalloprotease (MDC-3) without the zinc-binding catalytic site sequence, and thus probably does not have proteolytic activity,209 while ADAM-28 does contain the zinc-binding site. ADAM-28 is expressed as a 115 kDa zymogen that is activated to an 88 kDa mature form that can be detected on the cell surface. A smaller, soluble variant of ADAM-28 has been observed. Interestingly, ADAM-28 lacks the furin recognition site, and may depend on autolytic activation, or activity of other metalloproteases (MMP-7) for prodomain removal.24,210 Purified ADAM-28 has proteolytic activity in vitro and is able to cleave myelin basic protein, but not ECM constituents like collagen I-IV, fibronectin, and laminin. The in vitro substrate specificity seems to overlap largely with ADAM-8 and ADAM15, as demonstrated by screening against a library of synthetic peptides, and ADAM-28 is capable of cleavage of the low affinity IgE receptor CD23.157 The soluble form of ADAM-28 is also capable of in vitro cleavage of insulin-like growth factor binding protein-3.210 ADAM-28 catalytic activity is not inhibited by TIMP1, and only weakly inhibited by TIMP-2.211 ADAM-28 can bind integrin R4β1 by interaction with its disintegrin domain.212,213 The expression of ADAM-28 in the epididymis suggests a role in reproduction. A soluble splice variant was found in mouse epididymus but no functional role could be attributed to this protein in sperm.214 ADAM-28 may have another function in
reviews development of dental tissue due to its expression in developing tooth and appears to be associated with tooth root hypoplasia in patients.215 The mechanism behind this biological effect is postulated to be related to ADAM-28-mediated survival due to induced proliferation of dental papilla mesenchymal cells, while silencing of ADAM-28 results in apoptosis of dental mesenchymal cells.216,217 Some studies have included ADAM-28 in screening experiments for overexpressed proteins in cancer. Expression of ADAM-28 was found to be high in nonsmall cell lung carcinoma and correlated with proliferation and metastasis.218 Serum levels of the soluble variant were found to be elevated making it a possible biomarker for lung cancer.219 ADAM-28 expression in breast cancer is also high and proteolytic activity of ADAM-28 in shedding of IGFBP-3 may contribute to cell proliferation in breast cancer.220 ADAM-33. ADAM-33 was first described in 2002 as a novel disintegrin-metalloprotease in mouse and humans.221 ADAM33 is quite unique within the metzincin family due to the fact that it was already associated with a disease state within 6 months after its discovery even before ADAM-33 was well characterized at the protein level.222 ADAM-33 is widely expressed, except in liver. An interesting structural peculiarity is that ADAM-33 lacks SH3 binding sites in its cytoplasmic domain, which may indicate that the role in intracellular signaling is different than for other ADAMs.221 ADAM-33 is produced as a 123 kDa glycosylated zymogen and may be activated by cleavage of one of three putative furin recognition sites between the pro- and metalloprotease domains resulting in a 100 kDa mature enzyme that can be detected at the cell surface. ADAM-33 contains the zinc-binding metalloprotease active site and recombinant ADAM-33 has been demonstrated to possess proteolytic activity. Soluble ADAM-33 is capable of cleaving R2-macroglobulin.223 The disintegrin domain of recombinant ADAM-33 has affinity toward integrin R9β1, but not R4β1 and R4β7 (implicated in ADAM-28 mediated interaction with lymphocytes),224 but later studies have revealed a possible mechanism for inhibition of cell migration by ADAM-33- mediated interaction with integrins R4β1 and R5β1.225 ADAM-33 has a limited range of in vitro substrate specificity as shown in a screen of synthetic peptides. Only four peptides, based on the putative cleavage sites of kit ligand-1, APP, TRANCE and insulin B-chain were cleaved, while broadly recognized sheddase cleavage sites such as in EGF, HB-EGF, proTNFR, p55 and p75 TNF receptors and TGFR were not hydrolyzed by ADAM-33.226 The cleavage sites of the four recognized peptides are similar to those observed for ADAM19, an observation corroborating the closeness of ADAM-19 and ADAM-33 on the phylogenic tree of ADAMs.221 The catalytic activity of ADAM-33 is quite different from ADAM-17, which can be explained by marked differences in the catalytic pocket as demonstrated by crystallographic resolution of the structures of both proteins.227 Cellular shedding of KL-1 was evaluated by cotransfection of full length ADAM-33 into COS-7 cells. After transfection KL-1 shedding was slightly higher, and transfection of a nonfunctional ADAM-33 mutant slightly decreased KL-1 release. A similar experiment with APP shedding resulted in no increase in soluble RAPP release from the cells, leading to the conclusion that ADAM-33 is not a relevant R secretase in vivo. ADAM-33 activity is inhibited in vitro by TIMP-3 albeit at a much higher concentration than for ADAM-17.226 As expected from the genetic association with asthma, most research efforts involving ADAM-33 have been focused on the Journal of Proteome Research • Vol. 10, No. 1, 2011 25
reviews biological and pathophysiological function in the lung. Pulmonary ADAM-33 expression has been found in cells of mesenchymal origin such as smooth muscle cells and fibroblasts, but expression in epithelial cells has been a matter of debate. Early reports showed no expression in airway epithelium, while the consensus now seems to be that epithelium does indeed produce ADAM-33,46,228 but that expression is sensitive to gene silencing by hypermethylation of the promoter region.228 ADAM-33 is found in smooth muscle tissue and airway epithelium, while its expression in the immune system is limited, which may be an indication that the role of ADAM33 lies more in tissue remodeling than in the allergic component of asthma.229 ADAM-33 may be expressed in a number of isoforms as a result of alternative splicing. Originally ADAM33 was described as having a β-isoform due to a 26 amino acid deletion in the region linking the cysteine-rich to the EGF-like domain,221 but a study investigating the production of ADAM33 isoforms by fibroblasts from a healthy volunteer has revealed that a large number of isoforms may be expressed in fibroblasts, six of which miss the metalloprotease domain. The alternative mRNA sequences are partially translated into protein as demonstrated by Western blot with at least 5 specific bands corresponding to proteins of smaller molecular size. Several of the bands in the 50-60 kDa region are hypothesized to correspond to isoforms lacking the metalloprotease domain, although this hypothesis has not been supported by experimental data.230 Later investigation of different splice variants in biopsies from asthmatic lungs revealed a similar result showing transcripts corresponding to many isoforms, a of which minority retained the metalloprotease domain.231 These findings, combined with the observation that the alternatively spliced ADAM-33β appears to be insensitive to proteolytic activation of the zymogen may indicate a limited role for the catalytic domain in vivo.232 The truncated catalytically active form of ADAM-33 was shown to influence differentiation of endothelial cells and to stimulate neovascularization, a trait that was not observed with the nonactive soluble form.233 The 55 kDa isoform of ADAM-33 has been detected in Bronchoalveolar Lavage (BAL) fluid of patients, and levels were higher in patients with moderate and severe asthma. The level of ADAM-33 correlated inversely with the measured Forced Expiratory Volume in one second (FEV1), which associates ADAM-33 production in the lung with airway obstruction.234 Expression of ADAM-33 in airway smooth muscle cells from asthma patients was found to be higher than in healthy controls and overexpression could be reversed by incubation of the cells with interferon γ.235 Expression of ADAM-33, like that of ADAM-8 was found to increase with disease severity in asthma patients.46 Knockout experiments in mice have demonstrated that ADAM-33 is not essential for development and survival. ADAM33 null mice show no morphological abnormalities and are fertile. Interestingly, the response of knockout mice to allergen sensitization/challenge is normal when compared to wild type animals and pharmacologically induced bronchoconstriction gives a normal response. These results indicate that, at least in the mouse, the role of ADAM-33 in allergic airway disease may be limited, although the model may not correspond exactly to the development of asthma in humans.236 The genetic association of ADAM-33 with asthma and bronchial hyperresponsiveness has been extensively studied, with groups around the world attempting to reproduce the association found in 2002 in other populations. Many groups 26
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Klein and Bischoff do find polymorphisms that are associated with asthma,237-239 while others failed to do so.240,241 There seems to be a rather high heterogeneity in Single Nucleotide Polymorphisms (SNPs) that appear to be responsible for the association, a trait that is observed more often in population-wide genetic screening experiments. Maternal smoking may have a role in ADAM-33 mediated development of asthma, since a genetic interaction between exposure to cigarette smoke in utero and ADAM-33 polymorphisms was demonstrated.242 In recent years, several reviews have been published on this topic summarizing the status of research.243-245 Since the biology of ADAM-33 is not clear to date, interpretation of the effect of individual SNPs on protein function are difficult to assess. In theory both dysfunction of the metalloprotease domain (shedding of EGFR ligand and inflammatory cytokines) and the disintegrin domain (cellular adhesion and migration) are possible causes of smooth muscle remodeling observed in asthma. Evidence points to a minor role of the metalloprotease domain, since most studies have found low levels of metalloprotease domain containing ADAM-33. More research on the biological role of ADAM-33 and elucidation of its endogenous substrate(s) are necessary to explain the genetic association found in many studies. Although almost all research on ADAM-33 has been focused on asthma, there appears to be an association of an ADAM-33 polymorphism in the cytoplasmic domain and the development of chronic obstructive pulmonary disease (COPD) with increased airway hyperresponsiveness and higher infiltration of inflammatory cells.246 Recent studies have also found an association of ADAM-33 with susceptibility to psoriasis, with one study reproducing two out of three SNPs identified in an earlier screening, making a strong case for involvement of ADAM-33 in this disease.247-249
Conclusions Since the discovery of the ADAMs in the mid-1990s, this family of proteins has attracted considerable interest from scientists in many fields of biomedical research. The discovery of ADAM proteolytic activity as the key player in shedding of many biologically active soluble proteins such as cytokines, chemokines and growth factors yielded a multitude of publications describing possible substrates and hypotheses about correlations with pathophysiological states ranging from malignancies to pulmonary diseases and many inflammatory processes. After the initial optimistic outlook on the biological relevance of ADAMs as proteases, several conclusions concerning the interpretation of experimental data with respect to the role of ADAMs in disease have been challenged, the first being that in vitro catalytic activity toward certain substrates may in fact be irrelevant in vivo, especially in the case of membrane anchored substrates and proteases where cellular localization of both species is of essential importance and cannot be mimicked in the test tube. The second observation complicating the determination of single ADAMs as culprits in pathological states is the considerable redundancy in substrate specificity between related ADAMs. This effect may be relevant for TNFR shedding, where both ADAM-17 and ADAM-10 are capable of liberating soluble TNFR opening the possibility of compensation of proteolytic activity if one or the other protease is inhibited or removed. Another field, where this effect was thoroughly investigated relates to the R-secretase activity displayed by ADAM-9, -10, and -17. This issue of redundancy complicates the task of
Active Metalloproteases of the ADAM Family identifying the major players in certain shedding events and may even lead to the conclusion that there is in fact no major player but that other factors depending on the biochemical environment (e.g., localization of enzyme and substrate) are more important than substrate specificity. The ADAMs family is a group of highly interesting proteases, with a wide scope of biological and pathological effects. To fully elucidate the role of proteolytic activity of single members, or groups of closely related ADAMs in health and disease, the current trend of investigating effects of these proteases in more complex cellular systems and at the organism level by using knock-out or knock-down animal models as well as proteolytically inactive variants is a fruitful and necessary step that needs to be undertaken before ADAMs should be considered as therapeutic targets for a variety of disease states. Abbreviations: ADAM, a disintegrin and metalloproteinase; AR, androgen receptor; Aβ, amyloid peptide β; BAL, bronchoalveolary lavage; cDNA, complementary deoxynucleic acid; CHL-1, close homologue of L-1; CNS, central nervous system; COPD, chronic obstructive pulmonary disease; CXCL, chemokine (C-X-C) ligand; DTACE, drosophila TACE homologue; ECM, extracellular matrix; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; HB-EGF, Heparin binding EGF-like growth factor; hCG, human chorionic gonadotropin; HER, human epidermal growth factor receptor; Ig, immunoglobulin; IGFBP, insulin-like growth factor binding proteins; IL, interleukin; KL, kit ligand; L-CAM, liver cell adhesion molecule; LPS, lipopolysaccharide; MADDAM, metalloprotease and disintegrin dendritic antigen marker; MADM, mammalian disintegrin-metalloproteinase; MDC, metalloproteinase-like, disintegrin-like, cysteine-rich proteins; MHC, major histocompatibility complex; MICA, MHC class I-related chain A; MMP, matrix metalloproteinase; MT-MMP, membrane-type matrix metalloproteinase; NRG, neuregulin; PAPP-A, pregnancy-associated plasma protein A; PC, proprotein convertase; PKC, protein kinase; C RAGE, receptor for advance glycation endproducts; RNA, ribonucleic acid; ROS, reactive oxygen species; sADAM, soluble a disintegrin and metalloproteinase; SH, Srchomology 3; SNP, single nucleotide polymorphism; TACE, TNF alpha converting enzyme; TAPI, TNF alpha protease inhibitor; TGF, transforming growth factor; TIMP, tissue inhibitor of metalloproteinases; TNF, tumor necrosis factor; TNF-R, tumor necrosis factor receptor; TRANCE, TNF related activation induced cytokine; VCAM, vascular cell adhesion molecule.
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