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Review

ADAM-15 Disintegrin-Like Domain Structure and Function

by
Dong Lu
1,2,
Mike Scully
1,
Vijay Kakkar
1 and
Xinjie Lu
1,*
1
Thrombosis Research Institute, Manresa Road, London, SW3 6LR, UK
2
Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK
*
Author to whom correspondence should be addressed.
Toxins 2010, 2(10), 2411-2427; https://doi.org/10.3390/toxins2102411
Submission received: 30 August 2010 / Revised: 13 October 2010 / Accepted: 18 October 2010 / Published: 19 October 2010
(This article belongs to the Special Issue Disintegrins: Structure-Function and Translational Potential)
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Abstract

:
The ADAM (a disintegrin-like and metalloproteinase) proteins are a family of transmembrane cell-surface proteins with important functions in adhesion and proteolytic processing in all animals. Human ADAM-15 is the only member of the ADAM family with the integrin binding motif Arg-Gly-Asp (RGD) in its disintegrin-like domain. This motif is also found in most snake venom disintegrins and other disintegrin-like proteins. This unique RGD motif within ADAM-15 serves as an integrin ligand binding site, through which it plays a pivotal role in interacting with integrin receptors, a large family of heterodimeric transmembrane glycoproteins. This manuscript will present a review of the RGD-containing disintegrin-like domain structures and the structural features responsible for their activity as antagonists of integrin function in relation to the canonical RGD template.

1. Introduction

The “disintegrin” terminology was initially applied in 1990 to describe a family of cysteine-rich, RGD-containing proteins, isolated from the venom of snakes that inhibit platelet aggregation and integrin-mediated cell adhesion [1,2,3]. Subsequently, homologous proteins in which the arginine residue was replaced within the RGD motif including the motifs: KGD [4,5], MGD [6], VGD [7], WGD or MLDG [8,9] were also adopted into the disintegrin family. The RGD sequence is also found in proteins such as decorsin [10] and ornatin [11] from leech toxins, and variabilin [12] from hard tick toxin. The term “disintegrins” was eventually reserved for a particular form of snake venom toxins, and the term “disintegrin-like protein” for RGD proteins with similar properties but different general structures, including the disintegrin-like/cysteine-rich (D/C) domains of the PIII class snake venom metalloproteinases (SVMP) [13,14]; the ADAM (a disintegrin-like and metalloproteinase) [15,16,17,18] and ADAMTS (ADAM with thrombospondin motifs) [19,20]; ADAMTSL (ADAMTS-like) families [21] and MDC (metalloproteinase disintegrin-like cysteine-rich) proteins [22,23]. The primary sequences of disintegrin-like domains in the ADAMs family were homologous to those found in snake venom disintegrins. These proteins constitute one subfamily of the so-called adamalysins, which is a protein family belonging to metzincin superfamily of metalloproteinases. Members of this large and conserved protein family have been isolated from a variety of organisms, including mammals, reptiles and invertebrates. Of the 34 ADAM proteins described including the 19 human ADAMs, human ADAM-15 (also called MDC-15, ADAM metallopeptidase domain 15 or metargidin) is the only ADAM protein with the RGD integrin ligand consensus motif in a position analogous to that found in snake venom disintegrins. The RGD sequence is followed by an additional cysteine residue that is not present in RGD-type snake venom disintegrins and has only been detected in non-RGD-type SVMP and ADAM proteins. In this review, we focus on the disintegrin-like domain in ADAM 15 and its structure and function.

2. Overview of the ADAM-15 Gene Structure

Human ADAM-15 was discovered in a screen for novel ADAMs by PCR [24]. Expression of a disintegrin-like protein had already been observed in cultured human vascular cells and in vivo [25]. ADAM-15 was named metargidin since it carried an RGD sequence in a similar position as snake venom disintegrins (metalloproteinase-RGD-disintegrin protein) [26].
Human ADAM 15 is located at 1q21.3 of chromosome 1, the largest human chromosome, with ~8% of all human genetic information starting at 153,290,386 bp and ending at 153,301,876 bp from the pter (phosphotriesterase related) and reported to have six transcripts and 11,491 bases. Large introns (intron 1, 1183 bp) occur on the 5¢ and 3¢ sides of the gene with a cluster of exons between them (Figure 1) [27].
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Figure 1. Schematic of partial chromosome 1 with ADAM-15 gene indicated by an arrow.
Figure 1. Schematic of partial chromosome 1 with ADAM-15 gene indicated by an arrow.
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The gene for ADAM-15 contains 23 exons varying in size from 63–316 bp and 22 introns ranging between 79–1283 bp [28]. The ADAM-15 protein isoforms deduced have combinations of cytosolic regulatory protein interacting motifs with one or both of the almost identical proline-rich regions encoded by exons 20 and 21, where the residues RxLPxxP are indispensable for nephrocystin SH3 binding [29].
Human ADAM-15 contains a signal peptide sequence (1 to 17 amino acids (aa)) (Figure 2), followed by a pro‑peptide or pro-domain (18–206 aa) thought to function as an intramolecular chaperone (IMC). The pro-domain is cleaved from the metalloproteinase domain by furin [30], a membrane associated endoprotease that cleaves precursor proteins on the C-terminal side of the consensus sequence.
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Figure 2. Domain structures of ADAMs compared to snake venom metalloproteinases (SVMP). Members of the ADAM gene family are classified as membrane-anchored ADAMs containing cysteine-rich domain, cytosolic tail, disintegrin-like domain, epidermal growth factor-like domain, metalloproteinase domain, Pro-peptide domain and transmembrane (TM) domain. SVMP can be classified into four subgroups ((P-I to P-IV). S.P. denotes signal peptide.
Figure 2. Domain structures of ADAMs compared to snake venom metalloproteinases (SVMP). Members of the ADAM gene family are classified as membrane-anchored ADAMs containing cysteine-rich domain, cytosolic tail, disintegrin-like domain, epidermal growth factor-like domain, metalloproteinase domain, Pro-peptide domain and transmembrane (TM) domain. SVMP can be classified into four subgroups ((P-I to P-IV). S.P. denotes signal peptide.
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3. Overview of the Structural Domains of ADAM 15

The pro-domain maintains the metalloproteinase site of ADAM in an inactive state through a cysteine switch [31] similar to that of matrix metalloproteinases (MMPs) and other reprolysins. In this regard, ADAMs, including ADAM-15, are reprolysin-like proteins. The MMPs or matrixins are synthesized as zymogens, which in the case of soluble matrixins are secreted while other members of the family remain bound to the cell surface. The cysteine switch motif in ADAMs may play a role during ADAM biosynthesis. The cysteine residue preferentially coordinates the active site zinc atom sequestering the metalloproteinase domain in an inactive conformation. There are several zinc interacting sites in ADAM-15 (179, 348, 352, 358 aa). Inhibitors of the early secretory pathway block the processing of ADAM-15 and ADAM-9, thus positioning the location of ADAMs processing and activation at the trans-Golgi network [32]. The secondary function of the pro-domain is to chaperone proper folding of the ADAMs, especially the metalloproteinase domain since an ADAM-10 construct lacking the pro‑domain is catalytically inactive in vivo [33].
The metalloproteinase domain of ADAM-15 (207–419 aa) and other ADAMs are well conserved, but only 25 out of 40 ADAMs, including ADAM-15 (348–359 aa) and ADAMs 1, 8–10, 12, 13, 16, 17, 19–21, 24–26, 28, 30, 33–40, have the zinc binding catalytic site consensus sequence HExxHxxGxxHD where x is any amino acid. Three His residues and a water molecule tetrahedrally coordinate the zinc, and the Glu residue acts as a catalytic base [34].
The disintegrin-like domain is downstream of the metalloproteinase domain. The ADAM-15 disintegrin-like domain contains 90 aa (Met420 to Glu510), while in other ADAMs this domain contains 60–90 aa. ADAM-15 and has 15 Cys residues showing sequence similarity to the snake venom disintegrins [35].
The cysteine-rich domain of ADAM-15 (511–656 aa) is thought to regulate cell fusion and may be involved in the activation of latent ADAM-15 and removal of the pro-domain through mechanisms that are not fully elucidated [17,36].
An EGF-like domain (657–685 aa) is downstream of the cysteine-rich domain, named for its similarity to epidermal growth factor (EGF) and other related growth factors and containing six, highly conserved cysteine residues with characteristic spacing [37]. Certain data suggest the EGF-like domain is involved in substrate specificity including substrate cleavage and recognition [38].
ADAM-15 and many others are type I membrane proteins anchored to the surface of the cell through the extracellular domain (207–696 aa), TM domain (697–717 aa) including a putative phosphorylation site (715 aa) and cytoplasmic domain near the C-terminus (718–814 aa). The cytoplasmic domain of ADAM-15 interacts with endophilin I and the sorting nexin 9. In contrast, all the ADAMTSs lack a TM domain and are secreted proteases.
The cytosolic portion (cytoplasmic tail) of ADAM-15 (718–814 aa) and many other ADAMs vary in length (between 40–250 aa) and sequence composition. Similar to other proteolytically active ADAMs, the cytosolic part of ADAM-15 is rich in proline-rich consensus binding sites motif (766–772 aa and 801–806 aa). The cytosolic domain of ADAM-15 is encoded by exons used alternatively in normal tissues giving rise to splice variants with different compositions of putative protein binding motifs [29]. Certain ADAM-15 variants have been associated with poor survival of breast cancer patients [39].
ADAM-15 has another putative phosphorylation site (tyrosine 735 aa) as do many other ADAMs for serine-threonine and/or tyrosine kinases. Phosphorylation of ADAMs may serve to modulate adaptor functions of the protein to assemble complexes of proteins at sites of functional activity.

4. Integrin Interactions of the Disintegrin-Like Domain of ADAM-15

The initial identification of disintegrin-like domains within mammalian ADAMs led to the hypothesis that these regions interact with integrins similar to the related domains in snake venom proteins [17]. There is now considerable evidence that the extracellular domains of ADAMs interact with integrins. Recombinant disintegrin-like domains have been identified with a consensus-binding motif, CRxxxxxCDxxExC, in their disintegrin loops [40]. These interactions influence cell adhesion and cell–cell interactions including those dependent upon the integrins: α2β1, αIIbβ3, α4β1, α4β7, α5β1, α6β1, α6β4, α9β1, αVβ3 and αVβ5 [41,42].

5. Structural Model of the Disintegrin-Like Domains of ADAMs Proteins

The disintegrin-like domain (D-domain), which is located downstream of the metalloprotease domain, consists of 60 to 90 aa with 6 to 15 Cys residues. Most D-domains of ADAMs have an XCD motif with the exception of ADAM-15, which contains the RGD sequence (484–486) [43] similar to the snake venom disintegrins. Snake venom disintegrins are known to be potent inhibitors of various integrins. Snake venom disintegrins usually have a RGD motif that confers the ability to interact with integrins [44]. The disulfide bridge of RGD-containing disintegrins has been evaluated by chemical methods, NMR spectroscopy and crystallography. The most striking feature is the consistency of the disulfide bonds around the RGD sequence leading to the proposal of an “RGD-containing loop” in each protein, which may be important to their potency and selectivity. NMR studies of this loop in snake venom proteins, including kistrin [45,46,47], flavoridin [48], echistatin [49,50,51], albolabrin [52] and dendroaspin [53] along with the crystal structure of trimestatin [54], show that the RGD sequence is presented at the apex of a β-turn. Although the active sequence in most disintegrins is the RGD tripeptide, some members of the family contain other sequences such as KGD, MVD, MLD, VGD, ECD, or MDG (single letter amino acid code) in complimentary positions and have been characterized as integrin-binding motifs [55]. The disintegrin-like domains of ADAMs and the P-III group SVMPs is larger than the RGD-disintegrins, and most of them have an XCD motif (where X is any amino acid) in their disintegrin-like domains, with the exception of ADAM-15 which contains the RGD sequence [56]. P-III group SVMPs comprising the metalloproteinase, disintegrin-like and cysteine‑rich domains belong to the ADAM/adamalysin/reprolysin family [14,57,58,59,60,61]. Several ADAMs share a sequence Rx6DLPE in the D-domain, which can bind avidly to α9β1 e.g., ADAM-1, -2, -12, and -15, whereas ADAM-10 and -17 do not since they lack this motif [56].
In the study of metalloproteinase domain-containing proteins including the active sequence in terms of structure and function, the crystal structure of the entire ectodomain of mature ADAM‑22 [62] reported following the crystallographic studies of two PIII SVMP proteins, VAP1 (vascular apoptosis-inducing protein-1) and VAP2B (vascular apoptosis-inducing protein 2B), proved very useful [63,64]. Overlaying the SVMP structures on ADAM-22 revealed a positional shift in the D-domain and C-domains (the cysteine-rich domain, 530–676 aa) in ADAM-22 relative to the corresponding domains in the SVMPs.
The D-domain that follows the metalloproteinase domain (M-domain) is seen in VAP1 and VAP2B and divided into 2 sub-domains, the “D-shoulder” (Ds) and ‘‘D-arm” (Da) (Figure 3). Both the Ds (residues 396–440) and Da subdomains (residues 441–487) contain calcium-binding sites [64,65,66]. ADAM-22 contains three putative calcium ions, two in the D-domain and one in the M-domain M, metalloproteinase-like domain (residues 233–435). The Ds- and Da subdomains consist of a series of turns and two short regions of antiparallel β-sheet forming a continuous C-shaped structure, which, along with the N-terminal region of the C-domain, forms a “C-wrist” (Cw) segment. The Cw segment is followed by a ‘‘C-hand” (Ch) segment with a hypervariable region (HVR) at its distal portion [65]. These structural features are summarized in the schematic shown in Figure 3. There are three disulfide bonds in the Ds-segment, three in the Da-segment and one in the Cw-segment, and the segments are connected by single disulfide bonds (Figure 3). X-ray studies of atragin, a protein of P-III family of SVMPs, showed one disulfide bond connecting Ds and Da and another disulfide bond connecting Da and Cw comprised of one cystine residue in the disintegrin-like loop (XXCD) that caused it to become inaccessible for integrin-binding as in VAP1 and VAP2 [61].
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Figure 3. Schematic presentations of the MDC domain. (A) and (B) present orthogonal views of the MDC domain of catrocollastatin/VAP2B. The M-domain, linker, Ds, Da, Cw and Ch segments, Zn2+ binding site, and the HVR are shown in yellow, gray, cyan, pink, gray, light green, red and blue, respectively. The GM6001 (an inhibitor) bound to the protein molecule is shown in ball and stick representation and three Ca binding sites are indicated as I-III, adapted with permission [66].
Figure 3. Schematic presentations of the MDC domain. (A) and (B) present orthogonal views of the MDC domain of catrocollastatin/VAP2B. The M-domain, linker, Ds, Da, Cw and Ch segments, Zn2+ binding site, and the HVR are shown in yellow, gray, cyan, pink, gray, light green, red and blue, respectively. The GM6001 (an inhibitor) bound to the protein molecule is shown in ball and stick representation and three Ca binding sites are indicated as I-III, adapted with permission [66].
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6. Disintegrin-Like Domain of ADAM-15: Structure and Function

ADAM-15 has been implicated in cell-cell, cell-matrix interactions and in the proteolysis of molecules on the cell surface or the extracellular matrix [67,68,69,70]. The function of ADAM-15 in cell-cell adhesion has been attributed to the D-domain as integrin ligand [71]. Human ADAM-15 provided interesting insights into analyzing the structure/function of the RGD motif dependent interaction with integrin αVβ3 compared to its RGD-independent association with α9β1 [59]. The study mapped the α9β1-interaction site to a motif RxxxxxxDLPEF (481–492 aa in human ADAM-15 wherein the RGD motif is at 484–486 aa), that is conserved in all ADAMs excepting ADAM-10 and -17 [59].

7. Investigation of the Integrin Interaction Using a Recombinant Disintegrin Domain from ADAM‑15 (ddADAM-15) and Various Mutants

The integrin, α9β1, is widely expressed on smooth muscle and epithelial cells, and mediates adhesion to the extracellular matrix proteins, osteopontin and tenascin-C [72]. We have studied a number of mutants of ddADAM-15 (Figure 4). Recombinant GST-ddADAM-15 and its mutants supported the adhesion of α9β1-transfected CHO cells, which were shown to reach 50% of the maximum number of adherent cells as dd(den)-ADAM-15 > ddADAM-15 > dd(2)-ADAM-15 > dd(12)-ADAM-15 > dd(19)-ADAM-15 > dd(A64)-ADAM-15 [73]. RGD-independent binding of integrin α9β1 to ddADAM-15 mediates cell-cell interactions [71].
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Figure 4. Mutants of disintegrin-like domain of ADAM-15. Sequence alignment of ddADAM-15 and its mutants plotted using CLC protein workbench version 5.2. Numbering is based on the amino acid sequence of ddADAM-15. The dd(A64)-ADAM-15 shows that the R residue in R64GD of ddADAM-15 was replaced by Alanine; dd(12)-ADAM-15 denotes that the disintegrin-like RGD-loop of ADAM-15 was replaced by that of ADAM-12. A similar designation was applied to others. dd(den)-ADAM-15 denotes that the disintegrin-like RGD-loop of ADAM-15 was replaced by that of dendroaspin (den), a disintegrin-like protein [53].
Figure 4. Mutants of disintegrin-like domain of ADAM-15. Sequence alignment of ddADAM-15 and its mutants plotted using CLC protein workbench version 5.2. Numbering is based on the amino acid sequence of ddADAM-15. The dd(A64)-ADAM-15 shows that the R residue in R64GD of ddADAM-15 was replaced by Alanine; dd(12)-ADAM-15 denotes that the disintegrin-like RGD-loop of ADAM-15 was replaced by that of ADAM-12. A similar designation was applied to others. dd(den)-ADAM-15 denotes that the disintegrin-like RGD-loop of ADAM-15 was replaced by that of dendroaspin (den), a disintegrin-like protein [53].
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Inhibition of adhesion of αVβ3 integrin-mediated A375-SM cells (a highly metastatic variant of A375 cells, containing αVβ3 integrin) to fibrinogen, by dd-ADAM-15 and its mutants, is ranked as dd(den)-ADAM-15 > dd(2)-ADAM-15 > ddADAM-15 > dd(12)-ADAM-15 > dd(19)-ADAM-15 > dd(A64)-ADAM-15 [73]. Charrier et al. have reported that overexpression of ADAM-15, containing a mutation in the RGD motif in Caco2-BBE (human intestinal cell line) monolayers, decreases Jurkat cell adhesion, and showing ADAM-15-mediated binding of T cells on intestinal epithelial cells is RGD sequence-dependent [74]. This suggests that the αVβ3 and α5β1 integrins expressed on T lymphocyte membranes are putative binding partners for epithelial ADAM-15. In vitro experiments confirmed that ddADAM-15 interacts with αVβ3 and α5β1 integrins on hematopoietic cells [74], and ADAM-15 interaction with these integrins is RGD-dependent [75]. Mosnier et al. reported that ADAM-15 is upregulated in epi- and endothelial cells in close contact with α5β1-expressing leukocytes, suggesting a role in leukocyte migration [76]. ADAM-15 interacts with αVβ3 and α5β1 integrins, both of which are involved in endothelial cell migration indicating a possible role in atherosclerosis [77,78].
ddADAM-15 is reported to bind via α2β1 to HT1080 (a human fibrosarcoma cell line), but the binding is weaker than with dd(den)-ADAM-15, which showed the highest binding ability for HT1080 cells [73). The order of binding potency for dd recombinant proteins to α4β1-mediated MOLT 4 (human acute lymphoblastic leukemia cell line containing α4β1) cell is demonstrated to be dd(2)-ADAM-15 > dd(19)-ADAM-15 > dd(den)-ADAM-15 = ddADAM-15 > dd(12)-ADAM-15 while dd(A64)-ddADAM-15 showed little/no ability to support cell adhesion compared to its wild-type counterpart. These results suggest that the RGD tripeptide motif may play a role in this binding as dd(A64)-ddADAM-15 failed to bind to this cell line. However, since both dd(den)-ADAM-15 and ddADAM-15 contain the RGD-motif and others do not have the RGD, the difference in potencies emphasizes the importance of the flanking residues in determining potency [73].
Although no inhibition to platelet aggregation was found for dd(2)-ADAM-15, dd(A64)-ADAM-15, dd(19)-ADAM-15 and dd(12)-ADAM-15 with ADP-induced platelet aggregation in platelet-rich plasma, ddADAM-15 showed low activity with a maximum 25% inhibition at 10 μM despite the presence of the RGD motif, which is known to be favored for binding to platelet αIIBβ3[73]. Further, yeast-expressed ddADAM-15 inhibited binding of αIIBβ3 to its biological ligands fibrinogen in a dose‑dependent manner. Mutation of the three residues proximal to the RGD tripeptide sequence, RPTRGD sequence to NWKRGD (named NWK mutant), increased its affinity for αIIBβ3. The NWK mutant had a greater inhibitory action on human platelet aggregation than ddADAM-15 [79], suggesting that flanking amino acid residues are important for activity of the RGD motif.
We have shown that ddADAM-15 can bind to airway smooth muscle cells (ASMCs) and this binding can be modulated by putative disintegrin-like loops within the ddADAM-15 scaffold [80]. This adhesion was mediated by the β1-asociated integrins including α4β1, α5β1, α9β1. Hence, ddADAM-15 can serve as a β1 integrin antagonist as seen by the inhibition of ASMC binding to fibrinogen. ddADAM-15 inhibited PDGF-induced cell migration with the RGD-motif playing a crucial role as shown by the replacement of the putative disintegrin-like loop with those of ADAM-2, -12 and -19. We established that fibrinogen, rather than fibronectin, binding was blocked by ddADAM-15 in a dose-dependent manner in β1-mediated cell binding, implying that ddADAM-15 and fibrinogen share a similar β1 integrin binding site. Such a region may not be involved in fibronectin binding despite the location of an RGD sequence in the tenth type III repeat of fibronectin, which is the major binding sitefor β1 integrin with α5β1 [81,82]. The role of RGD in ddADAM-15 may be limited, as this is the only ADAM family protein containing this sequence. It cannot be ruled out that regions beyond the disintegrin-like loop also play a role in integrin-binding since ddADAM-15 and ddADAM-12, which lacks the RGD-motif can interact with β1-associated α9 integrin [68], and -associated α5 integrin [67] in other cell types.

8. ADAM-15 Is Associated with Diseases

The role of ADAM-15 in diseases appears to involve mechanisms as diverse as cell–cell interactions, cell-extracellular matrix (ECM) interactions and shedding activity. There is growing evidence of links between ADAM-15 and human diseases including cancer and atherosclerosis. It was reported that mRNA and/or protein levels of ADAM-15 are upregulated in multiple adenocarcinomas including cancer of the breast, stomach, lung, pancreas and prostate [83]. Horiuchi et al. reported that a deficiency of ADAM-15 in a mouse model for retinopathy resulted in reduced neovascularization [84]. Consistently, smaller tumors were formed in the ADAM-15-deficient mice after injection with melanoma cells [85]. Yamada et al. demonstrated that pancreatic cancer cells expressed significantly higher levels ADAM-15 mRNA than normal pancreatic epithelial cells [85]. Najy et al. [86] found that downregulation of ADAM-15 in the prostate cancer cell line, PC3 decreased migration and adhesion to specific extracellular matrix proteins. Using breast cancer cell lines, the same authors reported that ADAM-15 cleaved cadherin E after growth factor deprivation [87]. The cleaved cadherin E bound and transactivated HER2/HER3, resulting in increased migration and proliferation. Thus, enhanced HER2/HER3 signaling is a potential mechanism by which ADAM-15 could contribute to cancer progression. Sun et al. recently reported that ADAM-15 regulates endothelial permeability, which is considered as one of the key cellular processes in the development of inflammatory disorders, including atherosclerosis [88,89], diabetic complications [90] and inflammatory bowel disease [76]. In addition to RGD motif which has an ability to disturb integrin-mediated attachment on the cell surface, the RGD peptides are incorporated into cytoplasm and induce apoptosis [91]. Collectively, several RGD-containing proteins from venom toxins induced apoptosis, such as contortrostatin [92], rhodostomin [93] and salmosin [94]. Since these RGD peptides and RGD-containing proteins interact with integrins, the integrins may serve as targets for anti-cancer agents designed using RGD as a template. Several studies have shown the potential for these RGD proteins to function as integrin antagonists as well as antiagiogenic, antimetastatic and antithrombotic compounds leading to drug development for therapeutic usage [95,96,97].

9. Concluding Remarks

The ddADAM-15 selectively modulates integrin-mediated cell adhesion and ASMC migration. The amino acid sequence in the putative disintegrin-like loop plays a crucial role in controlling the selectivity and specificity of the ADAM proteins in their interaction with particular integrins. The RGD-tripeptide in the putative disintegrin-like loop in ADAM-15 serves as an integrin recognition sequence since conversion of RGD into AGD reduced potency, inhibiting A375-SM cell adhesion to fibrinogen mediated by αVβ3, and showed little/no activity inhibiting α4β1-mediated MOLT 4 cell attachment.
Details of conformational changes in the RGD-tri-peptide within ddADAM-15 while interacting with integrins remain unclear. A putative binding model has been constructed based on the 3D structure of integrin αVβ3 in complex, with a cyclic penta-peptide presenting the RGD sequence [98], where the RGD motif of ddADAM-15 is located at 64–66 aa (R64GD66) and fits a crevice between the propeller (α subunit) and βA (β1 subunit) domains on the β1-associated complex headpiece. Conversely, the RGD motif in atragin (538–540 aa according to the sequence number of atragin), located at the end of the η4 helix of the K-like domain, is inaccessible for integrin molecules implying that K-like domains bind to the integrin through a non-RGD region, such as the hypervariable region (HVR) [61,99]. In this review, we have mainly described the RGD-containing D-domain in ADAM-15 interacting with integrins, the non-RGD-containing D-domains in other ADAMs are also reported to associate with integrins, e.g., ADAM-23 can bind to αVβ3[100] and ADAM-28 can interact with α4β1 [101]. However, the structural basis for these associations has yet to be defined. Therefore, further studies are required to analyze ddADAM-15, ADAM-15 and other ADAMs by X-ray crystallography to gain structural information and increase understanding of ADAM-integrin interaction.

Acknowledgements

This work was supported by the Thrombosis Research Trust/Garry Weston Foundation. We thank Usha Narayan for editorial assistance.

References

  1. Gould, R.J.; Polokoff, M.A.; Friedman, P.A.; Huang, T.F.; Holt, J.C.; Cook, J.J.; Niewiarowski, S. Disintegrins: a family of integrin inhibitory proteins from viper venoms. Proc. Soc. Exp. Biol. Med. 1990, 195, 168–171. [Google Scholar]
  2. Niewiarowski, S.; McLane, M.A.; Kloczewiak, M.; Stewart, G.J. Disintegrins and other naturally occurring antagonists of platelet fibrinogen receptors. Semin. Hematol. 1994, 31, 289–300. [Google Scholar]
  3. McLane, M.A.; Sanchez, E.E.; Wong, A.; Paquette-Straub, C.; Perez, J.C. Disintegrins. Curr. Drug Targets Cardiovasc. Haematol. Disord. 2004, 4, 327–355. [Google Scholar] [CrossRef] [PubMed]
  4. Scarborough, R.M.; Rose, J.W.; Hsu, M.A.; Phillips, D.R.; Fried, V.A.; Campbell, A.M.; Nannizzi, L.; Charo, I.F. Barbourin. A GPIIb-IIIa-specific integrin antagonist from the venom of Sistrurus m. barbouri. J. Biol. Chem. 1991, 266, 9359–9362. [Google Scholar] [PubMed]
  5. Oshikawa, K.; Terada, S. Ussuristatin 2, a novel KGD-bearing disintegrin from Agkistrodon ussuriensis venom. J. Biochem. 1999, 125, 31–35. [Google Scholar]
  6. Nikai, T.; Taniguchi, K.; Komori, Y.; Masuda, K.; Fox, J.W.; Sugihara, H. Primary structure and functional characterization of bilitoxin-1, a novel dimeric P-II snake venom metalloproteinase from Agkistrodon bilineatus venom. Arch. Biochem. Biophys. 2000, 378, 6–15. [Google Scholar]
  7. Calvete, J.J.; Fox, J.W.; Agelan, A.; Niewiarowski, S.; Marcinkiewicz, C. The presence of the WGD motif in CC8 heterodimeric disintegrin increases its inhibitory effect on alphaII(b)beta 3, alpha (v)beta3, and alpha5beta1 integrins. Biochemistry 2002, 41, 2014–2021. [Google Scholar]
  8. Siigur, E.; Aaspollu, A.; Tu, A.T.; Siigur, J. cDNA cloning and deduced amino acid sequence of fibrinolytic enzyme (lebetase) from Vipera lebetina snake venom. Biochem. Biophys. Res. Commun. 1996, 224, 229–236. [Google Scholar]
  9. Marcinkiewicz, C.; Calvete, J.J.; Marcinkiewicz, M.M.; Raida, M.; Vijay-Kumar, S.; Huang, Z.; Lobb, R.R.; Niewiarowski, S. EC3, a novel heterodimeric disintegrin from Echis carinatus venom, inhibits alpha4 and alpha5 integrins in an RGD-independent manner. J. Biol. Chem. 1999, 274, 12468–12473. [Google Scholar]
  10. Seymour, J.L.; Henzel, W.J.; Nevins, B.; Stults, J.T.; Lazarus, R.A. Decorsin. A potent glycoprotein IIb-IIIa antagonist and platelet aggregation inhibitor from the leech Macrobdella decora. J. Biol. Chem. 1990, 265, 10143–10147. [Google Scholar] [PubMed]
  11. Mazur, P.; Henzel, W.J.; Seymour, J.L.; Lazarus, R.A. Ornatins: potent glycoprotein IIb-IIIa antagonists and platelet aggregation inhibitors from the leech Placobdella ornata. Eur. J. Biochem. 1991, 202, 1073–1082. [Google Scholar]
  12. Wang, X.; Coons, L.B.; Taylor, D.B.; Stevens, S.E., Jr.; Gartner, T.K. Variabilin, a novel RGD-containing antagonist of glycoprotein IIb-IIIa and platelet aggregation inhibitor from the hard tick Dermacentor variabilis. J. Biol. Chem. 1996, 271, 17785–17790. [Google Scholar]
  13. Bjarnason, J.B.; Fox, J.W. Hemorrhagic metalloproteinases from snake venoms. Pharmacol. Ther. 1994, 62, 325–372. [Google Scholar]
  14. Lu, X.; Lu, D.; Scully, M.F.; Kakkar, V.V. Snake venom metalloproteinase containing a disintegrin-like domain, its structure-activity relationships at interacting with integrins. Curr. Med. Chem. Cardiovasc. Hematol. Agents 2005, 3, 249–260. [Google Scholar]
  15. Weskamp, G.; Blobel, C.P. A family of cellular proteins related to snake venom disintegrins. Proc. Natl. Acad. Sci. USA 1994, 91, 2748–2751. [Google Scholar]
  16. Wolfsberg, T.G.; Primakoff, P.; Myles, D.G.; White, J.M. ADAM, a novel family of membrane proteins containing A Disintegrin and Metalloproteinase domain: multipotential functions in cell-cell and cell-matrix interactions. J. Cell Biol. 1995, 131, 275–278. [Google Scholar]
  17. Wolfsberg, T.G.; Straight, P.D.; Gerena, R.L.; Huovila, A.P.; Primakoff, P.; Myles, D.G.; White, J.M. ADAM, a widely distributed and developmentally regulated gene family encoding membrane proteins with a disintegrin and metalloproteinase domain. Dev. Biol. 1995, 169, 378–383. [Google Scholar]
  18. Wolfsberg, T.G.; White, J.M. ADAMs in fertilization and development. Dev. Biol. 1996, 180, 389–401. [Google Scholar]
  19. Kuno, K.; Kanada, N.; Nakashima, E.; Fujiki, F.; Ichimura, F.; Matsushima, K. Molecular cloning of a gene encoding a new type of metalloproteinase-disintegrin family protein with thrombospondin motifs as an inflammation associated gene. J. Biol. Chem. 1997, 272, 556–562. [Google Scholar]
  20. Tang, B.L.; Hong, W. ADAMTS: a novel family of proteases with an ADAM protease domain and thrombospondin 1 repeats. FEBS Lett. 1999, 445, 223–225. [Google Scholar]
  21. Hirohata, S.; Wang, L.W.; Miyagi, M.; Yan, L.; Seldin, M.F.; Keene, D.R.; Crabb, J.W.; Apte, S.S. Punctin, a novel ADAMTS-like molecule, ADAMTSL-1, in extracellular matrix. J. Biol. Chem. 2002, 277, 12182–12189. [Google Scholar]
  22. Perry, A.C.; Jones, R.; Hall, L. Analysis of transcripts encoding novel members of the mammalian metalloproteinase-like, disintegrin-like, cysteine-rich (MDC) protein family and their expression in reproductive and non-reproductive monkey tissues. Biochem. J. 1995, 312, 239–244. [Google Scholar]
  23. Selistre de Araujo, H.S.; de Souza, D.H.; Ownby, C.L. Analysis of a cDNA sequence encoding a novel member of the snake venom metalloproteinase, disintegrin-like, cysteine-rich (MDC) protein family from Agkistrodon contortrix laticinctus. Biochim. Biophys. Acta 1997, 1342, 109–115. [Google Scholar]
  24. Lum, L.; Reid, M.S.; Blobel, C.P. Intracellular maturation of the mouse metalloproteinase disintegrin MDC15. J. Biol. Chem. 1998, 273, 26236–26247. [Google Scholar]
  25. Herren, B.; Raines, E.; Ross, R. Expression of a disintegrin-like protein in cultured human vascular cells and in vivo. FASEB J. 1997, 11, 173–180. [Google Scholar]
  26. Kratzschmar, J.; Lum, L.; Blobel, C.P. Metargidin, a membrane-anchored metalloproteinase-disintegrin protein with an RGD integrin binding sequence. J. Biol. Chem. 1996, 271, 4593–4596. [Google Scholar]
  27. Kärkkäinen, I.; Karhu, R.; Huovila, A.P. Assignment of the ADAM15 gene to human chromosome band 1q21.3 by in situ hybridization. Cytogenet. Cell Genet. 2000, 88, 206–207. [Google Scholar] [CrossRef] [PubMed]
  28. Kleino, I.; Ortiz, R.M.; Huovila, A.P. ADAM15 gene structure and differential alternative exon use in human tissues. BMC Mol. Biol. 2007, 8, 90–119. [Google Scholar]
  29. Kleino, I.; Ortiz, R.M.; Yritys, M.; Huovila, A.P.; Saksela, K. Alternative splicing of ADAM15 regulates its interactions with cellular SH3 proteins. Cell Biochem. 2009, 108, 877–885. [Google Scholar]
  30. Hurskainen, T.L.; Hirohata, S.; Seldin, M.F.; Apte, S.S. ADAM-TS5, ADAM-TS6, and ADAM-TS7, novel members of a new family of zinc metalloproteinases. General features and genomic distribution of the ADAM-TS family. J. Biol. Chem. 1999, 274, 25555–25563. [Google Scholar] [PubMed]
  31. Becker, J.W.; Marcy, A.I.; Rokosz, L.L.; Axel, M.G.; Burbaum, J.J.; Fitzgerald, P.M.; Cameron, P.M.; Esser, C.K.; Hagmann, W.K.; Hermes, J.D.; Springer, J.P. Stromelysin-1: three-dimensional structure of the inhibited catalytic domain and of the C-truncated proenzyme. Protein Sci. 1995, 4, 1966–1976. [Google Scholar]
  32. Kang, T.; Zhao, Y.G.; Pei, D.; Sucic, J.F.; Sang, Q.X. Intracellular activation of human adamalysin 19/disintegrin and metalloproteinase 19 by furin occurs via one of the two consecutive recognition sites. J. Biol. Chem. 2002, 277, 25583–25592. [Google Scholar]
  33. Anders, A.; Gilbert, S.; Garten, W.; Postina, R.; Fahrenholz, F. Regulation of the alpha-secretase ADAM10 by its prodomain and proprotein convertases. FASEB J. 2001, 15, 1837–1879. [Google Scholar]
  34. Fox, J.W.; Bjarnason, J.B. Zinc Metalloproteinases in Health and Disease; Hooper, N.M., Ed.; Taylor & Francis: Bristol, UK, 1996; pp. 47–81. [Google Scholar]
  35. Marcinkiewicz, C. Functional characteristic of snake venom disintegrins: potential therapeutic implication. Curr. Pharm. Des. 2005, 11, 815–827. [Google Scholar]
  36. Loechel, F.; Gilpin, B.J.; Engvall, E.; Albrechtsen, R.; Wewer, U.M. Human ADAM-12 (meltrin α) is an active metalloproteinase. J. Biol. Chem. 1998, 273, 16993–16997. [Google Scholar]
  37. Wolfsberg, T.G.; Bazan, J.F.; Blobel, C.P.; Myles, D.G.; Primakoff, P.; White, J.M. The precursor region of a protein active in sperm-egg fusion contains a metalloproteinase and a disintegrin domain: structural, functional, and evolutionary implications. Proc. Natl. Acad. Sci. USA 1993, 90, 10783–10787. [Google Scholar]
  38. Smith, K.M.; Gaultier, A.; Cousin, H.; Alfandari, D.; White, J.M.; DeSimone, D.W. The cysteine-rich domain regulates ADAM protease function in vivo. J. Cell Biol. 2002, 159, 893–902. [Google Scholar]
  39. Zhong, J.L.; Poghosyan, Z.; Pennington, C.J.; Scott, X.; Handsley, M.M.; Warn, A.; Gavrilovic, J.; Honert, K.; Krüger, A.; Span, P.N.; et al. Distinct Functions of Natural ADAM-15 Cytoplasmic Domain Variants in Human Mammary Carcinoma. Mol. Cancer Res. 2008, 6, 383–394. [Google Scholar] [CrossRef] [PubMed]
  40. White, J.M.; Bridges, L.C.; DeSimone, D.W.; Tomczuk, M.; Wolfsberg, T.G. Introduction to the ADAM family. In The ADAM Family of Proteases: Proteases in Biology and Disease; Hooper, N.M., Lendeckel, V.D., Eds.; Springer: Dordrecht, The Netherlands, 2005; Volume 4, pp. 1–28. [Google Scholar]
  41. Langer, H.; May, A.E.; Bültmann, A.; Gawaz, M. ADAM 15 is an adhesion receptor for platelet GPIIb-IIIa and induces platelet activation. Thromb. Haemost. 2005, 94, 555–561. [Google Scholar]
  42. Eto, K.; Huet, C.; Tarui, T.; Kupriyanov, S.; Liu, H.Z.; Puzon-McLaughlin, W.; Zhang, X.P.; Sheppard, D.; Engvall, E.; Takada, Y. Functional classification of ADAMs based on a conserved motif for binding to integrin alpha 9beta 1: implications for sperm-egg binding and other cell interactions. J. Biol. Chem. 2002, 277, 17804–17810. [Google Scholar]
  43. Tomczuk, M.; Takahashi, Y.; Huang, J.; Murase, S.; Mistretta, M.; Klaffky, E.; Sutherland, A.; Bolling, L.; Coonrod, S.; Marcinkiewicz, C.; et al. Role of multiple beta1 integrins in cell adhesion to the disintegrin domains of ADAMs 2 and 3. Exp. Cell Res. 2003, 290, 68–81. [Google Scholar] [CrossRef] [PubMed]
  44. Lu, X.; Lu, D.; Scully, M.; Kakkar, V. ADAM proteins - therapeutic potential in cancer. Curr. Cancer Drug Targets 2008, 8, 720–732. [Google Scholar]
  45. Adler, M.; Lazarus, R.A.; Dennis, M.S.; Wagner, G. Solution structure of kistrin, a potent platelet aggregation inhibitor and GP IIb-IIIa antagonist. Science 1991, 253, 445–448. [Google Scholar]
  46. Adler, M.; Wagner, G. Sequential 1H NMR assignments of kistrin, a potent platelet aggregation inhibitor and glycoprotein IIb-IIIa antagonist. Biochemistry 1992, 31, 1031–1039. [Google Scholar]
  47. Adler, M.; Carter, P.; Lazarus, R.A.; Wagner, G. Cysteine pairing in the glycoprotein IIb-IIIa antagonist kistrin using NMR, chemical analysis, and structure calculations. Biochemistry 1993, 32, 282–289. [Google Scholar]
  48. Senn, H.; Klaus, W. The nuclear magnetic resonance solution structure of flavoridin, an antagonist of the platelet GP IIb-IIIa receptor. J. Mol. Biol. 1993, 232, 907–925. [Google Scholar] [CrossRef] [PubMed]
  49. Saudek, V.; Atkinson, R.A.; Lepage, P.; Pelton, J.T. The secondary structure of echistatin from 1H-NMR, circular-dichroism and Raman spectroscopy. Eur. J. Biochem. 1991, 202, 329–338. [Google Scholar]
  50. Cooke, R.M.; Carter, B.G.; Martin, D.M.A.; Murray-Rust, P.; Weir, M.P. Nuclear magnetic resonance studies of the snake toxin echistatin. 1H resonance assignments and secondary structure. Eur. J. Biochem. 1991, 202, 323–328. [Google Scholar] [CrossRef] [PubMed]
  51. Cooke, R.M.; Carter, B.G.; Murray-Rust, P.; Hartshorn, M.J.; Herzyk, P.; Hubbard, R.E. The solution structure of echistatin: evidence for disulphide bond rearrangement in homologous snake toxins. Protein Eng. 1992, 5, 473–477. [Google Scholar]
  52. Jaseja, M.; Smith, K.J.; Lu, X.; Williams, J.A.; Trayer, H.; Trayer, I.P.; Hyde, E.I. 1H-NMR studies and secondary structure of the RGD-containing snake toxin, albolabrin. Eur. J. Biochem. 1993, 218, 853–860. [Google Scholar] [CrossRef] [PubMed]
  53. Jaseja, M.; Lu, X.; Williams, J.A.; Sutcliffe, M.J.; Kakkar, V.V.; Parslow, R.A.; Hyde, E.I. 1H-NMR assignments and secondary structure of dendroaspin, an RGD-containing glycoprotein IIb-IIIa (alpha IIb-beta 3) antagonist with a neurotoxin fold. Eur. J. Biochem. 1994, 226, 861–868. [Google Scholar]
  54. Fujii, Y.; Okuda, D.; Fujimoto, Z.; Horii, K.; Morita, T.; Mizuno, H. Crystal structure of trimestatin, a disintegrin containing a cell adhesion recognition motif RGD. J. Mol. Biol. 2003, 332, 1115–1122. [Google Scholar]
  55. McLane, M.A.; Marcinkiewicz, C.; Vijay-Kumar, S.; Wierzbicka-Patynowski, I.; Niewiarowski, S. Viper venom disintegrins and related molecules. Proc. Soc. Exp. Biol. Med. 1998, 219, 109–119. [Google Scholar]
  56. Lu, X.; Lu, D.; Scully, M.F.; Kakkar, V.V. Structure-activity relationship studies on ADAM protein-integrin interactions. Cardiovasc. Hematol. Agents Med. Chem. 2007, 5, 29–42. [Google Scholar]
  57. Gomis-Ruth, F.X. Structural aspects of the metzincin clan of metalloendopeptidases. Mol. Biotechnol. 2003, 24, 157–202. [Google Scholar]
  58. White, J.M. ADAMs: modulators of cell–cell and cel–matrix interactions. Curr. Opin. Cell Biol. 2003, 15, 598–606. [Google Scholar]
  59. Terra, R.M.; Pinto, A.F.; Guimarães, J.A.; Fox, J.W. Proteomic profiling of snake venom metalloproteinases (SVMPs): insights into venom induced pathology. Toxicon 2009, 54, 836–844. [Google Scholar]
  60. Baldo, C.; Tanjoni, I.; León, I.R.; Batista, I.F.; Della-Casa, M.S.; Clissa, P.B.; Weinlich, R.; Lopes-Ferreira, M.; Lebrun, I.; Amarante-Mendes, G.P.; et al. BnP1, a novel P-I metalloproteinase from Bothrops neuwiedi venom: biological effects benchmarking relatively to jararhagin, a P-III SVMP. Toxicon 2008, 51, 54–65. [Google Scholar] [PubMed]
  61. Guan, H.H.; Goh, K.S.; Davamani, F.; Wu, P.L.; Huang, Y.W.; Jeyakanthan, J.; Wu, W.G.; Chen, C.J. Structures of two elapid snake venom metalloproteases with distinct activities highlight the disulfide patterns in the D domain of ADAMalysin family proteins. J. Struct. Biol. 2010, 169, 294–303. [Google Scholar]
  62. Liu, H.; Shim, A.H.; He, X. Structural characterization of the ectodomain of a disintegrin and metalloproteinase-22 (ADAM22), a neural adhesion receptor instead of metalloproteinase: insights on ADAM function. J. Biol. Chem. 2009, 284, 29077–29086. [Google Scholar]
  63. Takeda, S.; Igarashi, T.; Mori, H.; Araki, S. Crystal structures of VAP1 reveal ADAMs’ MDC domain architecture and its unique C-shaped scaffold. EMBO J. 2006, 25, 2388–2396. [Google Scholar]
  64. Igarashi, T.; Araki, S.; Mori, H.; Takeda, S. Crystal structures of catrocollastatin/VAP2B reveal a dynamic, modular architecture of ADAM/adamalysin/reprolysin family proteins. FEBS Lett. 2007, 581, 2416–2422. [Google Scholar]
  65. Takeda, S. VAP1: snake venom homolog of mammalian ADAMs. In Handbook of Metalloproteins; Messerschmidt, A., Ed.; John Wiley & Sons, Inc.: Somerset, NJ, USA, 2008. [Google Scholar]
  66. Takeda, S. Three-dimensional domain architecture of the ADAM family proteinases. Semin. Cell Dev. Biol. 2009, 20, 146–152. [Google Scholar]
  67. Nath, D.; Slocombe, P.M.; Stephens, P.E.; Warn, A.; Hutchinson, G.R.; Yamada, K.M.; Docherty, A.J.; Murphy, G. Interaction of metargidin (ADAM-15) with alphavbeta3 and alpha5beta1 integrins on different haemopoietic cells. J. Cell Sci. 1999, 112, 579–587. [Google Scholar]
  68. Eto, K.; Puzon-McLaughlin, W.; Sheppard, D.; Sehara-Fujisawa, A.; Zhang, X.P.; Takada, Y. RGD-independent binding of integrin alpha9beta1 to the ADAM-12 and -15 disintegrin domains mediates cell-cell interaction. J. Biol. Chem. 2000, 275, 34922–34930. [Google Scholar]
  69. Fourie, A.M.; Coles, F.; Moreno, V.; Karlsson, L. Catalytic activity of ADAM8, ADAM15, and MDC-L (ADAM28) on synthetic peptide substrates and in ectodomain cleavage of CD23. J. Biol. Chem. 2003, 278, 30469–30477. [Google Scholar]
  70. Seals, D.F.; Courtneidge, S.A. The ADAMs family of metalloproteinases: multidomain proteins with multiple functions. Genes Dev. 2003, 17, 7–30. [Google Scholar]
  71. Taooka, Y.; Chen, J.; Yednock, T.; Sheppard, D. The integrin alpha9beta1 mediates adhesion to activated endothelial cells and transendothelial neutrophil migration through interaction with vascular cell adhesion molecule-1. J. Cell Biol. 1999, 145, 413–420. [Google Scholar]
  72. Kanayama, M.; Kurotaki, D.; Morimoto, J.; Asano, T.; Matsui, Y.; Nakayama, Y.; Saito, Y.; Ito, K.; Kimura, C.; Iwasaki, N.; et al. Alpha9 integrin and Its Ligands Constitute Critical Joint Microenvironments for Development of Autoimmune Arthritis. J. Immunol. 2009, 182, 8015–8025. [Google Scholar] [CrossRef] [PubMed]
  73. Lu, D.; Chung, K.F.; Xia, M.; Lu, X.; Scully, M.; Kakkar, V. Integrin binding characteristics of the disintegrin-like domain of ADAM-15. Thromb. Haemost. 2006, 96, 642–651. [Google Scholar]
  74. Charrier, L.; Yan, Y.; Nguyen, H.T.; Dalmasso, G.; Laboisse, C.L.; Gewirtz, A.T.; Sitaraman, S.V.; Merlin, D. ADAM-15/metargidin mediates homotypic aggregation of human T lymphocytes and heterotypic interactions of T lymphocytes with intestinal epithelial cells. J. Biol. Chem. 2007, 282, 16948–16958. [Google Scholar]
  75. Zhang, X.P.; Kamata, T.; Yokoyama, K.; Puzon-McLaughlin, W.; Takada, Y. Specific interaction of the recombinant disintegrin-like domain of MDC-15 (metargidin, ADAM-15) with integrin alphavbeta3. J. Biol. Chem. 1998, 273, 7345–7350. [Google Scholar]
  76. Mosnier, J.F.; Jarry, A.; Bou-Hanna, C.; Denis, M.G.; Merlin, D.; Laboisse, C.L. ADAM15 upregulation and interaction with multiple binding partners in inflammatory bowel disease. Lab. Invest. 2006, 86, 1064–1073. [Google Scholar]
  77. Eliceiri, B.P.; Cheresh, D.A. Role of alpha v integrins during angiogenesis. Cancer J. 2000, 3, S245–S249. [Google Scholar]
  78. Kim, J.B.; Islam, S.; Kim, Y.J.; Prudoff, R.S.; Sass, K.M.; Wheelock, M.J.; Johnson, K.R. N-Cadherin extracellular repeat 4 mediates epithelial to mesenchymal transition and increased motility. J. Cell Biol. 2000, 151, 1193–1206. [Google Scholar]
  79. Jeon, O.H.; Kim, D.; Choi, Y.J.; Kim, S.H.; Choi, W.S.; Kim, D.S. Novel function of human ADAM15 disintegrin-like domain and its derivatives in platelet aggregation. Thromb. Res. 2007, 119, 609–619. [Google Scholar]
  80. Lu, D.; Xie, S.; Sukkar, M.B.; Lu, X.; Scully, M.F.; Chung, K.F. Inhibition of airway smooth muscle adhesion and migration by the disintegrin domain of ADAM-15. Am. J. Respir. Cell Mol. Biol. 2007, 37, 494–500. [Google Scholar]
  81. Pierschbacher, M.D.; Ruoslahti, E. Variants of the cell recognition site of fibronectin that retain attachment-promoting activity. Proc. Natl. Acad. Sci. USA 1984, 81, 5985–5988. [Google Scholar]
  82. Mould, A.P.; Burrows, L.; Humphries, M.J. Identification of amino acid residues that form part of the ligand-binding pocket of integrin alpha5 beta1. J. Biol. Chem. 1998, 273, 25664–25672. [Google Scholar]
  83. Murphy, G. The ADAMs: Signalling scissors in the tumour microenvironment. Nat. Rev. Cancer 2008, 8, 929–941. [Google Scholar]
  84. Horiuchi, K,; Weskamp, G.; Lum, L.; Hammes, H.P.; Cai, H.; Brodie, T.A.; Ludwig, T.; Chiusaroli, R.; Baron, R.; Preissner, K.T.; et al. Potential role for ADAM15 in pathological neovascularization in mice. Mol. Cell Biol. 2003, 23, 5614–5624. [Google Scholar] [CrossRef] [PubMed]
  85. Yamada, D.; Ohuchida, K.; Mizumoto, K.; Ohhashi, S.; Yu, J.; Egami, T.; Fujita, H.; Nagai, E.; Tanaka, M. Increased expression of ADAM 9 and ADAM 15 mRNA in pancreatic cancer. Anticancer Res. 2007, 27, 793–799. [Google Scholar]
  86. Najy, A.J.; Day, K.C.; Day, M.L. ADAM15 supports prostate cancer metastasis by modulating tumor cell-endothelial cell interaction. Cancer Res. 2008, 68, 1092–1099. [Google Scholar]
  87. Najy, A.J.; Day, K.C.; Day, M.L. The ectodomain shedding of E-cadherin by ADAM15 supports ErbB receptor activation. J. Biol. Chem. 2008, 283, 18393–18401. [Google Scholar]
  88. Ross, R. Atherosclerosis-an inflammatory disease. N. Engl. J. Med. 1999, 340, 115–126. [Google Scholar]
  89. Herren, B.; Raines, E.W.; Ross, R. Expression of a disintegrin-like protein in cultured human vascular cells and in vivo. FASEB J. 1997, 11, 173–180. [Google Scholar]
  90. Yuan, S.Y.; Ustinova, E.E.; Wu, M.H.; Tinsley, J.H.; Xu, W.; Korompai, F.L.; Taulman, A.C. Protein kinase C activation contributes to microvascular barrier dysfunction in the heart at early stages of diabetes. Circ. Res. 2000, 87, 412–417. [Google Scholar]
  91. Matsuki, K.; Sasho, T.; Nakagawa, K.; Tahara, M.; Sugioka, K.; Ochiai, N.; Ogino, S.; Wada, Y.; Moriya, H. RGD peptide-induced cell death of chondrocytes and synovial cells. J. Orthop. Sci. 2008, 13, 524–532. [Google Scholar]
  92. Zhou, Q.; Nakada, M.T.; Arnold, C.; Shieh, K.Y.; Markland, F.S., Jr. Contortrostatin, a dimeric disintegrin from Agkistrodon contortrix contortrix, inhibits angiogenesis. Angiogenesis 1999, 3, 259–269. [Google Scholar]
  93. Wu, W.B.; Peng, H.C.; Huang, T.F. Disintegrin causes proteolysis of beta-catenin and apoptosis of endothelial cells. Involvement of cellcell and cell-ECM interactions in regulating cell viability. Exp. Cell Res. 2003, 286, 115–127. [Google Scholar] [CrossRef] [PubMed]
  94. Chung, K.H.; Kim, S.H.; Han, K.Y.; Sohn, Y.D.; Chang, S.I.; Baek, K.H.; Jang, Y.; Kim, D.S.; Kang, I.C. Inhibitory effect of salmosin, a Korean snake venom-derived disintegrin, on the integrin alphav-mediated proliferation of SK-Mel-2 human melanoma cells. J. Pharm. Pharmacol. 2003, 55, 1577–1582. [Google Scholar]
  95. Kerr, J.S.; Slee, A.M.; Mousa, S.A. The alpha v integrin antagonists as novel anticancer agents: an update. Expert Opin. Investig. Drugs 2002, 11, 1765–1774. [Google Scholar]
  96. Hallahan, D.E.; Qu, S.; Geng, L.; Cmelak, A.; Chakravarthy, A.; Martin, W.; Scarfone, C.; Giorgio, T. Radiation-mediated control of drug delivery. Am. J. Clin. Oncol. 2001, 24, 473–480. [Google Scholar]
  97. Coller, B.S. Anti-GPIIb/IIIa drugs: current strategies and future directions. Thromb. Haemost. 2001, 86, 427–443. [Google Scholar]
  98. Xiao, T.; Takagi, J.; Coller, B.S.; Wang, J.H.; Springer, T.A. Structural basis for allostery in integrins and binding to fibrinogen-mimetic therapeutics. Nature 2004, 432, 59–67. [Google Scholar]
  99. Pinto, A.F.; Terra, R.M.; Guimaraes, J.A.; Fox, J.W. Mapping von Willebrand factor A domain binding sites on a snake venom metalloproteinase cysteinerich domain. Arch. Biochem. Biophys. 2007, 457, 41–46. [Google Scholar]
  100. Cal, S.; Freije, J.M.; López, J.M.; Takada, Y.; López-Otín, C. ADAM 23/MDC3, a human disintegrin that promotes cell adhesion via interaction with the alphavbeta3 integrin through an RGD-independent mechanism. Mol. Biol. Cell 2000, 11, 1457–1469. [Google Scholar]
  101. Bridges, L.C.; Tani, P.H.; Hanson, K.R.; Roberts, C.M.; Judkins, M.B.; Bowditch, R.D. The lymphocyte metalloprotease MDC-L (ADAM 28) is a ligand for the integrin α4β1. J. Biol. Chem. 2002, 277, 3784–3792. [Google Scholar]

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Lu, D.; Scully, M.; Kakkar, V.; Lu, X. ADAM-15 Disintegrin-Like Domain Structure and Function. Toxins 2010, 2, 2411-2427. https://doi.org/10.3390/toxins2102411

AMA Style

Lu D, Scully M, Kakkar V, Lu X. ADAM-15 Disintegrin-Like Domain Structure and Function. Toxins. 2010; 2(10):2411-2427. https://doi.org/10.3390/toxins2102411

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Lu, Dong, Mike Scully, Vijay Kakkar, and Xinjie Lu. 2010. "ADAM-15 Disintegrin-Like Domain Structure and Function" Toxins 2, no. 10: 2411-2427. https://doi.org/10.3390/toxins2102411

APA Style

Lu, D., Scully, M., Kakkar, V., & Lu, X. (2010). ADAM-15 Disintegrin-Like Domain Structure and Function. Toxins, 2(10), 2411-2427. https://doi.org/10.3390/toxins2102411

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