These associations trigger the tethering and rolling of leukocytes prior to their migration into lymphoid organs and sites of inflammation. Once tethered to the endothelial surface, there is rapid loss of L-selectin from the cell surface via proteolytic cleavage of its extracellular domain. It is possible that there may be effects of metalloprotease inhibitors on the rolling and ultimate transendothelial migration of leukocytes causing the arrest of cells in the endothelial lining Walcheck et al.
Alhough there is at least one case in which metalloprotease inhibitor treatment does not affect neutrophil adherence, rolling, or migration Allport et al. L-selectin shedding does not occur in cells with very low expression levels of ADAM In addition, thymocytes derived from ADAMdeficient mice do not show a reduction in surface L-selectin levels in response to TPA stimulation which has been interpreted as a lack of shedding.
In a number of renal diseases, including mesangial capillary glomerular nephritis, mesangial cells of the renal glomerulus inappropriately migrate through the mesangial matrix into the peri-capillary space. It has not yet been established whether overexpression or hyperactivity of ADAM15 underlies the human pathology.
Fertilization of an egg by a sperm is initiated by the close adhesion of the two cells, and the fusion of their membranes. ADAMs family members play a key role in this initiation of fertilization. Homologous recombination experiments have shown that targeted deletion of ADAM2 which also prevents the presentation of ADAM1 on the cell surface renders male mice infertile Cho et al. Targeted deletion experiments in mice have also shown an obligatory role in fertilization for ADAM3, another family member expressed on the sperm surface Nishimura et al.
Curiously, humans have neither a functional adam1 nor adam3 gene. It is intriguing that several other ADAMs are specifically expressed in the testis Table 1 , although their roles in fertilization have not been explored. Because ADAMs family members have sequences in their cysteine-rich region that resemble those present in viral fusion peptides, it was originally thought that ADAM2 would be required for sperm and egg membrane fusion. However, it was subsequently shown that it is the adhesion step, not fusion, that is defective in these knockout cells. Because ADAM2 is predicted to be proteolytically inactive, and both the prodomain and metalloprotease domain of ADAM2 are cleaved prior to the acquisition of fertilization competence Primakoff et al.
This has been most clearly demonstrated by the use of inhibitory synthetic peptides specific for this domain. Exactly which integrin receptors ADAM2 binds to on the egg surface is still the subject of some controversy.
However, it should be noted that mutation of virtually any amino acid within this region causes some inhibition, so it is likely that there are constraints on the tertiary structure of the entire disintegrin loop that help to maintain the integrity of this domain as an integrin receptor ligand. The integrin receptor to which ADAM2 binds is also still the subject of some debate. One reason for these discrepancies may be in the methodologies used for preparing the eggs for such binding assays. Myoblast cells differentiate align and fuse to form long, multinucleated myotubes during the course of skeletal muscle deposition.
Proteins involved in this developmental transformation include p21 a cyclin-dependent kinase inhibitor that leads to cell cycle arrest and MyoD a basic helix-loop-helix transcription factor that directs the synthesis of muscle-specific genes. ADAM12, in particular, showed a restricted spatial-temporal expression pattern that correlated well with early skeletal muscle development Yagami-Hiromasa et al.
The metalloproteinase ADAM A useful therapeutic target? - ScienceDirect
Most studies testing the role of ADAM12 in myogenesis have used cultured C2C12 myoblasts, which differentiate into myotubes when serum growth factors are removed from the culture medium Yagami-Hiromasa et al. In this system, antisense ADAM12 constructs inhibit myoblast fusion, suggesting a positive role for this protein in myogenesis Yagami-Hiromasa et al. However, overexpression of full-length ADAM12 also inhibits fusion. Because myoblasts often express a form of ADAM12 that lacks the prodomain and metalloprotease domain, the effect of expression of ADAM12 constructs containing a deletion in the metalloprotease domain was also tested.
In this case, myoblast fusion is stimulated two- to threefold Yagami-Hiromasa et al. C2C12 cells treated with the metalloprotease inhibitors TAPI and BB undergo enhanced differentiation concomitant with a block in the processing of myostatin Huet et al. Removal of the metalloprotease domain would prevent the processing of myostatin, and might also release the disintegrin and cysteine-rich domains to interact with cell surface C2C12 myoblast proteins to promote attachment and fusion Zolkiewska It will be important to determine whether, and under what conditions, the metalloprotease domain of ADAM12 might be cleaved.
PI 3-k-inase activity is required for myogenesis. This association appears to trigger an increase in Src activity, as measured in cells cotransfected with ADAM12 and Src. Curiously, the constitutively high kinase activity of the transforming viral Src protein inhibits the fusion of myoblasts to myotubes Falcone et al. Whether the association of cellular Src with ADAM12 would promote or inhibit myoblast fusion is an open question. Transient transfections of the myristylation-tagged, and hence, membrane-bound cytoplasmic tail from ADAM12 blocks fusion of C2C12 myoblasts Galliano et al. Presumably, this construct sequesters proteins that would normally associate with ADAM12, and that are required for myotube formation.
But it is not yet clear which of the proteins described above that associate with the tail of ADAM12 are most important. Members of the metzincin family have been implicated in a variety of human disease processes. For example, tumor cells are known to use matrix metalloproteases to promote their growth and metastasis Chang and Werb Furthermore, mutations of ADAM-TS13 cause thrombotic thrombocytopenic purpura, due to a failure to proteolytically cleave the clotting protein Von Willebrand factor Levy et al.
ADAMs are members of the zinc protease superfamily
In this section, we will discuss briefly other human diseases in which ADAMs have been implicated recently. As we have seen in the previous sections, ADAMs can mediate the shedding of growth factors and regulate the adhesion and motility of cells. Tumor cells frequently produce autocrine growth factors, and are often highly motile and invasive. Is there any evidence for the dysregulation or overexpression of ADAMs in tumors? The data on hand to date are largely correlative. For example, ADAM12 is overexpressed in a number of carcinoma tissues breast and colon and cell lines Wu et al.
ADAM10 is also overexpressed in pheochromocytomas and neuroblastomas Yavari et al. Many tumor cells produce growth factors, and their proliferation independently of exogenous growth factors may contribute to their tumorigenicity. Given the involvement of ADAMs family proteins in the regulated shedding of growth factors from normal cells, it seems reasonable to postulate that they might also be involved in this process in tumor cells.
To date, there have been few direct tests of this hypothesis. PGE2 is mitogenic for gastric epithelial cells and a number of colon cancer cell lines Pai et al.
Because prostaglandin levels are increased in colorectal carcinoma tissue, this pathway may represent an important autocrine mitogenic signal. Given the involvement of ADAMs in migratory processes during development, is it possible that they are involved in the migration of tumor cells? Again, very few direct analyses have been conducted. In the latter two cases, binding to an ADAM substratum stimulated cell migration of the tumor cells. ADAMs may also be able to bind to integrin ligands such as laminin or fibronectin with a similar effect Gilpin et al.
Furthermore, Src family kinases and ADAMs may regulate the shedding of L1 adhesion molecule from breast and ovarian carcinoma cells, potentially regulating their migrational capacity Gutwein et al.
The ADAMs family of metalloproteases: multidomain proteins with multiple functions
Cardiac hypertrophy is an adaptive response of the heart to maintain cardiovascular output during early cardiovascular disease. Vasoactivators like angiotensin II, endothelin-1, and phenylephrine all activate G protein-coupled receptors, leading to cellular responses such as gene activation, protein synthesis, and an increase in cell size Rockman et al.
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A new inhibitor of ADAMs family metalloproteases, KB-R, not only blocks the shedding of HB-EGF and the transactivation of the EGF receptor during vasoactivation of cardiomyocytes, but also shows some beneficial effects when used to treat chronic cardiac hypertrophy in an animal model Asakura et al. When the lung epithelium is exposed to pathogenic bacteria, mucin production occurs. This anti-bacterial response is usually beneficial to the host, although in cystic fibrosis patients in which mucin induction can obstruct air passages, the mucin layer can protect bacteria from antibiotics.
Mucin production is stimulated by the activation of G protein-coupled receptors by bacterial lipoteichoic acid, which, in turn, leads to the shedding of HB-EGF, the activation of an EGF receptor-signaling cascade, and an increase in mucin gene expression. These data suggest that drugs targeting ADAM10 may provide an alternative mechanism to controlling bacterial lung infections. Asthma is characterized by episodes of coughing, wheezing, and breathlessness. Allergen exposure and other environmental factors contribute to the development of asthma, but several studies have also suggested that there is a strong genetic component.
In a very recent study, a genome-wide scan was performed on families, and a locus linked to asthma and bronchial hyper-responsiveness was identified on chromosome 20 Van Eerdewegh et al. Subsequent analysis of polymorphisms in 23 genes in the p13 region of chromosome 20 led to the identification of adam33 as a putative asthma-susceptibility gene. It is expressed in lung fibroblasts and bronchial smooth muscle, and undergoes alternative splicing. Some of the polymorphisms found in the asthma study were in noncoding regions, and may affect splicing or RNA stability.
Others involve the transmembrane and the cytoplasmic domain Van Eerdewegh et al. Further analyses will seek to determine whether changes in ADAM33 activity or expression underlie airway dysfunction. In this review, we have described the involvement of ADAMs in a variety of cellular processes, including processing of proteins, interactions with integrin receptors and with signaling molecules. Figure 3 attempts to summarize much of this information, and shows how ADAMs may play a pivotal role in the transfer of information from the cell to its environment and vice versa.
It is clear that ADAMs family members are positioned to play important roles in development, cell signaling, and disease pathologies.
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But there are many unanswered questions about ADAMs regulation and function, which we will address here. An overview of ADAMs synthesis, processing, and function. Several representative activities of the ADAMs are schematized. Note that not all possible functions of the ADAMs are shown. In addition, as discussed in the text, some of the ADAMs may exert their effects in intracellular membranes.
It is notable that, of the ADAMs expressed outside of the testis, those that are predicted to be proteolytically active usually also contain multiple SH3 domain-binding sites PxxP motifs in their cytoplasmic tails Table 1 ; Fig. Does this observation have a functional significance?