| *603639 | |||||||||||||||||||||||||||||||||||||||||||||||||||
| A DISINTEGRIN AND METALLOPROTEINASE DOMAIN 17; ADAM17 | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | |||||||||||||||||||||||||||||||||||||||||||||||||||
| TUMOR NECROSIS FACTOR-ALPHA CONVERTING ENZYME; TACE | |||||||||||||||||||||||||||||||||||||||||||||||||||
| HGNC Approved Gene Symbol: ADAM17 | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Cytogenetic location: 2p25.1 Genomic coordinates (GRCh37): 2:9,629,391 - 9,695,916 (from NCBI) | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Gene Phenotype Relationships | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Cloning | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Black et al. (1997) cloned a human cDNA encoding ADAM17, which they called TACE. The gene encodes an 824-amino acid polypeptide containing the features of the ADAM family: a secretory signal sequence, a disintegrin domain, and a metalloprotease domain. Expression studies showed that the encoded protein cleaves precursor tumor necrosis factor-alpha (TNFA; 191160) to its mature form. Northern blot analysis revealed that the gene was expressed as a 5-kb mRNA in all tissues examined. Black et al. (1997) generated mouse T cells with a homozygous deficiency in the TACE gene; these cells showed an 80 to 90% reduction in the release of TNFA. By screening human leukocyte and monocyte cDNA libraries with DNA fragments from porcine Tace clones, Moss et al. (1997) obtained cDNAs encoding human TACE. Immunoblot analysis showed that TACE is expressed as a 70-kD enzyme that processes TNFA between ala76 and val77 to generate the mature form. Sequence analysis predicted that the proline-rich cytoplasmic tail of TACE has a tyrosine phosphorylation site with the potential to bind the SH3 domain. By differential display RT-PCR between normal and osteoarthritic-affected cartilage, Patel et al. (1998) obtained a full-length cDNA encoding TACE. The deduced transmembrane TACE protein contains a cysteine switch-like region, a catalytic region, a zinc-binding region, and an EGF-like region in addition to the motifs described by Black et al. (1997) and Moss et al. (1997). RT-PCR analysis detected upregulated expression of TACE and TNFA in both rheumatoid- and osteoarthritis-affected cartilage, but not in normal cartilage. | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Mapping | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Yamazaki et al. (1998) used PCR of a backcross panel to map the mouse Tace gene to the proximal arm of chromosome 12. Hirohata et al. (1998) used radiation hybrids to map ADAM17 to human chromosome 2p25. | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Gene Function | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Brou et al. (2000) purified the gamma-secretase-like activity that accounts for the S2 cleavage of NOTCH1 (190198) in vitro and showed that it is due to TACE. Furthermore, experiments on TACE -/- bone marrow-derived monocytic precursor cells suggested that TACE plays a prominent role in the activation of the Notch pathway. Using a yeast 2-hybrid analysis with the cytoplasmic tails of several ADAM proteins as bait, Nelson et al. (1999) found that MAD2L1 (601467) interacts strongly with TACE but not with ADAM9 (602713), which interacts with MAD2L2 (604094), or with other ADAMs tested. Further binding analyses defined a 35-amino acid stretch of TACE containing a proline-rich SH3-ligand domain (PXPXXP) as the interaction site for MAD2L1. Using mouse and human cells and DNA constructs, Garton et al. (2001) provided evidence that TACE is the protease responsible for phorbol ester-stimulated release of membrane-bound fractalkine (CX3CL1; 601880) from the surface of endothelial cells and fibroblasts. TACE was not required for constitutive fractalkine shedding. Fractalkine cleavage did not rely on a specific TACE-sensitive amino acid sequence, but showed relaxed sequence specificity and apparent recognition by TACE of the structure of the juxtamembrane stalk region of membrane-bound fractalkine. Mohan et al. (2002) examined the cleavage of TNFA by native and recombinant ADAM17. In contrast to the more broad specificity reported by others, they found that ADAM17 showed strict specificity for the TNFA cleavage site sequence. They also found that ADAM17 was 100- to 1,000-fold more efficient in TNFA processing than several matrix metalloproteinases. By transfecting double-stranded RNA corresponding to several ADAMs, Asai et al. (2003) determined that the alpha-secretase activity displayed by a human glioblastoma cell line toward amyloid precursor protein (APP; 104760) was catalyzed by the combined activity of ADAM9, ADAM10 (602192), and ADAM17. Chen et al. (2007) found that ADAM10 and ADAM17 mediated shedding of Klotho (KL; 604824) from cell membranes of Klotho-transfected COS-7 cells, a model system they validated by studies in rat kidney slices. Insulin enhanced Klotho shedding, and this effect was abolished by silencing of ADAM10 or ADAM17. Insulin appeared to stimulate ADAM10 and ADAM17 proteolytic activity toward Klotho, but did not increase their mRNA or protein levels. Using immunoprecipitation analysis, Adrain et al. (2012) showed that mouse iRhom2 (RHBDF2; 614404) interacted with mouse Tace in mouse macrophages and transfected human cells. They observed near abolition of serum Tnf in iRhom2 -/- mice and iRhom2 -/- macrophages injected or stimulated with lipopolysaccharide (LPS), respectively. FACS and immunoblot analyses showed increased expression of full-length Tnf on the surface of iRhom2 -/- cells. Inhibition of Tace in wildtype cells produced a similar phenotype. Lack of iRhom2 in macrophages did not affect expression of Tace, but it abolished its activity and interfered with its intracellular trafficking from the endoplasmic reticulum (ER). In iRhom2 -/- cells, Tace became resistant to endoglycosidase H and furin (FUR; 136950) cleavage and failed to reach the trans-Golgi network for activation. Knockdown of IRHOM2 via small interfering RNA in human cells inhibited maturation of endogenous TACE, similar to findings in iRhom2 -/- mice. Database analysis indicated that Tnf signaling upregulates iRhom2 expression, suggesting a positive-feedback loop. Adrain et al. (2012) concluded that IRHOM2 promotes trafficking and activation of TACE. Independently, McIlwain et al. (2012) found that overexpression of a short isoform of mouse iRhom2 protected mouse L929 cells from Tnf-induced apoptosis via metalloprotease-dependent release of Tnf receptors from the cell surface. Immunoblot analysis showed that full-length mouse iRhom2 associated with both the immature and active, mature forms of Tace. iRhom2 -/- macrophages stimulated with LPS showed upregulation of Tace and Tnf mRNA comparable to that in wildtype macrophages. However, iRhom2 -/- macrophages exhibited increased surface Tnf expression and significantly less secreted Tnf protein. Splenocytes and bone marrow-derived macrophages from iRhom2 -/- mice exhibited only immature, but not mature, Tace expression, and Tace was restricted to granular vesicular compartments. | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | |||||||||||||||||||||||||||||||||||||||||||||||||||
| In an affected brother and sister from a consanguineous family of Lebanese origin with neonatal inflammatory skin and bowel disease (NISBD; 614328), Blaydon et al. (2011) performed SNP-homozygosity mapping followed by targeted next-generation sequencing and identified homozygosity for a 4-bp deletion in the ADAM17 gene (603639.0001). | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Animal Model | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Peschon et al. (1998) found that mice lacking the zinc-binding domain of Tace died in utero after embryonic day 17.5 or failed to survive beyond 1 week of age. The lethality was TNF-independent, since mice lacking soluble TNF and its receptors were overtly normal. The eye, hair, and skin phenotype of the mice lacking the zinc-binding domain of Tace resembled that of soluble transforming growth factor-alpha (TGFA; 190170)-deficient mice. Radioimmunoassay analysis determined that shedding of Tgfa from the cell membrane of cells lacking the Tace zinc-binding domain was reduced 95%, suggesting an essential role for soluble TGFA in normal development. In addition, Peschon et al. (1998) found that Tace was essential for shedding of membrane-bound L-selectin (SELL; 153240) and TNFRSF1B (191191), implying a broad range of substrates for TACE. Diwan et al. (2004) compared transgenic mice with targeted cardiac overexpression of secreted wildtype Tnf to transgenic mice with targeted cardiac overexpression of a noncleavable transmembrane form of Tnf. Both lines of mice had overlapping levels of myocardial Tnf protein, but developed strikingly different cardiac phenotypes: the mice overexpressing the transmembrane form of Tnf developed concentric left ventricular hypertrophy, whereas the mice overexpressing secreted Tnf had dilated left ventricular hypertrophy. Diwan et al. (2004) suggested that posttranslational processing of TNF by TACE, as opposed to TNF expression per se, is responsible for the adverse cardiac remodeling that occurs after sustained TNF overexpression. Horiuchi et al. (2007) generated conditional Tace-deficient mice to avoid early postnatal mortality observed in mice lacking Tace. They found that either systemic or myeloid deletion of Tace at 6 weeks offered strong protection from endotoxin shock lethality by preventing increased Tnf serum levels. Horiuchi et al. (2007) concluded that Tace is the major endotoxin-stimulated Tnf sheddase in mouse myeloid cells in vivo and that TACE is a principal target for the treatment of TNF-dependent pathologies, such as rheumatoid arthritis (180300), Crohn disease (see 266600), and psoriasis (see 177900). | |||||||||||||||||||||||||||||||||||||||||||||||||||
| ALLELIC VARIANTS (Selected Examples): | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Table View | |||||||||||||||||||||||||||||||||||||||||||||||||||
| .0001 INFLAMMATORY SKIN AND BOWEL DISEASE, NEONATAL | |||||||||||||||||||||||||||||||||||||||||||||||||||
| ADAM17, 4-BP DEL, 603CAGA | |||||||||||||||||||||||||||||||||||||||||||||||||||
| In an affected brother and sister from a consanguineous family of Lebanese origin with neonatal inflammatory skin and bowel disease (NISBD; 614328), Blaydon et al. (2011) identified a 4-bp deletion (603delCAGA) in exon 5 of the ADAM17 gene, predicted to cause a frameshift and premature truncation with loss of the catalytic and disintegrin domains, transmembrane segment, and cytosolic tail. The unaffected parents were heterozygous for the mutation, which was not found in the unaffected brother. Western blotting of both peripheral-blood mononuclear cells (PBMCs) and keratinocyte lysates from the affected boy showed an absence of ADAM17 expression. In addition, patient PBMCs showed high levels of lipopolysaccharide-induced production of interleukin-1-beta (IL1B; 147720) and interleukin-6 (IL6; 147620), but impaired release of TNF-alpha (191160). | |||||||||||||||||||||||||||||||||||||||||||||||||||
| REFERENCES | |||||||||||||||||||||||||||||||||||||||||||||||||||
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