Disease relevance of Adam17

• Matrix metalloproteinases, tissue inhibitors of MMPs and TACE in experimental cerebral malaria [1].

High impact information on Adam17

• Unchecked TACE activity causes an increase in levels of soluble TNF-alpha, which subsequently promotes diabetes and vascular inflammation [2].
• Several EGFR agonists also stimulated Adam17(-/-) mammary organoid growth in culture, but only AREG was expressed abundantly in the developing ductal system in vivo [3].
• As the transmembrane metalloproteinase ADAM17 can process AREG in culture and Adam17(-/-) mice tend to phenocopy Egfr(-/-) mice, we examined the role of each of these molecules in mammary development [3].
• TNF shedding is mediated by TNF-alpha converting enzyme, which is selectively inhibited by the tissue inhibitor of metalloproteinase 3 (TIMP3) [4].
• Melphalan increased membrane-bound but not secreted TNF in Kupffer cells and inhibited recombinant TNF-alpha converting enzyme in vitro [5].

Biological context of Adam17

• These results indicate that PKCepsilon signal transduction pathways to TPA-stimulated TNFalpha ectodomain shedding are mediated by TACE, a transmembrane metalloprotease [6].
• We accounted for this by proposing that Glu(31), an acidic residue situated at the base of the AB-loop of N-TIMP-3, is drawn into contact with Lys(315), a prominent basic residue adjacent to the TACE catalytic site [7].
• Herein, we have found that TAPI, a synthetic inhibitor of TACE, inhibits embryonic mouse lung branching morphogenesis in culture [8].
• To further investigate the biological significance of TACE as a shedding enzyme during early lung organogenesis, we have devised an antisense oligonucleotide to specifically block endogenous TACE gene expression at both transcriptional and translational levels in embryonic mouse lung explant culture [8].
• Our findings provide evidence that TACE-mediated membrane protein shedding is indispensable for normal lung branching morphogenesis and cytodifferentiation, probably through regulating the availability of positive cytokines/growth factors essential for lung organogenesis such as TGF-alpha [8].

Anatomical context of Adam17

• Using the TNF-alpha converting enzyme (TACE) inhibitor, TAPI-1, TPA-stimulated TNFalpha shedding could be completely prevented in PKCepsilon transgenic mice and isolated keratinocytes [6].
• We conclude that the CD44 sheddase and TACE are distinct enzymes, and that Ab- and phorbol ester-enhanced cleavage of CD44 is controlled in a cell type-dependent fashion by Rho GTPases through the cytoskeleton [9].
• CD44 shedding proceeds normally in fibroblasts and monocytes deficient in TNF-alpha converting enzyme (TACE), a sheddase involved in the processing of several substrates [9].
• Tumour necrosis factor-alpha stimulates expression of TNF-alpha converting enzyme in endothelial cells [10].
• Soluble TGF-alpha, when included in the lung culture, rescued the TACE antisense oligonucleotide-treated lungs from inhibition of both lung branching morphogenesis and lung epithelial cell differentiation, suggesting an impaired release of circulating regulators necessary for lung development in the absence of TACE gene expression [8].

Associations of Adam17 with chemical compounds

• We hypothesized that Marimastat, a broad-spectrum MMP and TNF-alpha converting enzyme (TACE) inhibitor, might modulate this injury through interruption of inflammatory pathways [11].
• Taken together, this study identifies a novel sheddase, ADAM17, for Kitl1 and Kitl2, and demonstrates that ADAM19 can reduce ADAM17-dependent phorbol-ester-stimulated Kitl1 ectodomain shedding [12].

Other interactions of Adam17

• Consistent with the hypothesis that TACE regulates EGF receptor (EGFR) ligand availability in vivo, mice heterozygous for Tace and homozygous for an impaired EGFR allele (wa-2) were born with open eyes significantly more often than Tace(+/+)Egfr(wa-2)(/)(wa-2) counterparts [13].
• This high resolution map rules out candidate genes encoding apolipoprotein B, syndecan 1, and Adam17 [14].
• Reactive oxygen species-dependent TNF-alpha converting enzyme activation through stimulation of 5-HT2B and alpha1D autoreceptors in neuronal cells [15].
• TACE is known to be involved in the proteolytic release of TGF-alpha, an EGF family stimuli critical for lung growth and maturation [8].

References