Disease relevance of ADAM17

• Western blot, flow cytometry, and confocal microscopy analyses showed the aberrant expression of ADAM17/TACE protein in pancreatic cancer cell lines [1].
• To understand the role of ADAM17/tumor necrosis factor-alpha (TNF-alpha) converting enzyme (TACE) in pancreatic ductal adenocarcinoma (PDAC), we investigated its expression, function, and in vitro regulation [1].
• Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2) [2].
• The quantities of ADAM17 mRNA were significantly higher in poorly differentiated HCC than in well or moderately differentiated HCC, but no statistical difference was found concerning liver cirrhosis, tumor capsule formation or microvascular invasion of the cancer [3].
• ADAM17/TACE mRNA was expressed in 3 of 10 normal pancreatic tissues, 6 of 8 samples from patients with chronic pancreatitis, 10 of 10 PDAC tissues, and 9 of 9 pancreatic cancer cell lines, but it was absent in primary duct epithelial cells [1].
• Using Western blotting, ADAM-17 protein in breast cancer was shown to exist in two forms migrating with approximate molecular masses of 100 and 120 kDa [4].

Psychiatry related information on ADAM17

• While the amyloidogenic processing of APP in neurons is linked to the pathogenesis of Alzheimer's disease (AD), the expression of TACE in neurons has not yet been examined [5].

High impact information on ADAM17

• Structural comparisons with other disintegrin-containing enzymes indicate that TACE is unique, with noteable sequence identity to MADM, an enzyme implicated in myelin degradation, and to KUZ, a Drosophila homologue of MADM important for neuronal development [6].
• A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE [7].
• Targeting TACE-dependent EGFR ligand shedding in breast cancer [8].
• Using existing patient outcome data, we demonstrated a strong correlation between TACE and TGFA expression in human breast cancers that was predictive of poor prognosis [8].
• We show that TACE-dependent ligand shedding was prevalent in a series of additional breast cancer cell lines and, in all cases examined, was amenable to inhibition [8].

Chemical compound and disease context of ADAM17

• These results suggest that an inverse expression pattern of ADAM-17/TACE and TIMP-3, and the regulation of ADAMs with DHT might play an important role in the pathogenesis of prostate cancer [9].
• ADAM17 mediates epidermal growth factor receptor transactivation and vascular smooth muscle cell hypertrophy induced by angiotensin II [10].
• METHODS AND RESULTS: To identify the metalloprotease required for Ang II-induced EGFR transactivation, primary cultured aortic VSMCs were infected with retrovirus encoding dominant negative (dn) mutant of ADAM10 or ADAM17 [11].
• ADAM17 Mediates Epidermal Growth Factor Receptor Transactivation and Vascular Smooth Muscle Cell Hypertrophy Induced by Angiotensin II [11].
• To examine this hypothesis, we stimulated NCI-H292 cells with phorbol 12-myristate 13-acetate (PMA, an activator of TACE) and pathophysiologic stimuli [lipopolysaccharide (LPS) and supernatant from the Gram-negative bacterium Pseudomonas aeruginosa (PA sup)] [12].

Biological context of ADAM17

• Since loss of cell adhesion is an early event in tumor development, these results suggest that ADAM17 is a useful target in anticancer therapy [13].
• By screening a library of synthetic peptides as potential substrates, we show that soluble recombinant forms of these enzymes have similar proteolytic substrate specificity, clearly distinct from that of ADAM17 (TNFalpha-converting enzyme) [14].
• These results demonstrate that GPV is cleaved upon agonist-induced platelet activation and show that ADAM17 is the major enzyme mediating this process [15].
• Transfection analysis allowed us to further establish that the pro-hormone convertase 7 and ADAM10 but not ADAM17 (TACE, tumour necrosis factor alpha-converting enzyme) likely contribute to constitutive sAPPalpha secretion by LoVo cells [16].
• Chromosomal mapping places TACE/ADAM17 on mouse chromosome 12 and human chromosome 2p25 [17].

Anatomical context of ADAM17

• The constitutive shedding of CXCL16 from the endothelial cell surface is blocked by inhibitors of ADAM10 and is independent of additional inhibition of ADAM17 [18].
• We found that the ADAM2 and 15 disintegrin domains bound to oocytes, but the ADAM17 disintegrin domain did not [19].
• In addition, ADAM17 emerged as the major sheddase for neuregulins beta1 and beta2 in mouse embryonic fibroblasts [20].
• In this comparative study of ADAM9, ADAM10, and ADAM17, we examined the physiological role of ADAMs by expressing these ADAMs in COS-7 cells, and both "constitutive" and "regulated" alpha-secretase activities of these ADAMs were determined [21].
• ADAM17 but not ADAM10 mediates tumor necrosis factor-alpha and L-selectin shedding from leukocyte membranes [22].

Associations of ADAM17 with chemical compounds

• This shedding was inhibited by the broad range metalloproteinase inhibitor GM6001, the two potent ADAM17 inhibitors GW280264X and TAPI-2, and was absent in mice lacking functional ADAM17 (ADAM17 lacking Zn-binding domain; ADAM17(DeltaZn/DeltaZn)) [15].
• Evidence for a role of ADAM17 (TACE) in the regulation of platelet glycoprotein V [15].
• The role of ADAM10 and ADAM17 in the ectodomain shedding of angiotensin converting enzyme and the amyloid precursor protein [23].
• TACE shows the presence of an unknown prodomain, a cysteine switch, a catalytic domain, a zinc binding region, a disintegrin region, an EGF-like domain, a transmembrane domain, and a unique cytoplasmic region [24].
• Mutagenesis carried out on leucine 100 also upholds our previous findings that a leucine on the EF-loop is critical for TACE recognition [25].

Physical interactions of ADAM17

• TACE/ADAM17 is a member of the adamalysin class of zinc-binding metalloproteases or ADAM (a disintegrin and metalloprotease) [17].
• Also, mutations in the core of the MMP interaction surface of N-TIMP-3 dramatically reduce the binding affinity for MMPs but have little effect on the inhibitory activity for TACE [26].
• Identification of SAP97 as an intracellular binding partner of TACE [27].

Enzymatic interactions of ADAM17

• TNF-alpha-converting enzyme (TACE) cleaves pro-TGF-alpha into soluble TGF-alpha and can be activated by ROS [28].
• TNF-alpha-converting enzyme (TACE) is known to cleave TNF at the Ala-76-Val-77 site [29].
• The tumor necrosis factor (TNF)-alpha converting enzyme (TACE) can cleave the cell-surface ectodomain of the amyloid-beta precursor protein (APP), thus decreasing the generation of amyloid-beta (Abeta) by cultured non-neuronal cells [5].
• Here, we report that during its transport through the Golgi apparatus, ADAM17 is included in cholesterol-rich membrane microdomains (lipid rafts) where its prodomain is cleaved by furin [30].
• Additional studies implicated TGF-alpha as the active EGFR ligand cleaved by TACE during wound repair [31].

Regulatory relationships of ADAM17

• Taken together, these data provided direct evidence for the involvement of ADAM17 in the regulated ectodomain shedding of ACE2 [2].
• Furthermore, ADAM17/TACE mRNA expression was down-regulated in pancreatic cancer cells arrested in G(2)-M phase as well as in a time-dependent manner after TNF-alpha and interleukin-6 incubation [1].
• Among the four mammalian TIMPs (TIMP-1 to -4), TACE is selectively inhibited by TIMP-3 [25].
• Furthermore, constitutive N1 secretion is drastically reduced in fibroblasts deficient for ADAM10 whereas phorbol 12,13-dibutyrate-regulated N1 production is fully abolished in TACE-deficient cells [32].
• Furthermore, introduction of siRNAs targeting ADAM17 transcripts resulted in suppression of DC-induced activation of EGFR and ERK1/2 [33].

Other interactions of ADAM17

• Second, our study identifies ADAM10 and ADAM17 as the protease candidates responsible for normal cleavage of PrPc [32].
• After pro-domain removal, additional steps, such as protein kinase C-dependent phosphorylation, may be involved in regulating the catalytic activity of MDC9, which is likely to target different substrates than the related TNF-alpha-convertase [34].
• We conclude that HNE induces MUC5AC mucin expression via a cascade involving PKC-ROS-TACE in human airway epithelial cells [28].
• Here, we examine the molecular basis of TIMP-TACE selectivity using TIMP-2 as the scaffold [25].
• Small, interfering RNA directed against ADAM17 or MMP9 inhibited the acrolein-induced MUC5AC mRNA increase [35].

Analytical, diagnostic and therapeutic context of ADAM17

• ADAM17 mRNA expressions were compared among those groups by means of semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) [3].
• A strong expression of ADAM-17/TACE was further revealed by Western blot analysis in prostatic tumor cell lines [9].
• In a longitudinal study on 11 relapsing-remitting MS patients, we qualitatively determined mRNA expression of TNF-alpha and TACE in peripheral blood mononuclear cells (PBMCs) without ex vivo stimulation. mRNA expression was related to disease activity as assessed by monthly gadolinium (Gd)-enhanced brain magnetic resonance imaging (MRI) [36].
• Immunohistochemistry and immunofluorescence were used to localize ADAM17, EGFR, and the activated forms of EGFR [37].
• The activated form of ADAM17 was assessed in primary cancers and colon cell lines by immunoblotting [37].

References