Disease relevance of ADAM10

• MV-SMC exposed to chronic anoxia (24-48 hours) showed a decrease in expression of the 2 putative alpha-secretase enzymes, mature TACE (TNFalpha-converting enzyme) and ADAM10 (a disintegrin and metalloprotease) [1].
• The strongest inhibition of APLP2 shedding in neuroblastoma cells was observed with an ADAM10-preferring inhibitor [2].
• Platelet-activating factor receptor and ADAM10 mediate responses to Staphylococcus aureus in epithelial cells [3].
• Thus, ADAM10 represents an important pharmacotherapeutic target for the treatment of cerebral amyloidosis in Alzheimer disease [4].
• In this study we used a human fibrosarcoma reconstitution system to compare the effects of RNA interference-mediated knockdown of TACE vs. a related metalloprotease, ADAM10 [5].

Psychiatry related information on ADAM10

• Variation at the ADAM10 gene locus is not associated with Creutzfeldt-Jakob disease [6].
• ADAM10, a disintegrin and metalloprotease that plays a key role in the pathogenesis of Alzheimer's disease, was recently shown to use PrP(c) as a substrate [6].

High impact information on ADAM10

• Cleavage of ephrin-A2 by the ADAM10 membrane metalloprotease enables contact repulsion between Eph- and ephrin-expressing cells [7].
• Surprisingly, the cleavage occurs in trans, with ADAM10 and its substrate being on the membranes of opposing cells [7].
• This results in activation of a disintegrin and metalloproteinase (ADAM10), kuzbanian, cleavage of pro heparin-binding epidermal growth factor and activation of the epidermal growth factor receptor [3].
• 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 [8].
• ADAM 10 was implicated in the Notch signaling pathway [9].

Chemical compound and disease context of ADAM10

• Retinoic acid treatment of two neuroblastoma cell lines upregulated the expression of both APLP2 and ADAM10, thus leading to an increased release of soluble APLP2 [2].
• 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 [10].
• Here, we investigate the mechanisms of action of the AChEI donepezil on APP (amyloid precursor protein) metabolism and on the activity/trafficking of the alpha-secretase candidate ADAM 10, in differentiated human neuroblastoma cells (SH-SY5Y) [11].
• Expression of the disintegrin metalloprotease, ADAM-10, in prostate cancer and its regulation by dihydrotestosterone, insulin-like growth factor I, and epidermal growth factor in the prostate cancer cell model LNCaP [12].

Biological context of ADAM10

• However, we establish that ADAM9 was unable to increase N1 and sAPPalpha productions after transient transfection in fibroblasts depleted of ADAM10 [13].
• ADAM10-mediated E-cadherin shedding affects epithelial cell-cell adhesion as well as cell migration [14].
• Analysis of ADAM10-deficient fibroblasts, inhibitor studies, and RNA interference-mediated down-regulation of ADAM10 demonstrated that ADAM10 is responsible not only for the constitutive shedding but also for the regulated shedding of this adhesion molecule in fibroblasts and keratinocytes [14].
• We also present evidence that blockade of metalloproteinase-disintegrin ADAM10 (a disintegrin and metalloproteinase 10) by RNA interference suppresses CD44 cleavage induced by its ligation [15].
• Radiation hybrid mapping of human ADAM10 gene to chromosome 15 [16].

Anatomical context of ADAM10

• Interestingly, we demonstrate that shedded ADAM10 displays the ability to cleave endogenous PrP(c) in fibroblasts [13].
• 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 [17].
• Levels of beta-secretase BACE and alpha-secretase ADAM10 mRNAs in Alzheimer hippocampus [18].
• The expression of ADAM9 and ADAM10 is also induced in blood monocytes by anti-CD98 mAb [19].
• In sections of neonatal rat tibiae, ADAM10 is expressed in specific regions of articular cartilage and metaphyseal bone [20].

Associations of ADAM10 with chemical compounds

• ADAM10 mediates ectodomain shedding of the betacellulin precursor activated by p-aminophenylmercuric acetate and extracellular calcium influx [21].
• Studies with a range of hydroxamic acid-based compounds, such as batimastat, indicate that alpha-secretase is a zinc metalloproteinase, and members of the adamalysin family of proteins, TACE, ADAM10 and ADAM9, all fulfil some of the criteria required of alpha-secretase [22].
• In situ hybridization performed using combined biotin- and radiolabeled riboprobes provided evidence for the coexpression of beta-APP with BACE and ADAM10 in human cortical neurons [23].
• ADAM10 colocalized with integrin beta1D by confocal microscopy [24].
• Regulated ADAM10-dependent ectodomain shedding of gamma-protocadherin C3 modulates cell-cell adhesion [25].

Physical interactions of ADAM10

• Accordingly, ADAM9 is unable to cleave a fluorimetric substrate of membrane-bound alpha-secretase activity in ADAM10(-/-) fibroblasts [13].

Enzymatic interactions of ADAM10

• In this study, we show that Pcdh gamma C3 and Pcdh gamma B4 are specifically cleaved within their ectodomains by the disintegrin and metalloprotease ADAM10 [25].
• ADAM 10 correctly cleaves peptides and a soluble form of precursor TGF-alpha (proTGFecto) at the N-terminal site but not the C-terminal site [26].
• This profile suggests the potential involvement of the ADAM-10 protease which was subsequently shown to cleave membrane CD40L to generate sCD40L [27].

Regulatory relationships of ADAM10

• 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 [28].
• These results demonstrate, for the first time, activated pro-BTC shedding in response to extracellular calcium influx and APMA and provide evidence that ADAM10 mediates constitutive and activated pro-BTC shedding [21].
• Furthermore, RNAi studies showed that EGF induced ADAM10 (a disintegrin and metalloproteinase 10)-dependent CD44 cleavage and cell migration [29].
• The in vitro activity of ADAM-10 is inhibited by TIMP-1 and TIMP-3 [30].
• ADAM-10 was found to be expressed by astrocytes in all MS and control sections studied; however, in some MS sections, perivascular macrophages were determined as an additional cellular source as well [31].

Other interactions of ADAM10

• Transgenic mice with neuron-specific overexpression of ADAM10 showed significantly increased levels of soluble APLP2 and its C-terminal fragments [2].
• Inhibition of ADAM10-mediated CX3CL1 shedding not only increased adhesive properties of CX3CL1-ECV-304 cells but also prevented de-adhesion of bound THP-1 cells [32].
• Indeed we found that alpha(9)beta(1) bound avidly to the disintegrin domains of ADAM1, 2, 3, and 9 but not to the disintegrin domains of ADAM10 and 17 [33].
• CONCLUSIONS: AF is associated with an increase in the expression of ADAM10 and ADAM15 [34].
• The lack of TIMP inhibition of ADAM8 and 9 contrasts with other membrane-associated metalloproteinases characterised to date in this respect (ADAM10, 12, 17, and the membrane-type metalloproteinases) which have been implicated in protein processing at the cell surface [35].

Analytical, diagnostic and therapeutic context of ADAM10

• ADAM10 Inhibition of Human CD30 Shedding Increases Specificity of Targeted Immunotherapy In vitro [36].
• In situ hybridization performed in mice during prenatal and postnatal development and in adulthood revealed the coexpression of beta-APP, BACE, and ADAM10 [23].
• MATERIALS AND METHODS: Western Blot analysis of ADAM10 is performed on platelet homogenates from 33 sporadic AD patients and on 26 age-matched control subjects [37].
• It was shown by quantitative RT-PCR using continuous fluorescence monitoring that ADAM-10 mRNA expression was regulated in a bell shaped, dose-dependent manner by DHT [38].
• Sequential deletion of the cytoplasmic domain and site-directed mutagenesis suggest that a potential Src homology 3-binding domain is essential for ADAM10 sorting [39].

References