PubMed Health⌕ Search
Home/Archive/PubMed

PubMed · 12054507

BACE1 interacts with nicastrin.

Chinatsu Hattori·Masashi Asai·Yoko Oma·Yoshihiro Kino·Noboru Sasagawa·Takaomi C Saido·Kei Maruyama·Shoichi Ishiura
View original source ↗Export metadata ↓

Abstract

Beta-amyloid peptide (Abeta) is generated through the proteolytic cleavage of beta-amyloid precursor protein (APP) by beta- and gamma-secretases. The beta-secretase, BACE1, initiates Abeta formation followed by gamma-cleavage within the APP transmembrane domain. Although BACE1 localizes in the transGolgi network (TGN), its physiological substrates and modulators are not known. In addition, the relationship to other secretase(s) also remains unidentified. Here, we demonstrate that BACE1 binds to nicastrin, a component of gamma-secretase complexes, in vitro, and that nicastrin activates beta-secretase activity in COS-7 cells.

Explore related subjects

ADAM ProteinsADAM10 ProteinADAM17 ProteinAmyloid Precursor Protein SecretasesAnimalsAspartic Acid EndopeptidasesBacterial Outer Membrane ProteinsCOS CellsDisintegrinsEndopeptidasesHumansMembrane GlycoproteinsMembrane ProteinsMetalloendopeptidasesModels, BiologicalMuscle ProteinsPrecipitin TestsProtein BindingProtein Structure, TertiaryTime FactorsTransfectionJournal ArticleResearch Support, Non-U.S. Gov't

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Chinatsu Hattori, Masashi Asai, Yoko Oma, Yoshihiro Kino, Noboru Sasagawa, Takaomi C Saido, Kei Maruyama, Shoichi Ishiura. 2002-05-17. BACE1 interacts with nicastrin.. https://doi.org/10.1016/s0006-291x(02)00351-0

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related citations

PubMed2007

Metalloproteinases are enriched in microglia compared with leukocytes and they regulate cytokine levels in activated microglia.

Microglia are resident immune cells within the central nervous system (CNS). They become activated following neurological insults and increase their expression of cytokines. Also elevated in CNS injuries are proteases, including matrix metalloproteinases (MMPs) and A disintegrin and metalloproteinases (ADAMs). The spectrum of metalloproteinase members expressed by microglia and by the systemic leukocytes that infiltrate the injured CNS is unknown, as are their functions. We determined the levels of transcripts encoding all 24 MMPs, nine ADAMs, and their four physiological antagonists, tissue inhibitor of metalloproteinases (TIMPs), in human microglia, B and T cells, monocytes, and neutrophils. We found a distinct pattern for each immune subset and an enrichment of metalloproteinases in microglia compared with leukocytes. When microglia were activated, there was an upregulation of transcripts for nine metalloproteinases, and reduction of TIMP3. Activation of microglia also resulted in increased levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-10 protein in the conditioned media of cells. The amount of secreted TNF-alpha, but not IL-1beta or IL-10, was suppressed by BB94, a broad spectrum metalloproteinase inhibitor, and by TIMP3 but not TIMP1 or TIMP2. This inhibitory profile suggests the involvement of an ADAM member in TNF-alpha secretion. We conclude that microglia bear a metalloproteinase signature distinct from systemic cells, and that following activation, microglia upregulate TNF-alpha protein levels through a combination of elevated cytokine transcripts, increased metalloproteinase level and activity, and through the decrease of TIMP3. The results have implications for the regulation of neuroinflammation and its outcomes following CNS injuries.

ADAM Proteins↗
PubMed2007

Prognostic value of anti-ADAMTS 13 antibody features (Ig isotype, titer, and inhibitory effect) in a cohort of 35 adult French patients undergoing a first episode of thrombotic microangiopathy with undetectable ADAMTS 13 activity.

To study both the pathophysiologic and the prognostic value of ADAMTS13 in thrombotic microangiopathies (TMAs), we enrolled a cohort of 35 adult patients combining a first acute episode of TMA, an undetectable (below 5%) ADAMTS13 activity in plasma, and no clinical background such as sepsis, cancer, HIV, and transplantation. All patients were treated by steroids and plasma exchange, and an 18-month follow-up was scheduled. Remission was obtained in 32 patients (91.4%), and 3 patients died (8.6%) after the first attack. At presentation, ADAMTS13 antigen was decreased in 32 patients (91.4%), an ADAMTS13 inhibitor was detectable in 31 patients (89%), and an anti-ADAMTS13 IgG/IgM/IgA was present in 33 patients (94%). The 3 decedent patients were characterized by the association of several anti-ADAMTS13 Ig isotypes, including very high IgA titers, while mortality was independent of the ADAMTS13 inhibitor titer. In survivors, ADAMTS13 activity in remission increased to levels above 15% in 19 patients (59%) but remained undetectable in 13 patients (41%). Six patients relapsed either once or twice (19%) during the follow-up. High levels of inhibitory anti-ADAMTS13 IgG at presentation were associated with the persistence of an undetectable ADAMTS13 activity in remission, the latter being predictive for relapses within an 18-month delay.

ADAM Proteins↗
PubMed2007

Post-transcriptional up-regulation of ADAM17 upon epidermal growth factor receptor activation and in breast tumors.

ADAM17 is a transmembrane metalloprotease involved in the proteolytic release of the extracellular domain of many cell surface molecules, a process known as ectodomain shedding. Despite its likely participation in tumor progression and its current consideration as a therapeutic target, very little is known about the regulation of the expression of ADAM17. Here we show that long term treatment with epidermal growth factor (EGF) leads to a marked increase in the levels of ADAM17. EGF receptor activation does not affect the levels of the mRNA that encodes for, or the rate of synthesis of, ADAM17 but increases its half-life. The effect of EGF is biologically relevant because it increases the shedding of several substrates of ADAM17, including the desmosomal cadherin Dsg-2. Analysis of protein and mRNA levels in mammary tumor samples shows that in vivo the levels of ADAM17 can also be controlled post-transcriptionally. Finally, we show that both the shed extracellular domains of Dsg-2 and ADAM17 are frequently expressed in tumors, further supporting the participation of the metalloprotease in malignant progression.

ADAM Proteins↗