The role of ADAM10 and ADAM17 in the ectodomain shedding of angiotensin converting enzyme and the amyloid precursor protein

Allinson, Tobias M. J.; Parkin, Edward T.; Condon, Thomas P.; Schwager, S.L.U.; Sturrock, Edward D.; Turner, Anthony J.; Hooper, Nigel M.

doi:10.1111/j.1432-1033.2004.04184.x

Cited by 83 publications

(72 citation statements)

References 32 publications

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“…Although we demonstrated that ADAM10 was more potent than ADAM17 in shedding Nrg1 and a recent study also demonstrates that ADAM10 is a physiologically relevant ␣-secretase that processes APP constitutively (30), we can not exclude the compensatory processing of Nrg1 by ADAM17 or other ADAM proteases. Second, both ADAM10 and ADAM17 can function as an ␣-secretase (22,23), an observation similar to that obtained in this study. Despite the fact that ADAM10 is a more abundant protease in the axon (26), the presence of ADAM17 and other not yet characterized ADAM proteases may compensate for the loss of ADAM10 in ADAM10-null mice.…”

Section: Discussionsupporting

confidence: 89%

“…BACE1 is the only protease that cleaves APP at the ␤-secretase site, whereas three proteases (ADAM9, ADAM10, and ADAM17) are reported to process APP at an identical ␣-secretase site (22,23). To test our hypothesis, we incubated either ADAM10 or ADAM17 protease with a recombinant protein spanning the entire extracellular domain of human Nrg1 in an enzymatic assay.…”

Section: Resultsmentioning

confidence: 99%

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Cleavage of Neuregulin-1 by BACE1 or ADAM10 Protein Produces Differential Effects on Myelination

Luo

Prior

et al. 2011

Journal of Biological Chemistry

106

117

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Neuregulin-1 (Nrg1) is encoded by a single gene and exists in naturally secreted and transmembrane isoforms. Nrg1 exerts its signaling activity through interaction with its cognate ErbB receptors. Multiple membrane-anchored Nrg1 isoforms, present in six different membrane topologies, must be processed by a protease to initiate a signaling cascade. Here, we demonstrate that BACE1 and ADAM10 can process type I and III Nrg1 at two adjacent sites. Our cleavage site mapping experiments showed that the BACE1 cleavage site is located eight amino acids downstream of the ADAM10 cleavage site, and this order of cleavage is the opposite of amyloid precursor protein cleavage by these two enzymes. Cleavages were further confirmed via optimized electrophoresis. Cleavage of type I or III Nrg1 by ADAM10 and BACE1 released a signaling-capable N-terminal fragment (ntf), either Nrg1-ntf␣ or Nrg1-ntf␤, which could similarly activate an ErbB receptor as evidenced by increased phosphorylation of Akt and ERK, two downstream signaling molecules. Although both Nrg1-ntf␣ and Nrg1-ntf␤ could initiate a common signaling cascade, inhibition or down-regulation of ADAM10 alone in a co-culture system did not affect normal myelination, whereas specific inhibition of BACE1 impaired normal myelination. Thus, processing of Nrg1 by BACE1 appears to be more critical for regulating myelination. Our results imply that a significant inhibition of BACE1 could potentially impair Nrg1 signaling activity in vivo. Members of the neuregulin (Nrg)3 family of proteins contain an EGF-like domain that mediates cell-cell signaling functions via interaction with cognate ErbB receptors (1, 2). The Nrg protein family consists of four members (Nrg1-Nrg4), with Nrg1 being the most well characterized. Because of multiple splicing events, mammalian Nrg1 has a total of 33 isoforms that can be distinguished by six different membrane topologies (types I-VI) (3). Mice with a genetic deletion of Nrg1 are embryonic-lethal due to circulatory failure and defects in neural and cardiac development (4), indicating the importance of Nrg1 in normal growth. As a critical signaling molecule, Nrg1 has also been linked to developmental abnormalities and pathogenesis of multiple diseases. For example, Nrg1 polymorphism has been identified as a risk factor for schizophrenia (5).Mouse genetic studies also demonstrate that type III Nrg1 is a master regulator of myelination; its level in axons is correlated with the thickness of the myelin sheath (6, 7).Most of the 33 Nrg1 isoforms are membrane-anchored ligands, and proteolytic cleavage of these membrane-bound Nrg1 isoforms is required for the secreted Nrg1 fragment to bind to its cognate receptor, an ErbB2/ErbB3 heterodimer or ErbB4 homodimer (8 -10). In our recent study of Alzheimer ␤-secretase (BACE1), we demonstrated that membrane-anchored type I and III ␤1 Nrg1 isoforms are cleaved by BACE1 at the site between residues EF and ME, ϳ10 residues away from the transmembrane region (11). In BACE1-null mice, the cleavage of type I and III ␤1 ...

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Section: Discussionsupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Cleavage of Neuregulin-1 by BACE1 or ADAM10 Protein Produces Differential Effects on Myelination

Luo

Prior

et al. 2011

Journal of Biological Chemistry

106

117

View full text Add to dashboard Cite

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“…Reagents and Antibodies-The following antibodies were used: anti-HA HA.11 (Covance) and 12CA5 (Roche), anti-FLAG (Sigma), anti-GFP (Clontech), anti-␤-actin, (Sigma), anti-calnexin (Stressgene), horseradish peroxidase-coupled goat anti-mouse and anti-rabbit (Promega), Alexa 555/Alexa 488-coupled secondary anti-mouse (Molecular Probes), Alexa 555-coupled secondary anti-rat antibody (Molecular Probes), Alexa 488-coupled anti-rabbit secondary antibody (Molecular Probes), anti-giantin (Alexis) (31), 6E10 (against A␤ [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] , Senetek Inc.), 6687 (against APP C terminus) (32), 22C11 (against APP ectodomain, provided by Konrad Beyreuther), 192wt (specific for the C terminus of APPs␤, provided by Dale Schenk), W02 (against amino acids 5-8 of A␤, provided by Konrad Beyreuther) (33), 3552 (against A␤ ) (34), (against N terminus of BACE1, Sigma), Nicastrin (N1660, Sigma), and the antibodies GM130, GS15, GS27, GS28, p230, Syntaxin 6, Vti1a, and Vti1b of the Golgi Sampler Kit, as well as the antibody against TGN38 (both BD Transduction Laboratories). Polyclonal TMEM59-antiserum 93 was generated against a synthetic peptide (H 2 N-309 -323-CONH 2 ) from the C terminus of TMEM59 (Eurogentec Seraing, Belgium), 3F4 (antimouse PrP) (35).…”

Section: Methodsmentioning

confidence: 99%

The Novel Membrane Protein TMEM59 Modulates Complex Glycosylation, Cell Surface Expression, and Secretion of the Amyloid Precursor Protein

Ullrich

Münch

Neumann

et al. 2010

Journal of Biological Chemistry

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Ectodomain shedding of the amyloid precursor protein (APP) by the two proteases ␣-and ␤-secretase is a key regulatory event in the generation of the Alzheimer disease amyloid ␤ peptide (A␤). At present, little is known about the cellular mechanisms that control APP shedding and A␤ generation. Here, we identified a novel protein, transmembrane protein 59 (TMEM59), as a new modulator of APP shedding. TMEM59 was found to be a ubiquitously expressed, Golgi-localized protein. TMEM59 transfection inhibited complex N-and O-glycosylation of APP in cultured cells. Additionally, TMEM59 induced APP retention in the Golgi and inhibited A␤ generation as well as APP cleavage by ␣-and ␤-secretase cleavage, which occur at the plasma membrane and in the endosomes, respectively. Moreover, TMEM59 inhibited the complex N-glycosylation of the prion protein, suggesting a more general modulation of Golgi glycosylation reactions. Importantly, TMEM59 did not affect the secretion of soluble proteins or the ␣-secretase like shedding of tumor necrosis factor ␣, demonstrating that TMEM59 did not disturb the general Golgi function. The phenotype of TMEM59 transfection on APP glycosylation and shedding was similar to the one observed in cells lacking conserved oligomeric Golgi (COG) proteins COG1 and COG2. Both proteins are required for normal localization and activity of Golgi glycosylation enzymes. In summary, this study shows that TMEM59 expression modulates complex N-and O-glycosylation and suggests that TMEM59 affects APP shedding by reducing access of APP to the cellular compartments, where it is normally cleaved by ␣-and ␤-secretase. Processing of the amyloid precursor protein (APP)3 by two different proteases, called ␣-and ␤-secretase, is a central regulatory event in the generation of the amyloid ␤ peptide (A␤), which has a key role in Alzheimer disease (AD) pathogenesis (1). Both ␣-and ␤-secretase cleave the type I membrane protein APP within its ectodomain close to its transmembrane domain (2). This leads to the secretion of soluble forms of APP (APPs) and is referred to as APP shedding. The ␤-secretase is the aspartyl protease BACE1 and cleaves APP at the N terminus of the A␤ peptide domain, thus catalyzing the first step in A␤ peptide generation (3, 4). After the initial cleavage of APP by BACE1, the remaining C-terminal APP fragment is cleaved by ␥-secretase within its transmembrane domain at the C terminus of the A␤ domain, leading to the secretion of the A␤-peptide (5). In contrast to ␤-secretase, ␣-secretase cleaves within the A␤-sequence of APP, and thereby precludes A␤ peptide generation. Additionally, ␣-but not ␤-secretase cleavage generates a secreted form of APP (APPs␣), which has neurotrophic and neuroprotective properties (6 -8). The ␣-secretase is a member of the ADAM family (A disintegrin and metalloprotease) of proteases (9 -12). At present little is known about how the cell controls access of APP to its secretases and the amount of ␣-and ␤-secretase cleavage (reviewed in Refs. 13 and 14). Recent studies increasingl...

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“…In addition, like APP, PrP C is shed from the cell surface by zinc metalloproteases and is subject to endoproteolysis by ADAM10 and ADAM17 (12)(13)(14)(15). As a result of these pathological, genetic, and mechanistic similarities, we were led to investigate whether PrP C alters the proteolytic processing of APP.…”

mentioning

confidence: 99%

Cellular prion protein regulates β-secretase cleavage of the Alzheimer's amyloid precursor protein

Parkin

Watt²,

Hussain³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

256

255

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Proteolytic processing of the amyloid precursor protein (APP) by ␤-secretase, ␤-site APP cleaving enzyme (BACE1), is the initial step in the production of the amyloid ␤ (A␤) peptide, which is involved in the pathogenesis of Alzheimer's disease. The normal cellular function of the prion protein (PrP C ), the causative agent of the transmissible spongiform encephalopathies such as CreutzfeldtJakob disease in humans, remains enigmatic. Because both APP and PrP C are subject to proteolytic processing by the same zinc metalloproteases, we tested the involvement of PrP C in the proteolytic processing of APP. Cellular overexpression of PrP C inhibited the ␤-secretase cleavage of APP and reduced A␤ formation. Conversely, depletion of PrP C in mouse N2a cells by siRNA led to an increase in A␤ peptides secreted into the medium. In the brains of PrP knockout mice and in the brains from two strains of scrapieinfected mice, A␤ levels were significantly increased. Two mutants of PrP, PG14 and A116V, that are associated with familial human prion diseases failed to inhibit the ␤-secretase cleavage of APP. Using constructs of PrP, we show that this regulatory effect of PrP C on the ␤-secretase cleavage of APP required the localization of PrP C to cholesterol-rich lipid rafts and was mediated by the N-terminal polybasic region of PrP C via interaction with glycosaminoglycans. In conclusion, this is a mechanism by which the cellular production of the neurotoxic A␤ is regulated by PrP C and may have implications for both Alzheimer's and prion diseases.lipid raft ͉ proteolysis ͉ scrapie ͉ glycosaminoglycan A lzheimer's disease (AD) is characterized by the presence of extracellular senile plaques and intracellular neurofibrillary tangles within the afflicted brain. The major constituents of senile plaques are the amyloid ␤ (A␤) peptides, which are derived from the proteolytic processing of the amyloid precursor protein (APP) (1). In the amyloidogenic pathway, ␤-secretase cleavage of APP yields a soluble N-terminal fragment sAPP␤, along with a short membrane-bound C-terminal fragment that is subsequently cleaved by ␥-secretase to release the A␤ peptides. In the alternative, nonamyloidogenic pathway, ␣-secretase cleaves APP within the A␤ sequence, thus precluding the formation of A␤, and releases a soluble N-terminal fragment sAPP␣. The transmembrane aspartyl protease, ␤-site APP cleaving enzyme (BACE1), has been identified as ␤-secretase (2), members of the ADAM (a disintegrin and metalloprotease) family, particularly ADAM10 and ADAM17, are responsible for ␣-secretase cleavage (3), while a complex of at least four proteins, the presenilins, nicastrin, Aph-1, and Pen-2, constitutes the ␥-secretase (2).The prion protein (PrP) is the causative agent of the transmissible spongiform encephalopathies (TSEs) that include CreutzfeldtJakob disease (CJD), Gerstmann-Scheinker-Straussler (GSS) disease, kuru and fatal familial insomnia in humans, bovine spongiform encephalopathy in cattle, and scrapie in sheep (4). In these diseases, the normal ce...

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The role of ADAM10 and ADAM17 in the ectodomain shedding of angiotensin converting enzyme and the amyloid precursor protein

Cited by 83 publications

References 32 publications

Cleavage of Neuregulin-1 by BACE1 or ADAM10 Protein Produces Differential Effects on Myelination

Cleavage of Neuregulin-1 by BACE1 or ADAM10 Protein Produces Differential Effects on Myelination

The Novel Membrane Protein TMEM59 Modulates Complex Glycosylation, Cell Surface Expression, and Secretion of the Amyloid Precursor Protein

Cellular prion protein regulates β-secretase cleavage of the Alzheimer's amyloid precursor protein

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