Increased processing of APLP2 and APP with concomitant formation of APP intracellular domains in BDNF and retinoic acid‐differentiated human neuroblastoma cells

Holback, Sofia; Adlerz, Linda; Iverfeldt, Kerstin

doi:10.1111/j.1471-4159.2005.03440.x

Cited by 60 publications

(49 citation statements)

References 50 publications

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“…Western Blot Assay-Conditioned medium was collected and concentrated as described previously (21). Cells were harvested and analyzed by Western blot assay as described previously (21).…”

Section: Methodsmentioning

confidence: 99%

Insulin-like Growth Factor-1 (IGF-1)-induced Processing of Amyloid-β Precursor Protein (APP) and APP-like Protein 2 Is Mediated by Different Metalloproteinases

Jacobsen

Adlerz

Multhaup

et al. 2010

Journal of Biological Chemistry

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␣-Secretase cleavage of the amyloid precursor protein (APP) is of great interest because it prevents the formation of the Alzheimer-linked amyloid-␤ peptide. APP belongs to a conserved gene family including the two paralogues APP-like protein (APLP) 1 and 2. Insulin-like growth factor-1 (IGF-1) stimulates the shedding of all three proteins. IGF-1-induced shedding of both APP and APLP1 is dependent on phosphatidylinositol 3-kinase (PI3-K), whereas APLP2 shedding is independent of this signaling pathway. Here, we used human neuroblastoma SH-SY5Y cells to investigate the involvement of protein kinase C (PKC) in the proteolytic processing of endogenously expressed members of the APP family. Processing was induced by IGF-1 or retinoic acid, another known stimulator of APP ␣-secretase shedding. Our results show that stimulation of APP and APLP1 processing involves multiple signaling pathways, whereas APLP2 processing is mainly dependent on PKC. Next, we wanted to investigate whether the difference in the regulation of APLP2 shedding compared with APP shedding could be due to involvement of different processing enzymes. We focused on the two major ␣-secretase candidates ADAM10 and TACE, which both are members of the ADAM (a disintegrin and metalloprotease) family. Shedding was analyzed in the presence of the ADAM10 inhibitor GI254023X, or after transfection with small interfering RNAs targeted against TACE. The results clearly demonstrate that different ␣-secretases are involved in IGF-1-induced processing. APP is mainly cleaved by ADAM10, whereas APLP2 processing is mediated by TACE. Finally, we also show that IGF-1 induces PKC-dependent phosphorylation of TACE. Alzheimer disease (AD)2 is histopathologically characterized by the presence of amyloid plaques in the brain parenchyma. The major constituent of the plaques is the amyloid-␤ (A␤) peptide, which is derived from the A␤ precursor protein (APP) by ␤-and ␥-secretase cleavage in the amyloidogenic pathway (1). In addition to A␤, a larger secreted fragment, sAPP␤, and an intracellular fragment (APP intracellular domain) are formed. Proteolytic processing of APP occurs mainly by an alternative pathway. In this nonamyloidogenic pathway, A␤ formation is precluded because ␣-secretase cleaves APP in the middle of the A␤ region. In addition to sAPP␣, a small secreted peptide, p3, and APP intracellular domain are generated by subsequent ␥-secretase cleavage.APP belongs to a conserved gene family including the two mammalian paralogues amyloid precursor-like protein 1 and 2 (APLP1 and APLP2). The exact biological function of APP and its paralogues is still unknown, although several different studies have shown involvement of APP in cell adhesion, neurite outgrowth, synaptogenesis, modulation of synaptic plasticity, and neuroprotection (reviewed in Ref. 2). Homo-and heterotypic cis interactions of APP family members have been detected (3). APLP1 could also form trans interactions, suggesting a specific role of APLP1 in cell adhesion. Importantly, double knock-out studies in mi...

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“…Western Blot Assay-Conditioned medium was collected and concentrated as described previously (21). Cells were harvested and analyzed by Western blot assay as described previously (21).…”

Section: Methodsmentioning

confidence: 99%

Insulin-like Growth Factor-1 (IGF-1)-induced Processing of Amyloid-β Precursor Protein (APP) and APP-like Protein 2 Is Mediated by Different Metalloproteinases

Jacobsen

Adlerz

Multhaup

et al. 2010

Journal of Biological Chemistry

Self Cite

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“…It is known that BDNF/TrkB signaling can affect APP expression levels, glycosylation and cleavage [16][17][18][19]. We have found that TrkB isoforms can differentially affect the processing and the expression levels of over-ex-pressed APP in SH-SY5Y neuroblastoma cells [20].…”

Section: Introductionmentioning

confidence: 82%

“…PMA was able to increase the ADAM activity signal in both cell lines (Figure 3 (a)). SH-SY5Y cells have been shown to display accumulation of sAPP- when treated with retinoic acid [16]. The ADAM10 promoter contains retinoic acid responsive elements (RARE), so we hypothesized that this increase sAPP- release is mediated by an increased transcription and maybe activity of ADAM10 in this cell line.…”

Section: Adam10 Activity Is Not Affected Bymentioning

confidence: 99%

“…TrkB FL or TrkB T TrkB FL has been shown to increase APP promoter transcription but also to increase sAPP- levels in the media of SH-SY5Y cells [16]. We hypothesized that the increase in sAPP- might be due to TrkB FL mediated PLC- activation, since PLC- produces diacylglycerol (DAG), an ADAM activity stimulator.…”

Section: Adam10 Activity Is Not Affected Bymentioning

confidence: 99%

“…These results suggest an effect of TrkB isoforms on the APP processsing enzymes, such as -disintegrin metalloprotease 10 (ADAM10) and -secretase (BACE1). Previous work showed increased -secretase cleavage of APP in SH-SY5Y cells stimulated by all-trans retinoic acid (RA), RA induces up-regulation of TrkB [16]. These studies did not investigate if RA was able to increase ADAM10 activity or levels but only measured the products of APP -secretase cleavage, sAPP-, as indirect evidence of increased ADAM activity.…”

Section: Introductionmentioning

confidence: 99%

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Tyrosine kinase receptor B isoforms alter APP and BACE1 endogenous levels independently of BDNF

Ansaloni¹,

Leung²,

Dubey³

et al. 2012

AAD

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Brain derived neurotrophic factor (BDNF) levels and signaling via the tyrosine receptor kinase B (TrkB) have been shown to be altered in Alzheimer's Disease. In addition, it has been reported that the isoforms of TrkB can differentially affect metabolism of amyloid precursor protein (APP). Conversely, A, a neurotoxic cleavage product of APP, has been shown to impair TrkB/ BDNF signaling. Therefore, we investigated whether the changes observed in APP metabolism were due to the isoform-specific effects of TrkB on either APP expression, and/or on the expression and activity of ADAM10 and BACE1. Since BDNF levels are decreased in AD, we focused on BDNF independent effects of the TrkB isoforms. We found that TrkB FL increases endogenous APP levels in both HEK293 and SH-SY5Y naïve cells. We did not find an increase in ADAM10 activity in HEK293 cells, but an increase in BA-CE1 levels. Additionally, we have found that TrkB FL is able to increase NFAT3 mediated transcriptional activity and we suggest that this causes transcriptional activation of the BACE1 promoter.

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Secretome proteins as candidate biomarkers for aggressive thyroid carcinomas

et al. 2013

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Using proteomics in tandem with bioinformatics, the secretomes of nonaggressive and aggressive thyroid carcinoma (TC) cell lines were analyzed to detect potential biomarkers for tumor aggressiveness. A panel of nine proteins, activated leukocyte cell adhesion molecule (ALCAM/CD166), tyrosine-protein kinase receptor (AXL), amyloid beta A4 protein, amyloid-like protein 2, heterogeneous nuclear ribonucleoprotein K, phosphoglycerate kinase 1, pyruvate kinase isozyme M2, phosphatase 2A inhibitor (SET), and protein kinase C inhibitor protein 1 (14-3-3 zeta) was chosen to confirm their expression in TC patients' sera and tissues. Increased presurgical circulating levels of ALCAM were associated with aggressive tumors (p = 0.04) and presence of lymph node metastasis (p = 0.018). Increased serum AXL levels were associated with extrathyroidal extension (p = 0.027). Furthermore, differential expression of amyloid beta A4 protein, AXL, heterogeneous nuclear ribonucleoprotein K, phosphoglycerate kinase 1, pyruvate kinase muscle isozyme M2, and SET was observed in TC tissues compared to benign nodules. Decreased nuclear expression of AXL can detect malignancy with 90% specificity and 100% sensitivity (AUC = 0.995, p < 0.001). In conclusion, some of these proteins show potential for future development as serum and/or tissue-based biomarkers for TC and warrant further investigation in a large cohort of patients.

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Increased processing of APLP2 and APP with concomitant formation of APP intracellular domains in BDNF and retinoic acid‐differentiated human neuroblastoma cells

Cited by 60 publications

References 50 publications

Insulin-like Growth Factor-1 (IGF-1)-induced Processing of Amyloid-β Precursor Protein (APP) and APP-like Protein 2 Is Mediated by Different Metalloproteinases

Insulin-like Growth Factor-1 (IGF-1)-induced Processing of Amyloid-β Precursor Protein (APP) and APP-like Protein 2 Is Mediated by Different Metalloproteinases

Tyrosine kinase receptor B isoforms alter APP and BACE1 endogenous levels independently of BDNF

Secretome proteins as candidate biomarkers for aggressive thyroid carcinomas

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