PI3-K- and PKC-dependent up-regulation of APP processing enzymes by retinoic acid

Holback, Sofia; Adlerz, Linda; Gatsinzi, Tom; Jacobsen, Kristin; Iverfeldt, Kerstin

doi:10.1016/j.bbrc.2007.10.167

Cited by 24 publications

(13 citation statements)

References 31 publications

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“…Furthermore, in a later in vivo study, PKC activation failed to increase APP phosphorylation [176], indicating that the effect of PKC on APP metabolism is not mediated through direct phosphorylation of APP, but perhaps through regulation of APP-cleaving enzymes. This theory was also supported by studies in our laboratory [177] showing that TACE was upregulated in a PKC-dependent manner in response to retinoic acid, which induces neuronal differentiation of human neuroblastoma cells concomitant with increased APP a-site cleavage.…”

Section: Proteolysis-dependent Signalingsupporting

confidence: 50%

Amyloid precursor protein and its homologues: a family of proteolysis-dependent receptors

Jacobsen

Iverfeldt

2009

Cell. Mol. Life Sci.

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110

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The Alzheimer's amyloid precursor protein (APP) belongs to a conserved gene family that also includes the mammalian APLP1 and APLP2, the Drosophila APPL, and the C. elegans APL-1. The biological function of APP is still not fully clear. However, it is known that the APP family proteins have redundant and partly overlapping functions, which demonstrates the importance of studying all APP family members to gain a more complete picture. When APP was first cloned, it was speculated that it could function as a receptor. This theory has been further substantiated by studies showing that APP and its homologues bind both extracellular ligands and intracellular adaptor proteins. The APP family proteins undergo regulated intramembrane proteolysis (RIP), generating secreted and cytoplasmic fragments that have been ascribed different functions. In this review, we will discuss the APP family with focus on biological functions, binding partners, and regulated processing.

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Section: Proteolysis-dependent Signalingsupporting

confidence: 50%

Amyloid precursor protein and its homologues: a family of proteolysis-dependent receptors

Jacobsen

Iverfeldt

2009

Cell. Mol. Life Sci.

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110

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“…For LY294002, we observed a significant reduction in retinoid-driven promoter activity. This is in accordance with findings from Holback et al [16] who demonstrated a strong decrease in atRA-induced ADAM10 protein level by this compound.…”

Section: Retinoids As a Perspective In Treatment Of Alzheimer's Diseasesupporting

confidence: 82%

Retinoids as a Perspective in Treatment of Alzheimer’s Disease

Fahrenholz

Tippmann²

2010

Neurodegener Dis

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Background: In the past, we demonstrated that the disintegrin metalloproteinase ADAM10 has α-secretase activity in vitro and in cultured cells. We also found out that moderate overexpression of this proteinase inhibits Aβ peptide production and prevents the formation of amyloid plaques in an Alzheimer’s disease (AD) mouse model. Moreover, it corrects early hippocampal defects like LTP impairment and increases cortical synaptogenesis. Objective: Upregulation of ADAM10 might be an alternative approach concerning AD therapy. Our current research therefore focuses on substances and/or pathways which regulate ADAM10 gene expression. Methods: Analyses of ADAM10 promoter activity were performed in human and murine neuroblastoma cell lines and important findings were validated in an AD mouse model. Results: The outcome of our investigations indicates that a heterodimeric retinoid receptor mediates the activation of the ADAM10 promoter by all-trans-retinoic acid. This then results in enhanced ADAM10 expression, pronounced APPs-α secretion and diminished proteolytic processing products of the amyloidogenic pathway (APPs-β, Aβ). Conclusion: Nontoxic synthetic retinoids – like acitretin – offer a valuable therapeutic approach in treatment of AD by moderately enhancing ADAM10 gene expression.

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“…Instead, we show that also the RA-induced secretion of sAPP␣ is dependent on PI3-K. In addition, we have observed previously that RA treatment of SH-SY5Y cells resulted in significantly increased levels of ADAM10 and TACE (34). The up-regulation of ADAM10 was dependent on PI3-K and independent on PKC.…”

Section: Discussionmentioning

confidence: 63%

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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PI3-K- and PKC-dependent up-regulation of APP processing enzymes by retinoic acid

Cited by 24 publications

References 31 publications

Amyloid precursor protein and its homologues: a family of proteolysis-dependent receptors

Amyloid precursor protein and its homologues: a family of proteolysis-dependent receptors

Retinoids as a Perspective in Treatment of Alzheimer’s Disease

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

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