Phosphorylation of amyloid precursor carboxy-terminal fragments enhances their processing by a gamma-secretase-dependent mechanism

Vingtdeux, Valérie; Hamdane, Malika; Gompel, Marie; Bégard, Séverine; Drobecq, Hervé; Ghestem, Antoine; Grosjean, Marie-Eve; Kostanjevečki, Vesna; Grognet, Pierre; Vanmechelen, Eugeen; Buée, Luc; Delacourte, André; Sergeant, Nicolas

doi:10.1016/j.nbd.2005.05.004

Cited by 75 publications

(66 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In our conditions, the analysis with an antibody specific for the very N terminus of C99 (44,45) confirms that the first two bands represent C99 and its phosphorylated isoform (43). The increased expression of BACE1 resulted in a significantly enhanced CTFs formation, with cleavages at position 1 and 11 predominating (Fig.…”

Section: Characterization By Fluorescence Resonance Energy Transfer (supporting

confidence: 65%

Amyloid Precursor Protein and Presenilin1 Interact with the Adaptor GRB2 and Modulate ERK 1,2 Signaling

Nizzari

Venezia

Repetto

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

The amyloid precursor protein (APP) and the presenilins 1 and 2 are genetically linked to the development of familial Alzheimer disease. APP is a single-pass transmembrane protein and precursor of fibrillar and toxic amyloid-␤ peptides, which are considered responsible for Alzheimer disease neurodegeneration. Presenilins are multipass membrane proteins, involved in the enzymatic cleavage of APP and other signaling receptors and transducers. The role of APP and presenilins in Alzheimer disease development seems to be related to the formation of amyloid-␤ peptides; however, their physiological function, reciprocal interaction, and molecular mechanisms leading to neurodegeneration are unclear. APP and presenilins are also involved in multiple interactions with intracellular proteins, the significance of which is under investigation. Among the different APP-interacting proteins, we focused our interest on the GRB2 adaptor protein, which connects cell surface receptors to intracellular signaling pathways. In this study we provide evidence by co-immunoprecipitation experiments, confocal and electron microscopy, and by fluorescence resonance energy transfer experiments that both APP and presenilin1 interact with GRB2 in vesicular structures at the centrosome of the cell. The final target for these interactions is ERK1,2, which is activated in mitotic centrosomes in a PS1-and APP-dependent manner. These data suggest that both APP and presenilin1 can be part of a common signaling pathway that regulates ERK1,2 and the cell cycle.

show abstract

Section: Characterization By Fluorescence Resonance Energy Transfer (supporting

confidence: 65%

Amyloid Precursor Protein and Presenilin1 Interact with the Adaptor GRB2 and Modulate ERK 1,2 Signaling

Nizzari

Venezia

Repetto

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…However, a previous study showed that, while JNK phosphorylates APP to control its transport in distal neurites under normal conditions, Cdk5 is responsible for phosphorylating APP in naturally degenerating CAD cells overexpressing or not APP (Muresan and Muresan, 2007). Furthermore, the role of T668 phosphorylation in promoting the amyloidogenic cleavage of APP (Lee et al, 2003;Vingtdeux et al, 2005) has been disputed by evidence that a knock-in mouse model in which T668 was replaced by an alanine residue displayed normal level of A␤ (Sano et al, 2006). Similarly, there is an ongoing debate over the role of phospho-T668 in regulating APP metabolism as a consequence of modulating its ability to interact with its binding partners.…”

Section: Discussionmentioning

confidence: 99%

“…For example, T668 phosphorylation prevents ␥-mediated cleavage of wild-type APP (Feyt et al, 2007), while APPswe mutant requires to be phosphorylated at T668 before being cleaved by ␥-secretase (Vingtdeux et al, 2005). In contrast, the Swedish mutation that enhances the affinity of APP for ␤-secretase may bypass the requirement of T668 phosphorylation, which has been proposed to facilitate the cleavage of APP by ␤-secretase in primary cortical neurons (Lee et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

The Loss of c-Jun N-Terminal Protein Kinase Activity Prevents the Amyloidogenic Cleavage of Amyloid Precursor Protein and the Formation of Amyloid PlaquesIn Vivo

Mazzitelli¹,

Xu²,

Ferrer³

et al. 2011

J. Neurosci.

View full text Add to dashboard Cite

Phosphorylation plays a central role in the dynamic regulation of the processing of the amyloid precursor protein (APP) and the production of amyloid-␤ (A␤), one of the clinically most important factors that determine the onset of Alzheimer's disease (AD). This has led to the hypothesis that aberrant A␤ production associated with AD results from regulatory defects in signal transduction. However, conflicting findings have raised a debate over the identity of the signaling pathway that controls APP metabolism. Here, we demonstrate that activation of the c-Jun N-terminal protein kinase (JNK) is essential for mediating the apoptotic response of neurons to A␤. Furthermore, we discovered that the functional loss of JNK signaling in neurons significantly decreased the number of amyloid plaques present in the brain of mice carrying familial AD-linked mutant genes. This correlated with a reduction in A␤ production. Biochemical analyses indicate that the phosphorylation of APP at threonine 668 by JNK is required for ␥-mediated cleavage of the C-terminal fragment of APP produced by ␤-secretase. Overall, this study provides genetic evidence that JNK signaling is required for the formation of amyloid plaques in vivo. Therefore, inhibition of increased JNK activity associated with aging or with a pathological condition constitutes a potential strategy for the treatment of AD.

show abstract

“…Primary antibodies were applied in blocking solution over night at 4°C. Antibodies were mouse anti-Myc (1:100; Roche, #11667149001), rat anti-HA (1:100; Roche, #1867423), sheep anti-Digoxigenin (Roche, #11333089001), C23/nucleolin (1:50; Santa Cruz, sc-8031), PML (1:50; Santa Cruz, sc-966), Coilin (1:200; Sigma, C-1662), SC-35 (1:200; Sigma, S-4045), APP C-terminus (55,56), Tip60 (Abcam, ab23886). Cy3-or Cy5-conjugated secondary antibodies (Jackson Labs) were applied at 1:250 and after subsequent washing the cells were embedded in Mowiol with the addition of 2.5% 1.4 Diazobicyclo (2.2.2.)…”

Section: Immunocytochemistrymentioning

confidence: 99%

Co-localization of the amyloid precursor protein and Notch intracellular domains in nuclear transcription factories

Konietzko¹,

Goodger²,

Meyer³

et al. 2010

Neurobiology of Aging

View full text Add to dashboard Cite

The β-amyloid precursor protein (APP) plays a major role in Alzheimer's disease. The APP intracellular domain (AICD), together with Fe65 and Tip60, localizes to spherical nuclear AFT complexes that might represent sites of transcription. We now show that endogenous AICD is targeted to similar nuclear spots. AFT complexes were closely associated with Cajal and PML bodies but did not localize to nucleoli or splicing speckles. Live imaging revealed that AFT complexes were highly mobile within nuclei. Following pharmacological inhibition of transcription AFT complexes merged into a few large assemblies. We have previously shown that AICD regulates the expression of its own precursor APP. Transfection of APP promoter plasmids as substrates resulted in cytosolic AFT complex formation at the labeled APP promoter plasmids. In addition, identification of chromosomal APP or KAI1 gene loci by fluorescence in situ hybridization showed their close association with nuclear AFT complexes. The transcriptional activator Notch intracellular domain (NICD) localized to the same nuclear spots as occupied by AFT complexes, suggesting that these nuclear compartments correspond to transcription factories. Fe65 and Tip60 also co-localized with APP in the neurites of primary neurons. Pre-assembled AFT complexes may serve to assist fast nuclear signaling upon endoproteolytic APP cleavage.

show abstract

Phosphorylation of amyloid precursor carboxy-terminal fragments enhances their processing by a gamma-secretase-dependent mechanism

Cited by 75 publications

References 60 publications

Amyloid Precursor Protein and Presenilin1 Interact with the Adaptor GRB2 and Modulate ERK 1,2 Signaling

Amyloid Precursor Protein and Presenilin1 Interact with the Adaptor GRB2 and Modulate ERK 1,2 Signaling

The Loss of c-Jun N-Terminal Protein Kinase Activity Prevents the Amyloidogenic Cleavage of Amyloid Precursor Protein and the Formation of Amyloid PlaquesIn Vivo

Co-localization of the amyloid precursor protein and Notch intracellular domains in nuclear transcription factories

Contact Info

Product

Resources

About