Neuron‐Specific Phosphorylation of Alzheimer's β‐Amyloid Precursor Protein by Cyclin‐Dependent Kinase 5

Iijima, Koichi; Ando, Kanae; Takeda, Shuji; Satoh, Yasushi; Seki, Tatsunori; Itohara, Shigeyoshi; Greengard, Paul; Kirino, Yutaka; Nairn, Angus C.; Suzuki, Toshiharu

doi:10.1046/j.1471-4159.2000.0751085.x

Cited by 218 publications

(196 citation statements)

References 26 publications

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“…APP may also be phosphorylated on Thr 668 (37), which may result in alteration of the conformational structure of AID and reduced interaction with at least one cytoplasmic binding partner, Fe65 (38,39). To investigate the role of Thr 668 for the interaction of AID with Shc A PTB, we generated two AID mutants in which Thr 668 was mutated to either Ala or Glu and expressed these constructs as GST fusion proteins.…”

Section: Aid Interacts With the Shc A Ptb Domain In Vitro-mentioning

confidence: 99%

Tyrosine Phosphorylation of the β-Amyloid Precursor Protein Cytoplasmic Tail Promotes Interaction with Shc

Tarr

Roncarati

Pelicci

et al. 2002

Journal of Biological Chemistry

123

100

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The ␤-amyloid precursor protein (APP) 1 is a ubiquitously expressed cell membrane protein that is sequentially cleaved by ␤-secretase and ␥-secretase to release extracellular peptides (including the ␤-amyloid peptides, which are deposited in the brain in Alzheimer's disease) and the APP intracellular domain (AID) (reviewed in Ref. 1).The biological function of APP and the factor(s) that trigger the APP proteolytic cascade remain unclear. APP and its two closely related homologues, APP-like protein (APLP) -1 and -2, appear to share redundant but essential function(s), because mice with single knockouts of these genes only show mild phenotypic abnormalities, whereas double and triple knockouts are lethal in the prenatal period (2). ␥-Secretase cleavage of APP requires nicastrin and presenilins (reviewed in Ref.3). Presenilins and APP are the only identified proteins known to be mutated in cases of familial Alzheimer's disease. Presenilins are also required for the ␥-secretase proteolysis of the cellsurface receptor Notch (4), which releases the Notch intracellular domain (NICD) that translocates to the nucleus where it acts as a transcriptional regulator (5). Evidence is accumulating that APP is a receptor-like protein (6) whose function is mediated by AID, analogous to Notch/NICD (7-10). Peptides consistent with AID have been detected in brain homogenates of Alzheimer's and elderly control subjects (7-8) and in metabolically labeled cells (9). Overexpression of AID induces apoptosis or may augment apoptosis triggered by other factors (8), offering a potential mechanistic explanation for data functionally linking APP and presenilins to enhanced neuronal apoptosis (11-15). APP interacts via its cytoplasmic tail with a number of cytoplasmic proteins, including Fe65, X11, and murine DAB 1 (16 -18), all of which share characteristics of adapter proteins that could potentially link APP to intracellular signaling pathways. APP may anchor Fe65 in the cytosol, whereas the release of AID from APP by ␥-cleavage may allow the AID-Fe65 complex to translocate to the nucleus where it acts as a transcription factor (10, 19).To identify cellular pathways to which the AID peptide may signal, we used the yeast 2-hybrid system to identify proteins with which AID may interact. As expected, our yeast 2-hybrid screen identified known APP-interacting proteins, including Fe65 and X11. We (20) and others (21) recently identified human c-JUN N-terminal kinase (JNK) interacting protein (JIP)-1 as a novel APP-binding protein. X11, Fe65, mDAb-1, and JIP-1 share as a common feature the presence of phosphotyrosine binding (PTB) domains. PTB domains are protein interaction domains that bind tyrosine residues located within the cytoplasmic tails of activated cellular receptors (22-23). To investigate further the interaction between APP and the proteins identified in the yeast 2-hybrid screen, we performed glutathione S-transferase (GST) binding and co-immunoprecipitation experiments. As a negative control for these assays, we used the PTB domai...

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Section: Aid Interacts With the Shc A Ptb Domain In Vitro-mentioning

confidence: 99%

Tyrosine Phosphorylation of the β-Amyloid Precursor Protein Cytoplasmic Tail Promotes Interaction with Shc

Tarr

Roncarati

Pelicci

et al. 2002

Journal of Biological Chemistry

123

100

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“…Interestingly, Thr 668 -phosphorylated APP (pAPP) is preferentially localized to neurite endings (Ando et al, 1999;Iijima et al, 2000), suggesting that phosphorylation might regulate APP transport into neurites. Phosphorylation of APP has also been implicated in neuronal differentiation (Ando et al, 1999), APP processing by secretases (Lee et al, 2003), and localization of an APP fragment to the nucleus (Muresan and Muresan, 2004).…”

Section: Introductionmentioning

confidence: 99%

“…Potential candidates are cyclin-dependent kinase 5 (Cdk5) (Iijima et al, 2000), c-Jun NH 2 -terminal kinase (JNK) (Standen et al, 2001;Taru et al, 2002;Scheinfeld et al, 2003), and glycogen synthase kinase 3␤ (Aplin et al, 1996). These kinases phosphorylate Thr 668 in vitro and, under certain experimental conditions, in vivo.…”

Section: Introductionmentioning

confidence: 99%

c-Jun NH₂-Terminal Kinase-Interacting Protein-3 Facilitates Phosphorylation and Controls Localization of Amyloid-β Precursor Protein

Muresan¹,

Mureşan²

2005

J. Neurosci.

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Abnormal phosphorylation of amyloid-␤ precursor protein (APP) is a pathologic feature of Alzheimer's disease. To begin to understand the mechanism of APP phosphorylation, we studied this process in differentiating neurons under normal physiological conditions. We found that c-Jun NH 2 -terminal kinase (JNK), not cyclin-dependent kinase 5, is required for APP phosphorylation, leading to localized accumulation of phosphorylated APP (pAPP) in neurites. We show that JNK-interacting protein-3 (JIP-3), a JNK scaffolding protein that does not bind APP, selectively increases APP phosphorylation, accumulation of pAPP into processes, and stimulates process extension in both neurons and COS-1 cells. Downregulation of JIP-3 by small interfering RNA impairs neurite extension and reduces the amount of localized pAPP. Finally, whereas stress-activated JNK generates pAPP only in the cell body, concomitant expression of JIP-3 restores pAPP accumulation into neurites. Thus, APP phosphorylation, transport of the generated pAPP into neurites, and neurite extension are interdependent processes regulated by JIP-3/JNK, in a pathway distinct from stress-activated JNK signaling.

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“…Neuron-specific phosphorylation of APP695 at Thr-668, within the G o protein-binding domain of APP, can alter APP binding to partners (11). In the brain, phosphorylation of APP695 at Thr-668 is mediated by neuronal CDK5 (12), GSK-3␤ (13), or JNK3 (14).…”

mentioning

confidence: 99%

Amyloid Precursor Protein Enhances Nav1.6 Sodium Channel Cell Surface Expression

Liu

Tan

Xiao

et al. 2015

Journal of Biological Chemistry

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Background: Loss-of-function amyloid precursor protein (APP) and Nav1.6 transgenic mice share similar phenotypes. Results: APP interacts with Nav1.6 and enhances its cell surface expression through a G o -coupled JNK pathway. Conclusion: APP regulates Nav1.6 function, likely through a G o -coupled JNK pathway. Significance: This finding advances the current understanding of APP functions and has implications for novel therapies for neurodegenerative disorders.

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Neuron‐Specific Phosphorylation of Alzheimer's β‐Amyloid Precursor Protein by Cyclin‐Dependent Kinase 5

Cited by 218 publications

References 26 publications

Tyrosine Phosphorylation of the β-Amyloid Precursor Protein Cytoplasmic Tail Promotes Interaction with Shc

Tyrosine Phosphorylation of the β-Amyloid Precursor Protein Cytoplasmic Tail Promotes Interaction with Shc

c-Jun NH₂-Terminal Kinase-Interacting Protein-3 Facilitates Phosphorylation and Controls Localization of Amyloid-β Precursor Protein

Amyloid Precursor Protein Enhances Nav1.6 Sodium Channel Cell Surface Expression

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Neuron‐Specific Phosphorylation of Alzheimer's β‐Amyloid Precursor Protein by Cyclin‐Dependent Kinase 5

Cited by 218 publications

References 26 publications

Tyrosine Phosphorylation of the β-Amyloid Precursor Protein Cytoplasmic Tail Promotes Interaction with Shc

Tyrosine Phosphorylation of the β-Amyloid Precursor Protein Cytoplasmic Tail Promotes Interaction with Shc

c-Jun NH2-Terminal Kinase-Interacting Protein-3 Facilitates Phosphorylation and Controls Localization of Amyloid-β Precursor Protein

Amyloid Precursor Protein Enhances Nav1.6 Sodium Channel Cell Surface Expression

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c-Jun NH₂-Terminal Kinase-Interacting Protein-3 Facilitates Phosphorylation and Controls Localization of Amyloid-β Precursor Protein