Physiological Regulation of the  -Amyloid Precursor Protein Signaling Domain by c-Jun N-Terminal Kinase JNK3 during Neuronal Differentiation

Kimberly, W. Taylor; Zheng, Jessica B.; Town, Terrence; Flavell, Richard A.; Selkoe, Dennis J.

doi:10.1523/jneurosci.4883-04.2005

Cited by 108 publications

(87 citation statements)

References 63 publications

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“…We found that APP triggers a G o protein-dependent activation of the phosphorylation of c-Jun at Ser-63, indicating an activation of JNK. JNK3 has been reported to phosphorylate APP695 at Thr-668 (49). We found that the APP-dependent increases in cell surface expression of Nav1.6 required JNK and could be replicated by T668E mutation of APP695 to mimic phosphorylation.…”

Section: Discussionmentioning

confidence: 66%

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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Section: Discussionmentioning

confidence: 66%

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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“…Recent studies have suggested a physiological role of JNK3 in neuronal differentiation and neurite growth. 10,12 To study the potential role played by JNK3 palmitoylation in axonal development, we transfected cultured hippocampal neurons with the indicated constructs together with DsRed2 at 5 days in vitro (DIV) for 48 h. DsRed2 expression filled the neuron and was used to track the morphological changes of axons. At 7 DIV, neurons generated long and branched axons that were clearly labelled with both DsRed2 and the axonal marker Tau-1, and several short dendrites around neuronal somata, where only DsRed2 signals were detected (Figure 2a).…”

Section: Resultsmentioning

confidence: 99%

“…[3][4][5][6] However, accumulating evidence supports a physiological role of JNK in regulating neurite formation and morphogenesis. [7][8][9][10][11][12] Pharmacological inhibition of JNK activity blocks axogenesis in hippocampal neurons, arguing for an essential role of JNK in neurite development. 13 Growth factors and signalling molecules, including secreted proteins of the Wnt family, have also been found to activate JNK for remodelling dendrites and axons, a process that relies on cytoskeletal rearrangement.…”

mentioning

confidence: 99%

“…[3][4][5] JNK3 is thus considered as a key regulator of neuronal cell death, rather than that of neuronal development. However, recent studies highlight a physiological role of JNK3 in neuronal differentiation and neurite growth, 10,12 raising the possibility that each isoform may be differentially regulated to achieve selective functions. An understanding of how JNK isoforms are specifically regulated is essential for elucidating JNK isoform-specific roles in multiple biological processes.…”

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confidence: 99%

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Isoform-specific palmitoylation of JNK regulates axonal development

et al. 2011

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The c-jun N-terminal kinase (JNK) proteins are encoded by three genes (Jnk1-3), giving rise to 10 isoforms in the mammalian brain. The differential roles of JNK isoforms in neuronal cell death and development have been noticed in several pathological and physiological contexts. However, the mechanisms underlying the regulation of different JNK isoforms to fulfill their specific roles are poorly understood. Here, we report an isoform-specific regulation of JNK3 by palmitoylation, a posttranslational modification, and the involvement of JNK3 palmitoylation in axonal development and morphogenesis. Two cysteine residues at the COOH-terminus of JNK3 are required for dynamic palmitoylation, which regulates JNK3's distribution on the actin cytoskeleton. Expression of palmitoylation-deficient JNK3 increases axonal branching and the motility of axonal filopodia in cultured hippocampal neurons. The Wnt family member Wnt7a, a known modulator of axonal branching and remodelling, regulates the palmitoylation and distribution of JNK3. Palmitoylation-deficient JNK3 mimics the effect of Wnt7a application on axonal branching, whereas constitutively palmitoylated JNK3 results in reduced axonal branches and blocked Wnt7a induction. Our results demonstrate that protein palmitoylation is a novel mechanism for isoform-specific regulation of JNK3 and suggests a potential role of JNK3 palmitoylation in modulating axonal branching. The c-jun N-terminal kinase (JNK) family consists of JNK1, JNK2 and JNK3 subgroups, which participate in diverse biological and pathological processes. 1,2 At least 10 JNK isoforms of varied sizes, with most between 46 and 54 kDa, are produced from the Jnk1-3 genes, giving rise to JNK isoforms. 1 In the nervous system, JNKs (particularly isoform JNK3) have been extensively studied as the key players in apoptosis and neurodegeneration. [3][4][5][6] However, accumulating evidence supports a physiological role of JNK in regulating neurite formation and morphogenesis. 7-12 Pharmacological inhibition of JNK activity blocks axogenesis in hippocampal neurons, arguing for an essential role of JNK in neurite development. 13 Growth factors and signalling molecules, including secreted proteins of the Wnt family, have also been found to activate JNK for remodelling dendrites and axons, a process that relies on cytoskeletal rearrangement. 11,[14][15][16] This has led to the identification of several actin-or microtubule-associated proteins as JNK substrates that modulate different aspects of cytoskeletal activity. 17 However, all the 10 JNK isoforms share the same kinase domain and activation mechanism. 17 The differential roles of JNK isoforms in neurite development and the mechanisms underlying isoform-specific regulation are poorly understood.Analysis of animals null for particular JNK isoforms provides the first evidence to support isoform-specific roles of JNKs in the brain. Mice with Jnk1 À/À show abnormalities in neurite development, 7 whereas mice null for Jnk1 and Jnk2 show embryonic lethality due to severe neuro...

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“…The adaptor protein Fe65 has been implicated in AICDmediated transcriptional regulation (Cao and Sudhof, 2001) and Fe65 binding may stabilize AICD (Kimberly et al, 2001(Kimberly et al, , 2005; however, this effect was not observed in all reports (Cupers et al, 2001;Nakaya and Suzuki, 2006). To further investigate whether Fe65 could be a player in enhanced AICD stability, neprilysin expression, and concomitant A␤ decrease, we analyzed the effect of Fe65 on AICD stability and neprilysin expression.…”

Section: Increase In Aicd By Treatment With the Alkalizing Agent Nh 4mentioning

confidence: 99%

Gleevec Increases Levels of the Amyloid Precursor Protein Intracellular Domain and of the Amyloid-β–degrading Enzyme Neprilysin

Eisele

Baumann²,

Klebl³

et al. 2007

MBoC

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Amyloid-␤ (A␤) deposition is a major pathological hallmark of Alzheimer's disease. Gleevec, a known tyrosine kinase inhibitor, has been shown to lower A␤ secretion, and it is considered a potential basis for novel therapies for Alzheimer's disease. Here, we show that Gleevec decreases A␤ levels without the inhibition of Notch cleavage by a mechanism distinct from ␥-secretase inhibition. Gleevec does not influence ␥-secretase activity in vitro; however, treatment of cell lines leads to a dose-dependent increase in the amyloid precursor protein intracellular domain (AICD), whereas secreted A␤ is decreased. This effect is observed even in presence of a potent ␥-secretase inhibitor, suggesting that Gleevec does not activate AICD generation but instead may slow down AICD turnover. Concomitant with the increase in AICD, Gleevec leads to elevated mRNA and protein levels of the A␤-degrading enzyme neprilysin, a potential target gene of AICDregulated transcription. Thus, the Gleevec mediated-increase in neprilysin expression may involve enhanced AICD signaling. The finding that Gleevec elevates neprilysin levels suggests that its A␤-lowering effect may be caused by increased A␤-degradation. INTRODUCTIONThe main neuropathological features of Alzheimer's disease (AD) are the extracellular deposition of amyloid-␤ (A␤) peptides and the formation of intracellular neurofibrillary tangles, accompanied by neuron loss and dementia (Selkoe, 2001). A␤ is generated by sequential proteolytic cleavages of the amyloid precursor protein (APP) by ␤-secretase (BACE) and ␥-secretase. The ␥-secretase cleavage occurs within the membrane, releasing the APP intracellular domain (AICD) into the cytosol. AICD, together with its binding partners Fe65 and Tip60, is considered to be involved in transcriptional regulation (Cao and Sudhof, 2001). Putative target genes of AICD signaling have been suggested (Baek et al., 2002;Kim et al., 2003;von Rotz et al., 2004;Pardossi-Piquard et al., 2005;Ryan and Pimplikar, 2005;Muller et al., 2007), although results for some of these genes are controversial (Hass and Yankner, 2005;Hebert et al., 2006;Chen and Selkoe, 2007;Pardossi-Piquard et al., 2007). One potential AICD target gene is the A␤-degrading enzyme neprilysin (Pardossi-Piquard et al., 2005, a metalloprotease that is one of the main A␤-degrading enzymes in the brain (Carson and Turner, 2002).␥-Secretase is a multiprotein complex, processing several type I integral membrane proteins, including APP and the Notch receptor (Kopan and Ilagan, 2004). Therapeutic strategies aimed at lowering A␤ include the development of selective ␥-secretase inhibitors (Evin et al., 2006). However, long-term treatment with ␥-secretase inhibitors has shown severe side effects in preclinical animal studies due to inhibition of Notch processing and signaling (Searfoss et al., 2003;Wong et al., 2004).Recently, Gleevec (signal transduction inhibitor 571, STI571, imantinib mesylate), a tyrosine kinase inhibitor, has been described to lower A␤ in a cell-free system, in N2A cells e...

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Physiological Regulation of the -Amyloid Precursor Protein Signaling Domain by c-Jun N-Terminal Kinase JNK3 during Neuronal Differentiation

Cited by 108 publications

References 63 publications

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

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

Isoform-specific palmitoylation of JNK regulates axonal development

Gleevec Increases Levels of the Amyloid Precursor Protein Intracellular Domain and of the Amyloid-β–degrading Enzyme Neprilysin

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