Phosphorylation of Alzheimer β-Amyloid Precursor-like Proteins

Suzuki, Toshiharu; Ando, Kanae; Isohara, Toshio; Oishi, M.; Lim, Gloria S.; Satoh, Yasushi; Wasco, Wilma; Tanzi, Rudolph E.; Nairn, Angus C.; Greengard, Paul; Gandy, Samuel E.; Kirino, Yutaka

doi:10.1021/bi962618k

Cited by 54 publications

(44 citation statements)

References 23 publications

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“…One of these, Thr 668 , is located at position 16 in the amino-terminal region of the NPTY motif and is phosphorylated in brain tissue (48). Furthermore, we have found that Thr 668 phosphorylation of mature APP (mAPP, N-and O-glycosylated form) is neuron-specific, 5 although Thr 668 phosphorylation of immature APP (N-glycosylated form) is observed in nonneuronal cells during the mitotic phase of cell division (47)(48)(49). Therefore, we examined the effect of phosphorylation of APP at Thr 668 on the interaction between X11L and APP COOH .…”

Section: Fig 10mentioning

confidence: 82%

Interaction of a Neuron-specific Protein Containing PDZ Domains with Alzheimer's Amyloid Precursor Protein

Tomita

Ozaki

Taru

et al. 1999

Journal of Biological Chemistry

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225

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Alzheimer's amyloid precursor protein (APP) 1 is an integral membrane protein with a receptor-like structure (1). A principal component of parenchymal amyloid deposits in Alzheimer's disease (AD) is ␤-amyloid (A␤) (2-4), which is derived from APP by proteolytic cleavage (1, 5-11). A␤ is thought to be generated through an intracellular protein secretory pathway of APP (for a review, see Ref. 12). The short APP cytoplasmic domain consisting of 47 amino acid residues is thought to be responsible for determination of APP metabolism (13-15) and possible signal transduction from a putative extracellular ligand that has yet to be identified (for a review, see Ref. 16). Because APP is a candidate pathogenic factor of AD, elucidation of the physiological function of APP as well as the determination of the metabolic mechanism of A␤ production should increase our understanding of the pathogenesis of AD. Using a yeast two-hybrid system, we isolated cDNA of proteins that interact with the cytoplasmic domain of APP (APP COOH ) in order to elucidate the molecular mechanisms of APP metabolism and function of APP. Previous efforts to identify and isolate proteins associating with APP COOH , utilizing the yeast two-hybrid system, have resulted in the isolation of proteins carrying phosphotyrosine binding/phosphotyrosine interaction (PI) domains such as Fe65 (17), 19), and X11 (20). The X11 gene, which is located on chromosome 9, was originally isolated as a gene candidate for Friedreich ataxia (21) and its partial cDNA was identified as a clone encoding a protein that associates with APP COOH (22). The PI domain of X11 interacts with the YENPTY motif of APP COOH (20). In the present study, we isolated a complete cDNA encoding an X11-like protein (X11L) from a human adult brain cDNA library, utilizing the yeast two-hybrid system and APP COOH as a bait. A partial short cDNA encoding approximately 190 amino acids in the PI domain of X11L has already been isolated using a similar procedure (22). However, detailed characterization of X11L binding to APP and identification of the role X11L plays in the physiological function of APP have not been performed. We found that human X11L requires a sequence containing the NPXY motif of APP COOH for APP binding and that association of the PI domain with APP was suppressed by a deletion of a amino-terminal domain fused to the PI domain (PI ϩ C construct) but enhanced by a deletion of a carboxyl-terminal domain fused to the PI domain (N ϩ PI construct). Co-transfection of full-length human X11L into cells that express stably transfected human APP695 cDNA resulted in decreased secretion of A␤40 but not A␤42. However, co-transfection into cells of the cDNA lacking the carboxyl-terminal domain (N ϩ PI construct) or a cDNA encoding only the PI domain (PI construct), whose protein products preserve the ability to bind to APP COOH , did not present the ability to modulate A␤ production. The present results suggest that the amino-terminal region of the PI domain is needed to regulate binding affinity...

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Section: Fig 10mentioning

confidence: 82%

Interaction of a Neuron-specific Protein Containing PDZ Domains with Alzheimer's Amyloid Precursor Protein

Tomita

Ozaki

Taru

et al. 1999

Journal of Biological Chemistry

Self Cite

144

225

View full text Add to dashboard Cite

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“…4D). Interestingly, Thr 668 close to the APLP2 YENPTY interaction domain can be phosphorylated by a CDK1 kinase changing the binding properties of the YENPTY motif and thus couples APLP2 function and metabolism to the cell cycle (Suzuki et al, 1997;Tamayev et al, 2009). Similar to APLP2, CDK1 expression is also concentrated in the VZ/SVZ of developing cortex (Diez-Roux et al, 2011;Visel et al, 2004) suggesting that CDK1 could be involved in the regulation of neuronal development through APLP2.…”

Section: Discussionmentioning

confidence: 99%

APLP2 regulates neuronal stem cell differentiation during cortical development

Shariati

Lau

Hassan

et al. 2013

Journal of Cell Science

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SummaryExpression of amyloid precursor protein (APP) and its two paralogues, APLP1 and APLP2 during brain development coincides with key cellular events such as neuronal differentiation and migration. However, genetic knockout and shRNA studies have led to contradictory conclusions about their role during embryonic brain development. To address this issue, we analysed in depth the role of APLP2 during neurogenesis by silencing APLP2 in vivo in an APP/APLP1 double knockout mouse background. We find that under these conditions cortical progenitors remain in their undifferentiated state much longer, displaying a higher number of mitotic cells. In addition, we show that neuron-specific APLP2 downregulation does not impact the speed or position of migrating excitatory cortical neurons. In summary, our data reveal that APLP2 is specifically required for proper cell cycle exit of neuronal progenitors, and thus has a distinct role in priming cortical progenitors for neuronal differentiation.

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“…1B, lane 4), and therefore its tyrosine phosphorylation is unlikely. It was documented that APP is phosphorylated on Ser and Thr in vitro and in vivo (35,36). However, APP was never observed to be Tyr-phosphorylated.…”

Section: Abl Interacts With the Ww Domain Of The Fe65 Adaptormentioning

confidence: 99%