Phosphorylation of a Tyrosine in the Amyloid-beta Protein Precursor Intracellular Domain Inhibits Fe65 Binding and Signaling
ABSTRACT The phosphorylation of Tyr-682 residue in the intracellular domain (AID) of amyloid-beta protein precursor (AbetaPP) is significantly enhanced in Alzheimer's disease patients' brain. The role of this phosphotyrosine, however, remains elusive. Here we report that phosphorylation of Tyr-682 inhibits the interactions between AbetaPP and Fe65, which is the main regulatory mechanism controlling Fe65 nuclear signaling. Furthermore, we show that tyrosine phosphorylation of AbetaPP also inhibits interaction of the two other Fe65 family members, Fe65L1 and Fe65L2. Likewise, docking of Fe65, Fe65L1 and Fe65L2 to APLP1 and APLP2, the two other members of the AbetaPP-gene family, is abolished by analogous phosphorylation events. Our results indicate that phosphorylation of the cytoplasmic tail of AbetaPP on Tyr-682 represents a second mechanism, alternative to AbetaPP processing by secretases, that regulates AbetaPP/Fe65 downstream signaling pathways.
- SourceAvailable from: Siro Luvisetto
[Show abstract] [Hide abstract]
- "Phosphorylation of Y 682 is consequential. Some proteins, such as Grb2 (Russo et al., 2002; Zhou et al., 2004), Shc (Russo et al., 2002; Tarr et al., 2002), Grb7, and Crk (Tamayev et al., 2009), interact with APP only when Y 682 is phosphorylated, whereas others, like Fe65, Fe65L1, and Fe65L2, only when this tyrosine is not phosphorylated (Zhou et al., 2009), suggesting that phosphorylation–dephosphorylation on Y 682 modulates APP functions. "
ABSTRACT: Processing of Aβ-precursor protein (APP) plays an important role in Alzheimer's disease (AD) pathogenesis. The APP intracellular domain contains residues important in regulating APP function and processing, in particular the (682) YENPTY(687) motif. To dissect the functions of this sequence in vivo, we created an APP knock-in allele mutating Y(682) to Gly (APP(YG/YG) mice). This mutation alters the processing of APP and TrkA signaling and leads to postnatal lethality and neuromuscular synapse defects when expressed on an APP-like protein 2 KO background. This evidence prompted us to characterize further the APP(YG/YG) mice. Here, we show that APP(YG/YG) mice develop aging-dependent decline in cognitive and neuromuscular functions, a progressive reduction in dendritic spines, cholinergic tone, and TrkA levels in brain regions governing cognitive and motor functions. These data are consistent with our previous findings linking NGF and APP signaling and suggest a causal relationship between altered synaptic connectivity, cholinergic tone depression and TrkA signaling deficit, and cognitive and neuromuscular decline in APP(YG/YG) mice. The profound deficits caused by the Y(682) mutation underscore the biological importance of APP and indicate that APP(YG/YG) are a valuable mouse model to study APP functions in physiological and pathological processes.Aging cell 09/2012; DOI:10.1111/acel.12009 · 5.94 Impact Factor
[Show abstract] [Hide abstract]
- "Furthermore, Fe65, the histone acetyltransferase Tip60 and AICD form a tripartite complex (Cao and Südhof 2001) that is thought to drive AICD cellular compartmentalization and AICD-mediated function. Inhibition of this interaction by tyrosine phosphorylation (Zhou et al. 2009) or Fe65 sequestration by the estrogen a receptor (Bao et al. 2007) all lead to the abolishment of AICDmediated signaling. Conversely, Nakaya and Suzuki (2006) proposed that AICD increased Fe65-mediated nuclear signaling but that the two proteins did not traffic together to the nucleus. "
ABSTRACT: The amyloid-β precursor protein (βAPP) undergoes several cleavages by enzymatic activities called secretases. Numerous studies aimed at studying the biogenesis and catabolic fate of Aβ peptides, the proteinaceous component of the senile plaques that accumulate in Alzheimer's disease-affected brains. Relatively recently, another secretase-mediated β-APP-derived catabolite called APP IntraCellular Domain (AICD) entered the game. Whether AICD corresponded to a biologically inert by-pass product of βAPP processing or whether it could harbor its own function remained questionable. In this study, we review the mechanisms by which AICD is generated and how its production is regulated. Furthermore, we discuss the degradation mechanism underlying its rapid catabolic fate. Finally, we review putative AICD-related functions and more particularly, the numerous studies indicating that AICD could translocate to the nucleus and control at a transcriptional level, the expression of a series of proteins involved in various functions including the control of cell death and Aβ degradation.Journal of Neurochemistry 11/2011; 120 Suppl 1:109-24. DOI:10.1111/j.1471-4159.2011.07475.x · 4.24 Impact Factor
[Show abstract] [Hide abstract]
- "Some proteins interact with APP only when Y 682 is phosphorylated, others only when this tyrosine is not phosphorylated (C. Russo et al., 2002; P. E. Tarr et al., 2002a; D. Zhou et al., 2004; R. Tamayev et al., 2009; D. Zhou et al., 2009). Given this crucial role of Y 682 , it is conceivable that phosphorylation of this residue has fundamental biological and pathological consequences. "
ABSTRACT: The pathogenic model of Alzheimer's disease (AD) posits that aggregates of amyloid β, a product of amyloid precursor protein (APP) processing, cause dementia. However, alterations of normal APP functions could contribute to AD pathogenesis, and it is therefore important to understand the role of APP. APP is a member of a gene family that shows functional redundancy as documented by the evidence that single knock-out mice are viable, whereas mice with combined deletions of APP family genes die shortly after birth. A residue in the APP intracellular region, Y(682), is indispensable for these essential functions of APP. It is therefore important to identify pathways that regulate phosphorylation of Y(682) as well as the role of Y(682) in vivo. TrkA is associated with both phosphorylation of APP-Y(682) and alteration of APP processing, suggesting that tyrosine phosphorylation of APP links APP processing and neurotrophic signaling to intracellular pathways associated with cellular differentiation and survival. Here we have tested whether the NGF/TrkA signaling pathway is a physiological regulator of APP phosphorylation. We find that NGF induces tyrosine phosphorylation of APP, and that APP interacts with TrkA and this interaction requires Y(682). Unpredictably, we also uncover that APP, and specifically Y(682), regulates activation of the NGF/TrkA signaling pathway in vivo, the subcellular distribution of TrkA and the sensitivity of neurons to the trophic action of NGF. This evidence suggests that these two membrane protein's functions are strictly interconnected and that the NGF/TrkA signaling pathway is involved in AD pathogenesis and can be used as a therapeutic target.The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 08/2011; 31(33):11756-61. DOI:10.1523/JNEUROSCI.1960-11.2011 · 6.75 Impact Factor