Disease relevance of APBB1

• Finally, we demonstrate that Fe65, an important AICD-binding protein, transactivates a wide variety of different promoters, including the viral simian virus 40 promoter, independent of AICD coexpression [1].
• Selective up-regulation of only the FE65 neuronal isoform was seen in the cerebellar cortex in association with other neurodegenerative diseases (largely Parkinson's disease) [2].
• The aim of this study was to evaluate Doppler renal resistance index (RI) and RI ratio (RIR) in differentiating between obstructive and nonobstructive hydronephrosis in children and adolescents [3].
• Real-time PCR quantitation of FE65 a beta-amyloid precursor protein-binding protein after traumatic brain injury in rats [4].
• The RI and RIR differences were statistically significant between controls and patients with acute colic ( p<0.01), and between patients with acute obstruction and with nonobstructive hydronephrosis ( p<0.01) [3].

Psychiatry related information on APBB1

• Model study findings were confirmed by running indel DASH assays upon PCR-amplified targets representing four polymorphisms from Alzheimer's disease candidate genes APBB1 and LRP1 [5].
• A candidate molecular mechanism for the association of an intronic polymorphism of FE65 with resistance to very late onset dementia of the Alzheimer type [6].

High impact information on APBB1

• We now demonstrate that the cytoplasmic tail of APP forms a multimeric complex with the nuclear adaptor protein Fe65 and the histone acetyltransferase Tip60 [7].
• The disruption of pial basal membranes underlying the heterotopias and poor organization of fibrillar laminin by isolated meningeal fibroblasts from double knockouts suggests that FE65 proteins are involved in basement membrane assembly [8].
• Heterotopias resembling those found in cobblestone lissencephalies in which neuroepithelial cells migrate into superficial layers of the developing cortex, aberrant cortical projections and loss of infrapyramidal mossy fibers arise in FE65/FE65L1 compound null animals, but not in single gene knockouts [8].
• Here, we report that APP and FE65 are involved in regulation of cell movement [9].
• APP and FE65 colocalize with actin and Mena, an Abl-associated signaling protein thought to regulate actin dynamics, in lamellipodia [9].

Biological context of APBB1

• cDNA cloning and chromosome mapping of the human Fe65 gene: interaction of the conserved cytoplasmic domains of the human beta-amyloid precursor protein and its homologues with the mouse Fe65 protein [10].
• The human Fe65 mRNA was cloned from a fetal brain cDNA library [10].
• The human Fe65 gene was mapped on human metaphase chromosomes to band 11p15 using fluorescence in situ hybridization [10].
• Sequence analysis of the FE65 of mice, non-human primates and man revealed that the susceptibility allele, which codes for strong binding of the FE65 protein with betaPP, was favored by natural selection leading to our lineage [6].
• Coordinated metabolism of Alcadein and amyloid beta-protein precursor regulates FE65-dependent gene transactivation [11].

Anatomical context of APBB1

• In the present paper we show that the overexpression of Fe65 prevents G(1) --> S cell cycle progression of serum-stimulated fibroblasts and that the contemporary overexpression of APP abolishes this effect of Fe65 [12].
• APP and FE65 specifically concentrate with beta 1-integrin in dynamic adhesion sites known as focal complexes, but not in more static adhesion sites known as focal adhesions [9].
• FE65 in Alzheimer's disease: neuronal distribution and association with neurofibrillary tangles [13].
• We demonstrate here that APP and FE65 co-localize in the endoplasmic reticulum/Golgi and possibly in endosomes [14].
• The amyloid precursor protein and its regulatory protein, FE65, in growth cones and synapses in vitro and in vivo [15].

Associations of APBB1 with chemical compounds

• In neuronal PC12 cells, the overexpression of Fe65 or of Fe65L1 and Fe65L2 blocks cell cycle, as observed in fibroblasts, but thymidine supplementation to culture medium does not revert this block, thus suggesting that Fe65 proteins induce in neuronal cells a gene expression program different from that activated in fibroblasts [12].
• However, unlike the case for binding of the Shc PI/PTB domain, tyrosine phosphorylation of the YENPTY motif is not required for the binding of (beta)APP to X11 or FE65 [16].
• The phosphotyrosine interaction domains of X11 and FE65 bind to distinct sites on the YENPTY motif of amyloid precursor protein [16].
• These mice do not show any obvious phenotype; however, when fibroblasts (mouse embryonic fibroblasts), isolated from Fe65 KO embryos, were exposed to low doses of DNA damaging agents, such as etoposide or H(2)O(2), an increased sensitivity to genotoxic stress, compared with wild type animals, clearly emerged [17].
• The present study shows that 17beta-estradiol inhibits the transcriptional and apoptotic activities of the APPct complex by a process involving the interaction of estrogen receptor alpha (ERalpha) with Fe65 [18].

Physical interactions of APBB1

• The small size of the APP cytodomain and the overlapping of its regions involved in the binding of Fe65 and X11 suggest the existence of competitive mechanisms regulating the binding of the various ligands to this cytosolic domain [19].
• Fe65 and X11beta co-localize with and compete for binding to the amyloid precursor protein [20].
• AICD corresponding to S3-cleaved APP bound to Fe65 that transported it to nuclei and docked it to Tip60 [21].

Enzymatic interactions of APBB1

• We propose that the Alcs and APP are coordinately metabolized in neurons and that their cleaved cytoplasmic fragments are reciprocally involved in the regulation of FE65-dependent gene transactivation [11].

Regulatory relationships of APBB1

• Any imbalance in the metabolism of Alcs and APP may influence the FE65-dependent gene transactivation, which together with increased secretion of amyloid beta-protein may contribute to neural disorders [11].
• We also show that Fe65 is a substrate for phosphorylation by the mitogen-activated protein kinases ERK1/2 [22].
• Expression of MT3-MMP enhanced Fe65-dependent transactivation by APP fused to the Gal4 DNA-binding and transactivation domains [23].
• Dexras1 functions as a suppressor of FE65-APP-mediated transcription, and FE65 tyrosine 547 phosphorylation enhances FE65-APP-mediated transcription, at least in part, by modulating the interaction between FE65 and Dexras1 [24].

Other interactions of APBB1

• Here we show that the LRPICD is translocated to the nucleus, where it colocalizes in the nucleus with a transcription modulator, Tip60, which is known to interact with Fe65 and with the APP-derived intracellular domain [25].
• Demonstration by fluorescence resonance energy transfer of two sites of interaction between the low-density lipoprotein receptor-related protein and the amyloid precursor protein: role of the intracellular adapter protein Fe65 [26].
• LRPICD dramatically inhibits APP-derived intracellular domain/Fe65 transactivation mediated by Tip60 [25].
• Low-density lipoprotein receptor-related protein levels and endocytic function are reduced by overexpression of the FE65 adaptor protein, FE65L1 [27].
• We could demonstrate binding of the intracellular domain of Notch1 to the APP adaptor protein Fe65 [28].

Analytical, diagnostic and therapeutic context of APBB1

• Sequence analysis of the FE65 human gene family reveals the presence of two phosphotyrosine interaction (PI) domains [29].
• Using site-directed mutagenesis, we have identified a crucial residue within the PI domain involved in X11 and FE65 binding to (beta)APP [16].
• This interaction, previously demonstrated in vitro and in the yeast two hybrid system, also takes place in vivo in mammalian cells, as demonstrated here by anti-Fe65 co-immunoprecipitation experiments [30].
• We demonstrate by confocal microscopy and fluorescence resonance energy transfer analysis that APP-C58 translocates to the nucleus and forms a complex in the nucleus with the Tip60, independent of interactions with Fe65 [31].
• Using a combination of immunofluorescence, live imaging, and subcellular fractionation, we find that FE65 and APP localize in vitro and in vivo to the most motile regions of neurons, the growth cones [15].

References