Alternatively spliced isoforms of FE65 serve as neuron-specific and non-neuronal markers

Hu, Q.; Hearn, Mark G.; Jin, Lee‐Way; Bressler, Steven L.; Martin, George M.

doi:10.1002/(sici)1097-4547(19991201)58:5<632::aid-jnr4>3.0.co;2-p

Cited by 25 publications

(43 citation statements)

References 25 publications

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“…1A). The effect of APP-interacting proteins on AICD localization was analyzed with a Fe65 isoform containing the mini-exon 9, which has been shown to be expressed exclusively in neuronal cells (Hu et al, 1999). When we coexpressed AICD with Fe65 the two proteins localized both in cytosolic and nuclear compartments (Fig.…”

Section: Resultsmentioning

confidence: 99%

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The APP intracellular domain forms nuclear multiprotein complexes and regulates the transcription of its own precursor

Rotz

Kohli

Bosset

et al. 2004

Journal of Cell Science

306

298

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The physiological functions of the beta-amyloid precursor protein (APP) may include nuclear signaling. To characterize the role of the APP adaptor proteins Fe65, Jip1b, X11α (MINT1) and the chromatin-associated protein Tip60, we analyzed their interactions by confocal microscopy and co-immunoprecipitations. AICD corresponding to S3-cleaved APP bound to Fe65 that transported it to nuclei and docked it to Tip60. These proteins formed AICD-Fe65-Tip60 (AFT) complexes that were concentrated in spherical nuclear spots. γ-Secretase inhibitors prevented AFT-complex formation with AICD derived from full-length APP. The APP adaptor protein Jip1b also transported AICD to nuclei and docked it to Tip60, but AICD-Jip1b-Tip60 (AJT) complexes had different, speckle-like morphology. By contrast, X11α trapped AICD in the cytosol. Induced AICD expression identified the APP-effector genes APP, BACE, Tip60, GSK3β and KAI1, but not the Notch-effector gene Hes1 as transcriptional targets. These data establish a role for APP in nuclear signaling, and they suggest that therapeutic strategies designed to modulate the cleavage of APP affect AICD-dependent signaling.

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Section: Resultsmentioning

confidence: 99%

“…Neurons express high endogenous levels of APP, Fe65 and Tip60 (Card et al, 1988;Hu et al, 1999;Ran and Pereira-Smith, 2000;Russo et al, 1998;Shivers et al, 1988), and neurons process APP to form AICD. It is therefore conceivable that neurons can form AFT-and AJTcomplexes.…”

Section: Full-length App Functions In Nuclear Signalingmentioning

confidence: 99%

The APP intracellular domain forms nuclear multiprotein complexes and regulates the transcription of its own precursor

Rotz

Kohli

Bosset

et al. 2004

Journal of Cell Science

306

298

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“…We fused Gal4DB directly to either the N terminus (Gal4DB-p97FE65) or the C terminus (p97FE65-Gal4DB) of the neuronal form of p97FE65 (30), and we assessed their nuclear signaling in several cell lines. As expected, when Gal4DB-p97FE65 or p97FE65-Gal4DB was coexpressed with the luciferase reporter gene in HEK293 cells, transcription of the reporter gene could be turned on by either fusion protein (Fig.…”

Section: Resultsmentioning

confidence: 99%

A Dominant Role for FE65 (APBB1) in Nuclear Signaling

Yang

Cool

Martin

et al. 2006

Journal of Biological Chemistry

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FE65 has been described as an adaptor protein; its partners include the ␤-amyloid precursor protein (APP) and Tip60 (a histone acetyltransferase). Recent evidence suggests that APP may function in a nuclear signaling pathway via formation of APP-FE65-Tip60 complexes. The evidence is largely based on experiments in which APP/Tip60 is fused to the DNA binding domain of a yeast transcriptional factor Gal4 (Gal4DB) that can activate a reporter gene only when FE65 is coexpressed. One interpretation of published experiments has not yet been tested; however, there is the possibility that FE65 itself is the dominant transcriptional activator, whereas APP and Tip60 serve merely as positive/negative modulators or bridges for connecting FE65 to Gal4DB. To test this possibility, we fused Gal4DB directly to either end of FE65 and assessed their nuclear signaling in the presence or absence of exogenous APP/Tip60 or after knockdown of endogenous APP/Tip60. We found that FE65-Gal4DB by itself was able to trigger robust reporter activities. Increasing levels of APP could not further augment the reporter activity, but knocking down endogenous APP or interrupting FE65-APP binding reduced the signaling by up to 2-fold. The magnitudes of the reporter activities did not correlate with relative FE65 affinities for APP. Both overexpression and knockdown experiments showed that Tip60 plays a negative role. The results are consistent with the notion that FE65 is the key agent of Gal4DB-mediated transcriptional transactivation, whereas Tip60 is an FE65-associated repressor. Although APP may have modest stimulating effects, apparently there is no absolute requirement for that molecule for the nuclear signaling pathway.FE65 is a brain-enriched protein and has the ability to interact with several different proteins via its three protein-protein interaction domains as follows: a WW domain and two phosphotyrosine interaction domains (PID 2 domains) (1, 2). PID1 interacts with Tip60 (Tatinteractive protein, 60 kDa); PID2 is the main region bound by the APP intracellular domain (AICD). These interactions may have impacts on APP processing (1, 3, 4), membrane dynamics (including axonal projections and neuronal positioning) (5-7), learning and memory (8), and transcriptional transactivation (9).APP is the best studied protein in the field of Alzheimer research because causal relationships have been established with mutations in APP and presenilins, enzymes involved in APP processing (10 -12). Proteolytic fragments of APP are also key components of Alzheimer pathology (13). Despite extensive research efforts, however, APP functions are poorly understood. The protein undergoes two consecutive cleavages at sites near or within its transmembrane domain (12). The first cleavages (by ␣-/␤-secretases) shed APP ectodomains into extracellular environments, perhaps leading to modulations of cell proliferation and adhesion, neurite outgrowth, and synaptogenesis (6, 14,15). A subsequent cleavage (by ␥-secretases complexes) liberates P3 or the ␤-amyloid peptid...

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“…Cell Cultures and DNA Transfection-Cell cultures were performed as described previously (6). For transient transfection, cells were seeded at 80 -90% of confluence before transfection.…”

Section: Methodsmentioning

confidence: 99%

Endoproteolytic Cleavage of FE65 Converts the Adaptor Protein to a Potent Suppressor of the sAPPα Pathway in Primates

Wang

Yang

et al. 2005

Journal of Biological Chemistry

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Adaptor protein FE65 (APBB1) specifically binds to the intracellular tail of the type I transmembrane protein, ␤-amyloid precursor protein (APP). The formation of this complex may be important for modulation of the processing and function of APP. APP is proteolytically cleaved at multiple sites. The cleavages and their regulation are of central importance in the pathogenesis of dementias of the Alzheimer type. In cell cultures and perhaps in vivo, secretion of the ␣-cleaved APP ectodomain (sAPP␣) is the major pathway in the most cells. Regulation of the process may require extracellular/intracellular cues. Neither extracellular ligands nor intracellular mediators have been identified, however. Here, we show novel evidence that the major isoform of FE65 (97-kDa FE65, p97FE65) can be converted to a 65-kDa N-terminally truncated C-terminal fragment (p65FE65) via endoproteolysis. The cleavage region locates immediately after an acidic residue cluster but before the three major protein-protein binding domains. The cleavage activity is particularly high in human and non-human primate cells and low in rodent cells; the activity appears to be triggered/enhanced by high cell density, presumably via cell-cell/cell-substrate contact cues. As a result, p65FE65 exhibits extraordinarily high affinity for APP (up to 40-fold higher than p97FE65) and potent suppression (up to 90%) of secretion of sAPP␣. Strong p65FE65-APP binding is required for the suppression. The results suggest that p65FE65 may be an intracellular mediator in a signaling cascade regulating ␣-secretion of APP, particularly in primates.FE65 is a multimodular adaptor protein, consisting of three major protein-protein interaction domains, a WW domain and two phosphotyrosine interaction domains (PID) 1 (1, 2) ( Fig. 2A). The interaction between FE65 and APP mainly takes place between the C-terminal PID (PID2) and the APP intracellular domain (AICD), although other regions may also potentially contribute to the action. The physiological effects of FE65-〈PP complexes are not well understood. Genetic evidence suggests that strong FE65-〈PP binding was favored by natural selection during animal evolution toward human lineage (3). 〈PP is a widely studied protein because of its role in the pathogenesis of dementias of the Alzheimer type (DAT). FE65 is predominantly expressed in central nervous system neurons, and its expression is regulated during development and aging, with high levels corresponding to the timing of neural tissue formation and high neuronal activity (4 -8). Selective knockout of the p97FE65 isoform results in modest impairments in learning but severe deficits in relearning spatial tasks (8). These phenotypes reflect reduced synaptic plasticity. Thus, the APP-FE65 pathway may play roles in normal and abnormal cognitive functions. In addition to binding to AICD, FE65 can also interact, at least in vitro, with several other proteins through its WW and PID1 domains (1, 2). FE65 is able to translocate between the nucleus and cytoplasm, consistent with the d...

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Alternatively spliced isoforms of FE65 serve as neuron-specific and non-neuronal markers

Cited by 25 publications

References 25 publications

The APP intracellular domain forms nuclear multiprotein complexes and regulates the transcription of its own precursor

The APP intracellular domain forms nuclear multiprotein complexes and regulates the transcription of its own precursor

A Dominant Role for FE65 (APBB1) in Nuclear Signaling

Endoproteolytic Cleavage of FE65 Converts the Adaptor Protein to a Potent Suppressor of the sAPPα Pathway in Primates

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