1,721,035 research outputs found
The cytosolic domain of APP and its possible role in the pathogenesis of Alzheimer's disease
No full textFe65L2: a new member of the Fe65 protein family interacting with the intracellular domain of the Alzheimer's b-amyloid precursor protein
No full textFe65L2: a new member of the Fe65 protein family interacting with the intracellular domain of the Alzheimer's b-amyloid precursor protein
No full textFe65 matters: New light on an old molecule.
No full textThe discovery that the main constituents of amyloid deposits, characteristic of Alzheimer neuropathology, derive from the proteolytic processing of the membrane precursor amyloid precursor protein (APP) is one of the milestones of the research history of this disease. Despite years of intense studies, the functions of APP and of its amyloidogenic processing are still under debate. One focus of these studies was the complex network of protein-protein interactions centered at the cytosolic domain of APP, which suggests the involvement of APP in a lively signaling pathway. Fe65 was the first protein to be demonstrated to interact with the APP cytodomain. Starting from this observation, a large body of data has been gathered, indicating that Fe65 is an adaptor protein, which binds numerous proteins, further than APP. Among these proteins, the crosstalk with Mena, mDab, and Abl suggested the involvement of the Fe65-APP complex in the regulation of cell motility, with a relevant role in differentiation and development. Other partners, like the histone acetyltransferase Tip60, indicated the possibility that the nuclear fraction of Fe65 could be involved in gene regulation and/or DNA repair
The Fe65 adaptor protein interacts through its PID1 domain with the transcription factor CP2/LSF/LBP1
No full textActivation of amyloid precursor protein processing by growth factors is dependent on Ras GTPase activity
No full textThe β-amyloid peptide is generated by the proteolysis of the amyloid precursor protein (APP) by the action
of β- and γ-secretase. The mechanisms underlying this process are poorly understood. Using a cell-based
reporter gene assay we analysed the possible signals and pathways that could be involved in APP cleavage.
We used the stable cell line HeLa AG that expresses the human APP695 fused with the yeast transcription
factor Gal4. This fusion protein is normally translocated into the plasma membrane and after APP-Gal4
cleavage, the AICD-Gal4 fragment released can activate the transcription of a luciferase reporter gene.
Through this reporter system, we demonstrated that Ras GTPase, but not Ral and Rap, could promote APPGal4
cleavage. In addition HeLa AG cells stimulated with EGF or PDGF or overexpressing EGFR exhibit
increased APP proteolysis in a Ras-dependent way. This process is also dependent on γ-secretase activity,
being abolished by the γ-secretase inhibitor DAPT
Le molecole coinvolte nella patogenesi della malattia di Alzheimer come bersagli di farmaci.
No full textMolecular function of the WW domainof Fe65 adaptor protein: towardsunderstanding of signaling byAlzheimer’s amyloid precursor protein
No full textFE65 protein is an important component of the oligomeric complex assembled
by the Alzheimer’s amyloid precursor protein (APP). The interaction
between APP and FE65 was documented biochemically and genetically.
The emerging pathway of signaling by FE65 and APP resembles that of
Notch. It involves the presenilin-mediated cleavage of APP that results in
the APP fragment/FE65 complex translocation to the nucleus where it affects
transcription. FE65 is a typical adapter containing two types of protein
modules: theWWdomain and two PTB domains. The first PTB domain interacts
functionally with the transcripton factor LSF or the histone acetylase
Tip60. The second PTB mediates the complex with APP. The FE65 WW
domain interacts with several proteins involved in the nuclear function and
in the regulation of cytoskeleton, e.g. MENA and Abl. Since the effects of
FE65 on transcription are mediated by itsWWdomains and since FE65 with
mutated WW domain has biological effects on the processing of APP, we
elected to identify the repertoire of proteins, which interact with the wild-type
FE65WW. Two approaches were used. First, the mass spectrometry analysis
of proteins pulled-down from mammalian cell lysates by GST-FE65WW
fusion protein. Second, the acquisition of data from AxCell Biosciences
Company, which mapped all 70WWdomains found in the human proteome
for protein–protein interaction profiles. Two dozen proteins were identified
as ligands of FE65WW domain by these approaches and selected candidates
are being evaluated in cell culture models for their biological effects
on APP/FE65 complex and its transcriptional function. Understanding of
complexes that nucleate on FE65 and APP could provide rational strategies
for controlling APP processing and A peptide production in Alzheimer’s
brain
The oligomeric complexes involving FE65 and APP control cell cycle progression through the transcriptional regulation of thymidilate synthase gene
No full textThe functions of the oligomeric complexes that include the Alzheimer’s
beta-amyloid precursor protein (APP) and the adaptor protein Fe65 are still
unknown. We demonstrated that Fe65 is present both in the cytoplasm and
in the nucleus and that APP functions as an extranuclear anchor, which prevents
Fe65 nuclear translocation. This suggests the hypothesis that, similar
to what was observed for Notch, the presenilin-mediated cleavage of APP
could result in the translocation of Fe65 to the nucleus and, in turn, in the
regulation of transcription or of other nuclear functions. According to this
hypothesis, we and others demonstrated that Fe65 could play a role in the
regulation of transcription. We are addressing this hypothesis, and several
lines of evidence support it. First, we have demonstrated that the overexpression
of Fe65 affects cell cycle progression by inhibiting the expression of the
thymidylate synthase (TS), a key enzyme of the S phase of cell cycle. This
inhibition is observed only when overexpressed Fe65 accumulates in the nucleus
and several results suggest that it is the consequence of a Fe65-mediated
regulation of the TS gene. Second, Fe65 has three protein–protein interaction
domains, a PTB domain interacting with APP, a second PTB domain,
which binds to two nuclear proteins, the transcription factor LSF or to the
histone acetylase Tip60.We have now identified numerous possible ligands
of the third domain of Fe65, theWWdomain, and many of these molecules
are nuclear proteins. Third, when the WW domain is fused to a DNA binding
domain of a transcription factor, the fusion protein is able to regulate
the transcription of a reporter gene. The involvement of Fe65–APP complex
in the regulation of gene expression could have a significant impact
on understanding of the molecular basis of Alzheimer’s disease: in fact, the
increased beta–gamma-processing of APP could be accompanied by an increased
Fe65 nuclear translocation and, in turn, by an alteration of nuclear
functions
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