The Alzheimer Amyloid Precursor Protein (APP) and Fe65, an APP-Binding Protein, Regulate Cell Movement

Sabo, Shasta L.; Ikin, Annat; Buxbaum, Joseph D.; Greengard, Paul

doi:10.1083/jcb.153.7.1403

Cited by 204 publications

(200 citation statements)

References 53 publications

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“…APP-Fe65 complexes are present in neuronal growth cones (6) and regulate cell motility (7). Considering that Fe65 WW domain interacts with Mena (8) and APP also with mDab1 (9), these findings support the hypothesis that the APP-Fe65 complex is involved in actin-based membrane remodeling, neurite growth and/or synaptic plasticity.…”

supporting

confidence: 74%

Fe65 is required for Tip60-directed histone H4 acetylation at DNA strand breaks

Stante

Minopoli

Passaro

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Fe65 is a binding partner of the Alzheimer's ␤-amyloid precursor protein APP. The possible involvement of this protein in the cellular response to DNA damage was suggested by the observation that Fe65 null mice are more sensitive to genotoxic stress than WT counterpart. Fe65 associated with chromatin under basal conditions and its involvement in DNA damage repair requires this association. A known partner of Fe65 is the histone acetyltransferase Tip60. Considering the crucial role of Tip60 in DNA repair, we explored the hypothesis that the phenotype of Fe65 null cells depended on its interaction with Tip60. We demonstrated that Fe65 knockdown impaired recruitment of Tip60-TRRAP complex to DNA double strand breaks and decreased histone H4 acetylation. Accordingly, the efficiency of DNA repair was decreased upon Fe65 suppression. To explore whether APP has a role in this mechanism, we analyzed a Fe65 mutant unable to bind to APP. This mutant failed to rescue the phenotypes of Fe65 null cells; furthermore, APP/APLP2 suppression results in the impairment of recruitment of Tip60-TRRAP complex to DNA double strand breaks, decreased histone H4 acetylation and repair efficiency. On these bases, we propose that Fe65 and its interaction with APP play an important role in the response to DNA damage by assisting the recruitment of Tip60-TRRAP to DNA damage sites.Alzheimer ͉ APP ͉ DNA repair T he ␤-amyloid peptides, main constituents of senile plaques of Alzheimer disease (AD), derive from the proteolytic processing of a type I membrane protein, known as ␤-amyloid precursor protein (APP) (1). APP functions are not completely understood, and this knowledge could contribute, at least in principle, to the understanding of AD. Possible cues to study the functions of APP could emerge from the analysis of proteins interacting with the short APP cytosolic domain. Several reports indicated that this cytodomain interacts, among the others, with the Fe65 protein (2-4). The latter has the characteristics of an adaptor protein, whose distinctive traits are 3 protein-protein interaction domains, 1 WW and 2 PTB (PhosphoTyrosine Binding) domains (4). The PTB domain located in the C-terminal part of the protein (PTB2) interacts with the cytodomain of APP and of the 2 related proteins APLP1 and APLP2. Similarly, Fe65 has also been found associated with APP intracellular domain (AICD) (5), which is generated, together with the ␤-amyloid peptides, upon the cleavage of APP by secretases (1).Experimental evidence from cultured cells suggested 2 possible functions of Fe65, one depending on its presence in the cytosol and another one on its nuclear localization. APP-Fe65 complexes are present in neuronal growth cones (6) and regulate cell motility (7). Considering that Fe65 WW domain interacts with Mena (8) and APP also with mDab1 (9), these findings support the hypothesis that the APP-Fe65 complex is involved in actin-based membrane remodeling, neurite growth and/or synaptic plasticity. The analysis of the phenotypes of APP/APLP1/APLP2 triple KO ...

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supporting

confidence: 74%

Fe65 is required for Tip60-directed histone H4 acetylation at DNA strand breaks

Stante

Minopoli

Passaro

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Mena belongs to a small family of proteins involved in the control of cell movement and morphology and in chemotactic responses (37). It was demonstrated that Fe65 and APP are present in dynamic adhesion complexes present on the surface of the cells and that their overexpression causes the acceleration of cell migration (38). Therefore, it can be speculated that an APP/Fe65/Mena complex is involved in the regulation of cell movement.…”

Section: Fe65 Cytoskeleton Remodeling and Cell Movementmentioning

confidence: 99%

Fe65 matters: New light on an old molecule

et al. 2012

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SummaryThe 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.2012 IUBMB IUBMB Life, 64(12): 936-942, 2012

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“…Networks-The WW domain of Fe65 has been reported to bind to the PL motif of Mena, a cytosolic protein involved in cytoskeletal reconstruction (14,15). But Mena contains not only the PL but also PP motif.…”

Section: Functional Importance Of Group Ii/iii Ww Domains and The Ppmentioning

confidence: 99%

“…The WW domain of Fe65 binds the proline-rich region of Mena, a mammalian homologue of Drosophila melanogaster Ena, which has been identified in a specific screen for dominant mutations that alleviate the Abl phenotype (13,14). Fe65 and ␤-amyloid precursor protein are involved in the reconstruction of actin cytoskeleton, which suggests the concerted action of these proteins with Mena and/or Abl (9,15). The WW domain of FBP30 has been reported to bind the Pro-Arg (PR) motif (10,16).…”

mentioning

confidence: 99%

Common Mechanism of Ligand Recognition by Group II/III WW Domains

Kato

Nagata

Takahashi

et al. 2004

Journal of Biological Chemistry

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WW domain is a well known protein module that mediates protein to protein interactions by binding to proline-containing ligands. Based on the ligand predilections, the WW domains have been classified into four major groups. Group II and III WW domains have been reported to bind the proline-leucine and proline-arginine motifs, respectively. In the present study, using surface plasmon resonance technique we have shown that these WW domains have almost indistinguishable ligand preferences and kinetic properties. Hence, we propose that Group II and III WW domains should be joined together as one group (Group II/III). Unlike Group I and IV WW domains, Group II/III WW domains can bind simple polyprolines as well as the proline-leucine and proline-arginine motifs, and they possess two Xaa-proline (where Xaa is any amino acid) binding grooves similar to SH3 domains. Our work assigns Group II and III WW domains to a larger family of polyproline-binding modules and proteins, which includes SH3 domains and profilin. Because polyprolines belong to the most frequently found peptide motifs in several genomes, our study implies the versatile importance of Group II/III WW domains in signaling.

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The Alzheimer Amyloid Precursor Protein (APP) and Fe65, an APP-Binding Protein, Regulate Cell Movement

Cited by 204 publications

References 53 publications

Fe65 is required for Tip60-directed histone H4 acetylation at DNA strand breaks

Fe65 is required for Tip60-directed histone H4 acetylation at DNA strand breaks

Fe65 matters: New light on an old molecule

Common Mechanism of Ligand Recognition by Group II/III WW Domains

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