The beta-amyloid precursor protein APP is tyrosine-phosphorylated in cells expressing a constitutively active form of the Abl protoncogene.
The cytosolic domain of the beta-amyloid precursor protein APP interacts with three PTB (phosphotyrosine binding domain)-containing adaptor proteins, Fe65, X11, and mDab1. Through these adaptors, other molecules can be recruited at the cytodomain of APP; one of them is Mena, that binds to the WW domain (a protein module with two conserved tryptophans) of Fe65. The enabled and disabled genes of Drosophila, homologues of the mammalian Mena and mDab1 genes, respectively, are genetic modulators of the phenotype observed in flies null for the Abl tyrosine kinase gene. The involvement of Mena and mDab1 in the APP-centered protein-protein interaction network suggests the possibility that Abl plays a role in APP biology. We show that Fe65, through its WW domain, binds in vitro and in vivo the active form of Abl. Furthermore, in cells expressing the active form of Abl, APP is tyrosine-phosphorylated. Phosphopeptide analysis and site-directed mutagenesis support the hypothesis that Tyr(682) of APP(695) is the target of this phosphorylation. Co-immunoprecipitation experiments demonstrate that active Abl and tyrosine-phosphorylated APP also form a stable complex, which could result from the interaction of the pYENP motif of the APP cytodomain with the SH2 domain of Abl. These results suggest that Abl, Mena, and mDab1 are involved in a common molecular machinery and that APP can play a role in tyrosine kinase-mediated signaling.
Dipartimento di Biochimica e Biotecnologie Mediche, Università di Napoli Federico II, I-80131 Napoli, Italy.
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Zambrano
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Bruni
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Minopoli
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Mosca
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Molino
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Russo
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Schettini
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Sudol
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D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D003600:Cytosol / Q000378:metabolism; D017931:DNA Primers; D004330:Drosophila; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011233:Precipitin Tests; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D017931:DNA Primers; D014443:Tyrosine; D016315:Proto-Oncogene Proteins c-abl