The beta-amyloid precursor protein APP is tyrosine-phosphorylated in cellsexpressing a constitutively active form of the Abl protoncogene

The cytosolic domain of the beta -amyloid precursor protein APP interacts w ith three PTB (phosphotyrosine binding domain) containing adaptor proteins, Fe65, X11, and mDab1, Through these adaptors, other molecules can be recru ited at the cytodomain of APP; one of them is Mena, that binds to the WW do main (a protein module with two conserved tryptophans) of Fe65, The enabled and disabled genes of Drosophila, homologues of the mammalian Mena and mDa b1 genes, respectively, are genetic modulators of the phenotype observed in flies null for the Abl tyrosine kinase gene. The involve ment 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, throug h its WW domain, binds in vitro and in vivo the active form of Abl, Further more, in cells expressing the active form of Abl, APP is tyrosine-phosphory lated, Phosphopeptide analysis and site-directed mutagenesis support the hy pothesis that Tyr(682) Of APP(695) is the target of this phosphorylation. C o-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 mDabl are involved in a com mon molecular machinery and that APP can play a role in tyrosine kinase-med iated signaling.