title: Evidence for a role of the nerve growth factor receptor TrkA in tyrosine phosphorylation and processing of beta-APP.
abstract: The cytoplasmic tail of the beta-amyloid precursor protein (APP) contains a Y(682)ENPTY(687) sequence through which APP associates with phosphotyrosine binding (PTB) domain containing proteins in a tyrosine phosphorylation-independent manner. We have recently found that tyrosine phosphorylation of APP-Y(682) promotes docking of Shc proteins that modulate growth factor signaling to the ERK and PI3K/Akt pathways. We have also shown that APP is phosphorylated on Y(682) in cells that overexpress a constitutively active form of the tyrosine kinase abl. Here we present evidence that the nerve growth factor receptor TrkA may also promote phosphorylation of APP. Overexpression of TrkA, but not of mutated, kinase inactive TrkA resulted in tyrosine phosphorylation of APP. Site-directed mutagenesis studies showed that TrkA overexpression was associated with phosphorylation of APP-Y(682). Moreover, overexpression of TrkA also affected APP processing reducing the generation of the APP intracellular domain (AID). Thus, tyrosine phosphorylation of APP may functionally link APP processing and neurotrophic signaling to intracellular pathways associated with cellular differentiation and survival.
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Ullmann 1209, Bronx, NY 10461, USA.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Tarr
authors.forename: Cristina
authors.initials: C
authors.lastname: Contursi
authors.forename: Roberta
authors.initials: R
authors.lastname: Roncarati
authors.forename: Cristiana
authors.initials: C
authors.lastname: Noviello
authors.forename: Enrico
authors.initials: E
authors.lastname: Ghersi
authors.forename: Meir H
authors.initials: MH
authors.lastname: Scheinfeld
authors.forename: Nicola
authors.initials: N
authors.lastname: Zambrano
authors.forename: Tommaso
authors.initials: T
authors.lastname: Russo
authors.forename: Luciano
authors.initials: L
authors.lastname: D'Adamio
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D020917:Receptor, trkA / Q000737:chemistry / Q000502:physiology*
chemical_list: D016564:Amyloid beta-Protein Precursor; D020917:Receptor, trkA