title: The c-Abl tyrosine kinase phosphorylates the Fe65 adaptor protein to stimulate Fe65/amyloid precursor protein nuclear signaling.
abstract: The amyloid precursor protein (APP) is proteolytically processed to release a C-terminal domain that signals to the nucleus to regulate transcription of responsive genes. The APP C terminus binds to a number of phosphotyrosine binding (PTB) domain proteins and one of these, Fe65, stimulates APP nuclear signaling. Fe65 is an adaptor protein that contains a number of protein-protein interaction domains. These include two PTB domains, the second of which binds APP, and a WW domain that binds proline-rich ligands. One ligand for the Fe65WW domain is the tyrosine kinase c-Abl. Here, we show that active c-Abl stimulates APP/Fe65-mediated gene transcription and that this effect is mediated by phosphorylation of Fe65 on tyrosine 547 within its second PTB domain. The homologous tyrosine within the motif Tyr-(Leu/Met)-Gly is conserved in a variety of PTB domains, and this suggests that PTB tyrosine phosphorylation occurs in other proteins. As such, PTB domain phosphorylation may represent a novel mechanism for regulating the function of this class of protein.
authors.affiliation: Department of Neuroscience, The Institute of Psychiatry, King's College London, London, United Kingdom.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Perkinton
authors.forename: Claire L
authors.initials: CL
authors.lastname: Standen
authors.forename: Kwok-Fai
authors.initials: KF
authors.lastname: Lau
authors.forename: Sashi
authors.initials: S
authors.lastname: Kesavapany
authors.forename: Helen L
authors.initials: HL
authors.lastname: Byers
authors.forename: Malcolm
authors.initials: M
authors.lastname: Ward
authors.forename: Declan M
authors.initials: DM
authors.lastname: McLoughlin
authors.forename: Christopher C J
authors.initials: CC
authors.lastname: Miller
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D016466:CHO Cells; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism*; D006224:Cricetinae; D004591:Electrophoresis, Polyacrylamide Gel; D019084:Fluorescent Antibody Technique, Indirect; D017930:Genes, Reporter; D005982:Glutathione Transferase / Q000378:metabolism; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D013058:Mass Spectrometry; D016297:Mutagenesis, Site-Directed; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011392:Proline / Q000737:chemistry; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016315:Proto-Oncogene Proteins c-abl / Q000502:physiology*; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection; D014443:Tyrosine / Q000737:chemistry
chemical_list: D008024:Ligands; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D014443:Tyrosine; D011392:Proline; D008156:Luciferases; D005982:Glutathione Transferase; D016315:Proto-Oncogene Proteins c-abl