The c-Abl tyrosine kinase phosphorylates the Fe65 adaptor protein to stimulate Fe65/amyloid precursor protein nuclear signaling.
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.
Perkinton
Michael S
MS
Department of Neuroscience, The Institute of Psychiatry, King's College London, London, United Kingdom.
Standen
Claire L
CL
Lau
Kwok-Fai
KF
Kesavapany
Sashi
S
Byers
Helen L
HL
Ward
Malcolm
M
McLoughlin
Declan M
DM
Miller
Christopher C J
CC
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
D008024:Ligands; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D014443:Tyrosine; D011392:Proline; D008156:Luciferases; D005982:Glutathione Transferase; D016315:Proto-Oncogene Proteins c-abl