Abstract
The physiological functions of the beta-amyloid precursor protein (APP) may include nuclear signaling. To characterize the role of the APP adaptor proteins Fe65, Jip1b, X11alpha (MINT1) and the chromatin-associated protein Tip60, we analyzed their interactions by confocal microscopy and co-immunoprecipitations. AICD corresponding to S3-cleaved APP bound to Fe65 that transported it to nuclei and docked it to Tip60. These proteins formed AICD-Fe65-Tip60 (AFT) complexes that were concentrated in spherical nuclear spots. gamma-Secretase inhibitors prevented AFT-complex formation with AICD derived from full-length APP. The APP adaptor protein Jip1b also transported AICD to nuclei and docked it to Tip60, but AICD-Jip1b-Tip60 (AJT) complexes had different, speckle-like morphology. By contrast, X11alpha trapped AICD in the cytosol. Induced AICD expression identified the APP-effector genes APP, BACE, Tip60, GSK3beta and KAI1, but not the Notch-effector gene Hes1 as transcriptional targets. These data establish a role for APP in nuclear signaling, and they suggest that therapeutic strategies designed to modulate the cleavage of APP affect AICD-dependent signaling.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Acetyltransferases / metabolism
-
Active Transport, Cell Nucleus / physiology*
-
Adaptor Proteins, Signal Transducing / metabolism
-
Amyloid beta-Protein Precursor / metabolism*
-
Antigens, CD / metabolism
-
Basic Helix-Loop-Helix Transcription Factors
-
Cell Nucleus / metabolism*
-
Cells, Cultured
-
Fluorescence Resonance Energy Transfer
-
Histone Acetyltransferases
-
Homeodomain Proteins / metabolism
-
Humans
-
Kangai-1 Protein
-
Lysine Acetyltransferase 5
-
Membrane Glycoproteins / metabolism
-
Multiprotein Complexes / metabolism*
-
Nerve Tissue Proteins / metabolism
-
Nuclear Proteins / metabolism
-
Protein Binding
-
Proto-Oncogene Proteins / metabolism
-
Transcription Factor HES-1
-
Transcription, Genetic / physiology*
Substances
-
APBB1 protein, human
-
Adaptor Proteins, Signal Transducing
-
Amyloid beta-Protein Precursor
-
Antigens, CD
-
Basic Helix-Loop-Helix Transcription Factors
-
CD82 protein, human
-
Homeodomain Proteins
-
Kangai-1 Protein
-
Membrane Glycoproteins
-
Multiprotein Complexes
-
Nerve Tissue Proteins
-
Nuclear Proteins
-
Proto-Oncogene Proteins
-
Transcription Factor HES-1
-
HES1 protein, human
-
Acetyltransferases
-
Histone Acetyltransferases
-
KAT5 protein, human
-
Lysine Acetyltransferase 5