Role of 14-3-3γ in FE65-dependent Gene Transactivation Mediated by the Amyloid β-Protein Precursor Cytoplasmic Fragment

Akio Sumioka,Shinsuke Nagaishi,Tomohiro Yoshida,Anning Lin,Masayuki Miura,Toshiharu Suzuki

doi:10.1074/jbc.m504278200

Akio Sumioka, Shinsuke Nagaishi + Show 4 more

Open Access

https://doi.org/10.1074/jbc.m504278200

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Abstract

The amyloid beta-protein precursor intracellular domain fragment (AICD) is generated from amyloid beta-protein precursor by consecutive cleavages. AICD is thought to activate FE65-dependent gene expression, but the molecular mechanism remains under consideration. We found that dimeric 14-3-3gamma bound both AICD and FE65 simultaneously, and this binding facilitated FE65-dependent gene transactivation by enhancing the association of AICD with FE65. 14-3-3gamma bound to the 667VTPEER672 motif of AICD and, most interestingly, the phosphorylation of AICD at Thr-668 in this motif inhibited the interaction with 14-3-3gamma and blocked gene transactivation. 14-3-3gamma required a sequence between the WW domain and the first phosphotyrosine interaction domain of FE65 for association with FE65. Deletion of this region blocked 14-3-3gamma binding to FE65 and suppressed AICD-mediated FE65-dependent gene transactivation, although the deletion mutant FE65 was still able to bind Tip60, a histone acetyltransferase that forms a complex with FE65 in the nucleus. Taken together, these data demonstrate that 14-3-3gamma facilitates FE65-dependent gene transactivation by forming a complex containing AICD and FE65, and phosphorylation of AICD down-regulates FE65-dependent gene transactivation through the dissociation of 14-3-3gamma and/or FE65 from AICD. Our findings suggest that multiple interactions of AICD with FE65 and 14-3-3gamma modulate FE65-dependent gene transactivation.

Highlights

Cated at the ␣ and ␤ sites, respectively) is secreted, and following the second cleavage, p3 or ␤-amyloid peptides are secreted, together with release of the cytoplasmic fragment into the cytoplasm
We found that association of the 14-3-3␥ dimer with both nonphosphorylated amyloid ␤-protein precursor intracellular domain fragment (AICD) and FE65 facilitates gene expression, whereas the phosphorylation of AICD interferes with 14-3-3␥ binding and down-regulates FE65-dependent gene transactivation
Association of 14-3-3␥ with Nonphosphorylated APP and AICD—Comprehensive screening of a human brain cDNA library with the yeast twohybrid system using the cytoplasmic domain of APP as bait resulted in isolation of cDNA clones encoding a part of the 14-3-3␥ protein

Summary

Introduction

Cated at the ␣ and ␤ sites, respectively) is secreted, and following the second cleavage, p3 or ␤-amyloid peptides are secreted, together with release of the cytoplasmic fragment into the cytoplasm. We found that the 667VTPEER672 motif regulates AICD function in FE65-dependent gene transactivation through the phosphorylation of Thr-668 and interactions with the 14-3-3␥ protein.

Results

Conclusion