The Intracellular Domain of the β-Amyloid Precursor Protein Is Stabilized by Fe65 and Translocates to the Nucleus in a Notch-like Manner

W. Taylor Kimberly, Jessica B. Zheng, Suzanne Y. Guénette, Dennis J. Selkoe
2001 Journal of Biological Chemistry  
The ␤-amyloid precursor protein (APP) is a ubiquitous receptor-like molecule without a known function. However, the recent recognition that APP and Notch undergo highly similar proteolytic processing has suggested a potential signaling function for APP. After ligand binding, Notch is cleaved by the ADAM-17 metalloprotease followed by an intramembrane cleavage mediated by ␥-secretase. The ␥-secretase cut releases the Notch intracellular domain (NICD), which enters the nucleus and modulates
more » ... and modulates transcription. Because APP is processed similarly by ADAM-17 and ␥-secretase, we reasoned that the APP intracellular domain (AICD) has a role analogous to the NICD. We therefore generated a plasmid encoding the AICD sequence and studied the subcellular localization of the expressed protein (C60). Our results demonstrate that the cytoplasmic domain of APP is a highly labile fragment that is stabilized by forming complexes with Fe65 and can then enter the nucleus in neurons and non-neural cells. These findings strongly support the hypothesis that APP signals in the nucleus in a manner analogous to the function of Notch.
doi:10.1074/jbc.c100447200 pmid:11544248 fatcat:ykavkxeby5dcxlgusg53kfywci