Human Molecular Genetics Advance Access originally published online on January 13, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 5 475-488
DOI: 10.1093/hmg/ddh054
A phosphorylated, carboxy-terminal fragment of ß-amyloid precursor protein localizes to the splicing factor compartment
Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106-4970, USA
Received September 5, 2003; Revised December 15, 2003; Accepted January 2, 2004
ß-Amyloid precursor protein (APP) is implicated in the pathobiology of Alzheimer's disease (AD). To gain insight into its function, we have investigated the proteolytic processing and post-translational modification of APP in relation to its intracellular traffic and localization. The proteolytic processing that generates the amyloid ß-peptide (Aß) also releases into the cytoplasm the carboxy-terminal fragment of APP, C
. Using the catecholaminergic cell line, CAD, and an antibody to a form of APP that is phosphorylated at Thr668 (pAPP; numbering for APP695), we show that a phosphorylated, carboxy-terminal fragment of APP, probably C, is present in the nucleus, where it localizes to subnuclear particles. The labeling with anti-pAPP antibody co-localizes with proteins that define the splicing factor compartment (SFC) [e.g. the small nuclear ribonucleoprotein (snRNP), U2B, and serine/arginine-rich (SR) proteins], but is excluded from the coiled bodies and the gems. This distribution of pAPP epitopes was found in CAD cells independent of their state of differentiation, as well as in primary cortical neurons, epithelial cells and fibroblasts. We further show that exogenously expressed C becomes phosphorylated, and distributes throughout the cell. A fraction of this C is translocated into the nucleus, where it co-localizes with endogenous pAPP epitopes. Finally, we show that the APP binding, scaffolding protein, Fe65 co-localizes with pAPP epitopes and with expressed C at intranuclear speckles. These results suggest that phosphorylated C accumulates at the SFC. Thus, APP may play a role in pre-mRNA splicing, and Fe65 and APP phosphorylation may regulate this function.
* To whom correspondence should be addressed at: Department of Physiology and Biophysics, School of Medicine, E553, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-4970, USA. Tel: +1 2163684766; Fax: +1 2163683952; Email: virgil.muresan{at}case.edu
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