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S655 phosphorylation enhances APP secretory traffic

Abstract

Cellular protein phosphorylation regulates proteolytic processing of the Alzheimer’s Amyloid Precursor Protein (APP). This appears to occur both indirectly and directly via APP phosphorylation at residues within cytoplasmic motifs related to targeting and protein–protein interactions. The sorting signal 653YTSI656 comprises the S655 residue that can be phosphorylated by PKC, particularly in mature APP molecules. The YTSI domain has been associated with APP internalization and Golgi polarized sorting, but no functional significance has been attributed to S655 phosphorylation thus far. Using APP695-GFP S655 phosphomutants we show that S655 phosphorylation is a signal that positively modulates APP secretory traffic. The phosphomimicking and dephosphomimicking S655 mutants exhibited contrasting Golgi dynamics, which correlated with differential Golgi vesicular exit and secretory cleavage to sAPP. The role of S655 phosphorylation in APP trafficking at sorting stations, such as the Golgi, its contribution toward cytoprotective alpha sAPP production, and implications for Alzheimer’s disease are discussed.

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Abbreviations

p/s:

Penicillin/streptomycin

AD:

Alzheimer’s disease

AICD:

APP intracellular domain

APP:

Amyloid precursor protein

CHX:

Cycloheximide

GFP:

Green fluorescence protein

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Acknowledgments

This work was supported by the European Union V and VI Framework Program of the European Union (DIADEM and APOPIS), and by grants from the Fundação para a Ciência e a Tecnologia of the Portuguese Ministry of Sciences and Tecnhology (Projects POCTI/NSE/40682/2001 and POCI/58469/2004 and REEQ/1023/BIO/2005), from the Fundação Calouste Gulbenkian (prémio Estímulo à Investigação, 2003), and from the Centro de Biologia Celular, Universidade de Aveiro. SIV is recipient of a FCT fellowship (SFRH/BPD/19515/2004).

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Correspondence to Odete A. B. da Cruz e Silva.

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Vieira, S.I., Rebelo, S., Domingues, S.C. et al. S655 phosphorylation enhances APP secretory traffic. Mol Cell Biochem 328, 145–154 (2009). https://doi.org/10.1007/s11010-009-0084-7

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Keywords

  • Alzheimer’s disease
  • Amyloid precursor protein
  • Anterograde transport
  • Golgi sorting
  • Alpha-secretase
  • sAPP secretion