Phosphorylation of presenilin 1 at the caspase recognition site regulates its proteolytic processing and the progression of apoptosis

J Biol Chem. 2004 Jan 16;279(3):1585-93. doi: 10.1074/jbc.M306653200. Epub 2003 Oct 22.


The Alzheimer's disease-associated presenilin (PS) 1 is intimately involved in gamma-secretase cleavage of beta-amyloid precursor protein and other proteins. In addition, PS1 plays a role in beta-catenin signaling and in the regulation of apoptosis. Here we demonstrate that phosphorylation of PS1 is regulated by two independent signaling pathways involving protein kinase (PK) A and PKC and that both kinases can directly phosphorylate the large hydrophilic domain of PS1 in vitro and in cultured cells. A phosphorylation site at serine residue 346 was identified that is selectively phosphorylated by PKC but not by PKA. This site is localized within a recognition motif for caspases, and phosphorylation strongly inhibits proteolytic processing of PS1 by caspase activity during apoptosis. Moreover, PS1 phosphorylation reduces the progression of apoptosis. Our data indicate that phosphorylation/dephosphorylation at the caspase recognition site provides a mechanism to reversibly regulate properties of PS1 in apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis*
  • COS Cells
  • Caspases / physiology*
  • Cell Line
  • Cyclic AMP-Dependent Protein Kinases / physiology
  • Glycogen Synthase Kinase 3 / physiology
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Membrane Proteins / chemistry
  • Membrane Proteins / metabolism*
  • Molecular Sequence Data
  • Phosphorylation
  • Presenilin-1
  • Protein Kinase C / physiology
  • Serine / metabolism


  • Membrane Proteins
  • PSEN1 protein, human
  • Presenilin-1
  • Serine
  • Glycogen Synthase Kinase 3 beta
  • Cyclic AMP-Dependent Protein Kinases
  • Protein Kinase C
  • Glycogen Synthase Kinase 3
  • Caspases