Proteolytic processing of the Alzheimer disease-associated presenilin-1 generates an in vivo substrate for protein kinase C
10.1073/pnas.94.10.5349
Crossref journal-article
Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences (341)
Abstract

The majority of familial Alzheimer disease mutations are linked to the recently cloned presenilin (PS) genes, which encode two highly homologous proteins (PS-1 and PS-2). It was shown that the full-length PS-2 protein is phosphorylated constitutively within its N-terminal domain by casein kinases, whereas the PS-1 protein is not. Full-length PS proteins undergo endoproteolytic cleavage within their hydrophilic loop domain resulting in the formation of ≈20-kDa C-terminal fragments (CTF) and ≈30-kDa N-terminal fragments [Thinakaran, G., et al. (1996) Neuron 17, 181–190]. Here we describe the surprising finding that the CTF of PS-1 is phosphorylated by protein kinase C (PKC). Stimulation of PKC causes a 4- to 5-fold increase of the phosphorylation of the ≈20-kDa CTF of PS-1 resulting in reduced mobility in SDS gels. PKC-stimulated phosphorylation occurs predominantly on serine residues and can be induced either by direct stimulation of PKC with phorbol-12,13-dibutyrate or by activation of the m1 acetylcholine receptor-signaling pathway with the muscarinic agonist carbachol. However, phosphorylation of full-length PS-1 and PS-2 is not altered upon PKC stimulation. In addition, a mutant form of PS-1 lacking exon 10, which does not undergo endoproteolytic cleavage [Thinakaran, G., et al. (1996) Neuron 17, 181–190] is not phosphorylated by PKC, although it still contains all PKC phosphorylation sites conserved between different species. These results show that PKC phosphorylates the PS-1 CTF. Therefore, endoproteolytic cleavage of full-length PS-1 results in the generation of an in vivo substrate for PKC. The selective phosphorylation of the PS-1 CTF indicates that the physiological and/or pathological properties of the CTF are regulated by PKC activity.

Bibliography

Walter, J., Grünberg, J., Capell, A., Pesold, B., Schindzielorz, A., Citron, M., Mendla, K., George-Hyslop, P. S., Multhaup, G., Selkoe, D. J., & Haass, C. (1997). Proteolytic processing of the Alzheimer disease-associated presenilin-1 generates an in vivo substrate for protein kinase C. Proceedings of the National Academy of Sciences, 94(10), 5349–5354.

Authors 11
  1. Jochen Walter (first)
  2. Jürgen Grünberg (additional)
  3. Anja Capell (additional)
  4. Brigitte Pesold (additional)
  5. Alice Schindzielorz (additional)
  6. Martin Citron (additional)
  7. Klaus Mendla (additional)
  8. Peter St George-Hyslop (additional)
  9. Gerd Multhaup (additional)
  10. Dennis J. Selkoe (additional)
  11. Christian Haass (additional)
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Dates
Type When
Created 23 years ago (July 26, 2002, 10:35 a.m.)
Deposited 3 years, 4 months ago (April 13, 2022, 2:47 p.m.)
Indexed 4 months, 1 week ago (April 16, 2025, 3:27 a.m.)
Issued 28 years, 3 months ago (May 13, 1997)
Published 28 years, 3 months ago (May 13, 1997)
Published Online 28 years, 3 months ago (May 13, 1997)
Published Print 28 years, 3 months ago (May 13, 1997)
Funders 0

None

@article{Walter_1997, title={Proteolytic processing of the Alzheimer disease-associated presenilin-1 generates an in vivo substrate for protein kinase C}, volume={94}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.94.10.5349}, DOI={10.1073/pnas.94.10.5349}, number={10}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Walter, Jochen and Grünberg, Jürgen and Capell, Anja and Pesold, Brigitte and Schindzielorz, Alice and Citron, Martin and Mendla, Klaus and George-Hyslop, Peter St and Multhaup, Gerd and Selkoe, Dennis J. and Haass, Christian}, year={1997}, month=may, pages={5349–5354} }