title: Proteolytic processing of the Alzheimer disease-associated presenilin-1 generates an in vivo substrate for protein kinase C.
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 approximately 20-kDa C-terminal fragments (CTF) and approximately 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 approximately 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.
authors.affiliation: Central Institute of Mental Health, Department of Molecular Biology, J5, 68159 Mannheim, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Walter
authors.forename: J
authors.initials: J
authors.lastname: Grünberg
authors.forename: A
authors.initials: A
authors.lastname: Capell
authors.forename: B
authors.initials: B
authors.lastname: Pesold
authors.forename: A
authors.initials: A
authors.lastname: Schindzielorz
authors.forename: M
authors.initials: M
authors.lastname: Citron
authors.forename: K
authors.initials: K
authors.lastname: Mendla
authors.forename: P S
authors.initials: PS
authors.lastname: George-Hyslop
authors.forename: G
authors.initials: G
authors.lastname: Multhaup
authors.forename: D J
authors.initials: DJ
authors.lastname: Selkoe
authors.forename: C
authors.initials: C
authors.lastname: Haass
mesh_terms: D000469:Alkaline Phosphatase; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D001483:Base Sequence; D002460:Cell Line; D017124:Conserved Sequence; D017931:DNA Primers; D006801:Humans; D007668:Kidney; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D053764:Presenilin-1; D011493:Protein Kinase C / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity; D014162:Transfection
chemical_list: D017931:DNA Primers; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D011994:Recombinant Proteins; D011493:Protein Kinase C; D000469:Alkaline Phosphatase