Phosphorylation of presenilin 1 at the caspase recognition site regulates its proteolytic processing and the progression of apoptosis.
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.
Fluhrer
Regina
R
Department of Neurology, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany.
Friedlein
Arno
A
Haass
Christian
C
Walter
Jochen
J
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D019556:COS Cells; D020169:Caspases / Q000502:physiology*; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D010766:Phosphorylation; D053764:Presenilin-1; D011493:Protein Kinase C / Q000502:physiology; D012694:Serine / Q000378:metabolism
D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D012694:Serine; D000071679:Glycogen Synthase Kinase 3 beta; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D038362:Glycogen Synthase Kinase 3; D020169:Caspases