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