title: Regulation of Beclin 1 Protein Phosphorylation and Autophagy by Protein Phosphatase 2A (PP2A) and Death-associated Protein Kinase 3 (DAPK3).
abstract: Autophagy is an evolutionarily conserved intracellular degradation system that is involved in cell survival and activated in various diseases, including cancer. Beclin 1 is a central scaffold protein that assembles components for promoting or inhibiting autophagy. Association of Beclin 1 with its interacting proteins is regulated by the phosphorylation of Beclin 1 by various Ser/Thr kinases, but the Ser/Thr phosphatases that regulate these phosphorylation events remain unknown. Here we identify Ser-90 in Beclin 1 as a regulatory site whose phosphorylation is markedly enhanced in cells treated with okadaic acid, an inhibitor of protein phosphatase 2A (PP2A). Beclin 1 Ser-90 phosphorylation is induced in skeletal muscle tissues isolated from starved mice. The Beclin 1 S90A mutant blocked starvation-induced autophagy. We found association of PP2A B55α with Beclin 1, which dissociate by starvation. We also found that death-associated protein kinase 3 directly phosphorylates Beclin 1 Ser-90. We propose that physiological regulation of Beclin 1 Ser-90 phosphorylation by PP2A and death-associated protein kinase 3 controls autophagy.
authors.affiliation: From the Laboratories of Veterinary Pharmacology and.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Fujiwara
authors.affiliation: Toxicology, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi 753-8515, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Usui
authors.affiliation: From the Laboratories of Veterinary Pharmacology and t.ohama@yamaguchi-u.ac.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ohama
authors.affiliation: From the Laboratories of Veterinary Pharmacology and.
authors.forename: Koichi
authors.initials: K
authors.lastname: Sato
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D064550:Death-Associated Protein Kinases / Q000378:metabolism; D019319:Okadaic Acid / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors*
chemical_list: D019319:Okadaic Acid; D064550:Death-Associated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2
keywords: Beclin 1 (BECN1); autophagy; phosphatase; protein phosphatase 2 (PP2A); protein serine/threonine phosphatase (PSP)