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J Biol Chem. 2016 May 13;291(20):10858-66. doi: 10.1074/jbc.M115.704908. Epub 2016 Mar 18.

Regulation of Beclin 1 Protein Phosphorylation and Autophagy by Protein Phosphatase 2A (PP2A) and Death-associated Protein Kinase 3 (DAPK3).

Author information

1
From the Laboratories of Veterinary Pharmacology and.
2
Toxicology, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi 753-8515, Japan.
3
From the Laboratories of Veterinary Pharmacology and t.ohama@yamaguchi-u.ac.jp.

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.

KEYWORDS:

Beclin 1 (BECN1); autophagy; phosphatase; protein phosphatase 2 (PP2A); protein serine/threonine phosphatase (PSP)

PMID:
26994142
PMCID:
PMC4865930
DOI:
10.1074/jbc.M115.704908
[Indexed for MEDLINE]
Free PMC Article

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