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.
Highlights
Beclin 1, the mammalian ortholog of yeast Atg6, functions as a molecular scaffold that assembles an interactome comprising autophagy stimulators and suppressors that regulate the initia
Protein phosphatase 2A (PP2A)2 is an essential Ser/Thr phosphatase conserved from yeast to human that regulates a myriad of biological processes, including cell proliferation, apoptosis, development, and motility [12]
We discovered that Ser-90 of Beclin 1 is a target of PP2A and that this phosphorylation is physiologically regulated by nutrient status
Summary
Beclin 1, the mammalian ortholog of yeast Atg6, functions as a molecular scaffold that assembles an interactome comprising autophagy stimulators and suppressors that regulate the initia-. The Type2A Protein Phosphatase Inhibitor Enhances Ser-90 Phosphorylation of Beclin 1—MCF7 human breast carcinoma cells were used to stably express FLAG-Beclin 1. Beclin 1 Ser-90 Phosphorylation Promotes Autophagy— MCF7 cells expressing FLAG-Beclin 1 were treated with Earle’s balanced salt solution (EBSS) to examine whether starvation induces Ser-90 phosphorylation in cultured cells.
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