Regulation of autophagy by coordinated action of mTORC1 and protein phosphatase 2A

Pui-Mun Wong, Yan Feng, Junru Wang, Rong Shi and Xuejun Jiang ()
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Pui-Mun Wong: Cell Biology Program, Memorial Sloan-Kettering Cancer Center
Yan Feng: Cell Biology Program, Memorial Sloan-Kettering Cancer Center
Junru Wang: Cell Biology Program, Memorial Sloan-Kettering Cancer Center
Rong Shi: Cell Biology Program, Memorial Sloan-Kettering Cancer Center
Xuejun Jiang: Cell Biology Program, Memorial Sloan-Kettering Cancer Center

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: Abstract Autophagy is a cellular catabolic process critical for cell viability and homoeostasis. Inhibition of mammalian target of rapamycin (mTOR) complex-1 (mTORC1) activates autophagy. A puzzling observation is that amino acid starvation triggers more rapid autophagy than pharmacological inhibition of mTORC1, although they both block mTORC1 activity with similar kinetics. Here we find that in addition to mTORC1 inactivation, starvation also causes an increase in phosphatase activity towards ULK1, an mTORC1 substrate whose dephosphorylation is required for autophagy induction. We identify the starvation-stimulated phosphatase for ULK1 as the PP2A–B55α complex. Treatment of cells with starvation but not mTORC1 inhibitors triggers dissociation of PP2A from its inhibitor Alpha4. Furthermore, pancreatic ductal adenocarcinoma cells, whose growth depends on high basal autophagy, possess stronger basal phosphatase activity towards ULK1 and require ULK1 for sustained anchorage-independent growth. Taken together, concurrent mTORC1 inactivation and PP2A–B55α stimulation fuel ULK1-dependent autophagy.

Date: 2015
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DOI: 10.1038/ncomms9048

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