Regulation of autophagy by coordinated action of mTORC1 and protein phosphatase 2A Journal Article
| Authors: | Wong, P. M.; Feng, Y.; Wang, J.; Shi, R.; Jiang, X. |
| Article Title: | Regulation of autophagy by coordinated action of mTORC1 and protein phosphatase 2A |
| 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. © 2015 Macmillan Publishers Limited. All rights reserved. |
| Keywords: | signal transduction; protein phosphorylation; unclassified drug; cancer growth; nonhuman; protein function; mass spectrometry; animal cell; mouse; mammalia; cell viability; cell survival; complex formation; cell growth; green fluorescent protein; cell protein; protein; in vitro study; enzyme activity; mammal; cancer cell; western blotting; immunoprecipitation; fibroblast; pancreas adenocarcinoma; fluorescence microscopy; amino acid; crystal structure; autophagy; homeostasis; anchorage independent growth; rapamycin; polyacrylamide gel electrophoresis; enzyme active site; phosphoprotein phosphatase; starvation; inhibition; catabolism; dephosphorylation; phosphoprotein phosphatase 2a; mammalian target of rapamycin complex 1; okadaic acid; cells and cell components; article; ulk1 protein |
| Journal Title: | Nature Communications |
| Volume: | 6 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2015-08-27 |
| Start Page: | 8048 |
| Language: | English |
| DOI: | 10.1038/ncomms9048 |
| PROVIDER: | scopus |
| PMCID: | PMC4552084 |
| PUBMED: | 26310906 |
| DOI/URL: | |
| Notes: | Export Date: 2 October 2015 -- Source: Scopus |
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