Cited by 2,025Autophagy in Disease and TherapyPI3K/AKT/mTOR signaling in cancerCalcium signaling and nucleotide metabolism

ULK-Atg13-FIP200 Complexes Mediate mTOR Signaling to the Autophagy Machinery

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Jung, Chang Hwa, Jun, Chang Bong, Ro, Seung-Hyun, Kim, Young-Mi, Otto, Neil Michael, Cao, Jing, Kundu, Mondira, Kim, Do-Hyung·2009·Molecular Biology of the Cell

Abstract

Autophagy, the starvation-induced degradation of bulky cytosolic components, is up-regulated in mammalian cells when nutrient supplies are limited. Although mammalian target of rapamycin (mTOR) is known as the key regulator of autophagy induction, the mechanism by which mTOR regulates autophagy has remained elusive. Here, we identify that mTOR phosphorylates a mammalian homologue of Atg13 and the mammalian Atg1 homologues ULK1 and ULK2. The mammalian Atg13 binds both ULK1 and ULK2 and mediates the interaction of the ULK proteins with FIP200. The binding of Atg13 stabilizes and activates ULK and facilitates the phosphorylation of FIP200 by ULK, whereas knockdown of Atg13 inhibits autophagosome formation. Inhibition of mTOR by rapamycin or leucine deprivation, the conditions that induce autophagy, leads to dephosphorylation of ULK1, ULK2, and Atg13 and activates ULK to phosphorylate FIP200. These findings demonstrate that the ULK-Atg13-FIP200 complexes are direct targets of mTOR and important regulators of autophagy in response to mTOR signaling.

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  • Initiation of autophagosome formation begins with dissociation of MTOR from the phagophore assembly site, cued by nutrient starvation or treatment with rapamycin or its derivatives.

    “The initiation step begins with the dissociation of MTOR (mechanistic target of rapamycin kinase) from the PAS, cued by nutrient starvation or treatment with rapamycin or its various derivatives [36,37].”

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Authors
Jung, C. H., Jun, C. B., Ro, S.-H., Kim, Y.-M., Otto, N. M., Cao, J., Kundu, M., & Kim, D.-H.
Affiliations
  • University of Minnesota (US)
  • St. Jude Children's Research Hospital (US)
Venue
Molecular Biology of the Cell
Published
2009-04
Volume
20
Issue
7
Pages
1992-2003
ISSN
  • 1059-1524 (ISSN-L)
  • 1939-4586
OpenAlex
W2113432343
Cited by
2,025
References
43
Citations by year
2026: 64 · 2025: 65 · 2024: 108 · 2023: 132 · 2022: 111 · 2021: 146 · 2020: 154 · 2019: 118 · 2018: 116 · 2017: 149 · 2016: 146 · 2015: 126 · 2014: 132 · 2013: 117 · 2012: 122
FWCI
76.67
Type
journal article
Language
en
Open access
Locations
  • Molecular Biology of the Cell (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Lincoln (University of Nebraska) (submittedVersion)
Funders
  • American Diabetes Association
  • American Heart Association
  • Tuberous Sclerosis Alliance
  • National Institutes of Health (DK072004)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK072004, P30 DK 50456, P30DK050456, DK072004, R56DK072004)
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
Keywords
autophagy, mTOR signaling, ULK1, ULK2, ATG13, FIP200, autophagosome formation, protein phosphorylation, leucine deprivation, rapamycin, nutrient deprivation
MeSH terms
Autophagy-Related Proteins, Autophagy-Related Protein-1 Homolog, Animals, Autophagy, Cell Line, Humans, Phagosomes, Phosphorylation, Protein Binding, Protein Kinases, Protein-Tyrosine Kinases, Signal Transduction, Protein Serine-Threonine Kinases, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Mice, TOR Serine-Threonine Kinases

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