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Mol Cell. 2015 Jun 18;58(6):989-1000. doi: 10.1016/j.molcel.2015.05.010. Epub 2015 Jun 4.

Skp2-Mediated RagA Ubiquitination Elicits a Negative Feedback to Prevent Amino-Acid-Dependent mTORC1 Hyperactivation by Recruiting GATOR1.

Author information

1
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
2
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA.
3
Department of Biotechnology, Asia University, Taichung 41354, Taiwan.
4
College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan; Department of Medical Genetics, Pediatrics and Medical Research, China Medical University Hospital, Taichung 40402, Taiwan.
5
Department of Biotechnology, Asia University, Taichung 41354, Taiwan; Center of Molecular Medicine, China Medical University Hospital, Taichung 40402, Taiwan.
6
Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 10031, Taiwan.
7
Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 10031, Taiwan; Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, Taipei 10031, Taiwan.
8
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 10031, Taiwan; School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 10031, Taiwan; Department of Laboratory Medicine, Taipei Medical University Hospital, Taipei 10031, Taiwan; Comprehensive Cancer Center of Taipei Medical University, Taipei 10031, Taiwan.
9
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA; Graduate Institute of Basic Medical Science, China Medical University, Taichung 40402, Taiwan; Department of Biotechnology, Asia University, Taichung 41354, Taiwan. Electronic address: hklin@mdanderson.org.

Abstract

The regulation of RagA(GTP) is important for amino-acid-induced mTORC1 activation. Although GATOR1 complex has been identified as a negative regulator for mTORC1 by hydrolyzing RagA(GTP), how GATOR1 is recruited to RagA to attenuate mTORC1 signaling remains unclear. Moreover, how mTORC1 signaling is terminated upon amino acid stimulation is also unknown. We show that the recruitment of GATOR1 to RagA is induced by amino acids in an mTORC1-dependent manner. Skp2 E3 ligase drives K63-linked ubiquitination of RagA, which facilitates GATOR1 recruitment and RagA(GTP) hydrolysis, thereby providing a negative feedback loop to attenuate mTORC1 lysosomal recruitment and prevent mTORC1 hyperactivation. We further demonstrate that Skp2 promotes autophagy but inhibits cell size and cilia growth through RagA ubiquitination and mTORC1 inhibition. We thereby propose a negative feedback whereby Skp2-mediated RagA ubiquitination recruits GATOR1 to restrict mTORC1 signaling upon sustained amino acid stimulation, which serves a critical mechanism to maintain proper cellular functions.

PMID:
26051179
PMCID:
PMC4476372
DOI:
10.1016/j.molcel.2015.05.010
[Indexed for MEDLINE]
Free PMC Article

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