The PtdIns3-phosphatase MTMR3 interacts with mTORC1 and suppresses its activity

Feike Hao; Takashi Itoh; Eiji Morita; Kanae Shirahama-Noda; Tamotsu Yoshimori; Takeshi Noda

doi:10.1002/1873-3468.12048

The PtdIns3-phosphatase MTMR3 interacts with mTORC1 and suppresses its activity

FEBS Lett. 2016 Jan;590(1):161-73. doi: 10.1002/1873-3468.12048. Epub 2015 Dec 31.

Authors

Feike Hao^{1

2}, Takashi Itoh¹, Eiji Morita³, Kanae Shirahama-Noda¹, Tamotsu Yoshimori^{2

4}, Takeshi Noda^{1

4}

Affiliations

¹ Center for Frontier Oral Science, Graduate School of Dentistry, Osaka University, Japan.
² Department of Genetics, Graduate School of Medicine, Osaka University, Japan.
³ Department of Biochemistry and Molecular Biology, Faculty of Agriculture and Life Science, Hirosaki University, Japan.
⁴ Graduate School of Frontier Biosciences, Osaka University, Japan.

Abstract

Macroautophagy is a major intracellular degradation system. We previously reported that overexpression of phosphatase-deficient MTMR3, a member of the myotubularin phosphatidylinositol (PI) 3-phosphatase family, leads to induction of autophagy. In this study, we found that MTMR3 interacted with mTORC1, an evolutionarily conserved serine/threonine kinase complex, which regulates cell growth and autophagy in response to environmental stimuli. Furthermore, overexpression of MTMR3 inhibited mTORC1 activity. The N-terminal half of MTMR3, including the PH-G and phosphatase domains, was necessary and sufficient for these effects. Phosphatase-deficient MTMR3 provided more robust suppression of mTORC1 activity than wild-type MTMR3. Furthermore, phosphatase-deficient full length MTMR3 and the phosphatase domain alone were localized to the Golgi. These results suggest a new regulatory mechanism of mTORC1 in association with PI3P.

Keywords: MTMR3; PI3P; Ptdlns3P phosphatase; autophagy; mTOR; mTOR complex1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / antagonists & inhibitors*
Adaptor Proteins, Signal Transducing / chemistry
Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism
Amino Acid Substitution
Animals
Autophagy / drug effects
Catalytic Domain
Cells, Cultured
Embryo, Mammalian / cytology
Enzyme Activation / drug effects
Gene Deletion
HEK293 Cells
Humans
Mechanistic Target of Rapamycin Complex 1
Mice
Multiprotein Complexes / antagonists & inhibitors*
Multiprotein Complexes / chemistry
Multiprotein Complexes / genetics
Multiprotein Complexes / metabolism
Mutation
Peptide Fragments / chemistry
Peptide Fragments / genetics
Peptide Fragments / metabolism
Protein Interaction Domains and Motifs
Protein Kinase Inhibitors / pharmacology
Protein Transport / drug effects
Protein Tyrosine Phosphatases, Non-Receptor / antagonists & inhibitors
Protein Tyrosine Phosphatases, Non-Receptor / chemistry
Protein Tyrosine Phosphatases, Non-Receptor / genetics
Protein Tyrosine Phosphatases, Non-Receptor / metabolism*
RNA Interference
Recombinant Fusion Proteins / chemistry
Recombinant Fusion Proteins / metabolism
Regulatory-Associated Protein of mTOR
TOR Serine-Threonine Kinases / antagonists & inhibitors*
TOR Serine-Threonine Kinases / chemistry
TOR Serine-Threonine Kinases / genetics
TOR Serine-Threonine Kinases / metabolism
mTOR Associated Protein, LST8 Homolog

Substances

Adaptor Proteins, Signal Transducing
MLST8 protein, human
Multiprotein Complexes
Peptide Fragments
Protein Kinase Inhibitors
RPTOR protein, human
Recombinant Fusion Proteins
Regulatory-Associated Protein of mTOR
mTOR Associated Protein, LST8 Homolog
MTOR protein, human
Mechanistic Target of Rapamycin Complex 1
TOR Serine-Threonine Kinases
MTMR3 protein, human
Protein Tyrosine Phosphatases, Non-Receptor